Next Article in Journal
Nutritional Metabolites as Biomarkers of Previous Feed Intake in European Rabbit (Oryctolagus cuniculus): Applications on Conservation
Previous Article in Journal
Effects of Feed Composition in Different Growth Stages on Rumen Fermentation and Microbial Diversity of Hanwoo Steers
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Animals
Volume 12
Issue 19
10.3390/ani12192607
animals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Antibacterial Drug Residues in Small Ruminant Edible Tissues and Milk: A Literature Review of Commonly Used Medications in Small Ruminants

by
Emily D. Richards
1,
Krysta L. Martin
1,
Catherine E. Donnell
2,
Maaike O. Clapham
1 and
Lisa A. Tell
1,*
1
Food Animal Residue Avoidance and Depletion Program and Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, USA
2
School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, NC 27514, USA
*
Author to whom correspondence should be addressed.
Animals 2022, 12(19), 2607; https://doi.org/10.3390/ani12192607
Submission received: 8 August 2022 / Revised: 9 September 2022 / Accepted: 16 September 2022 / Published: 28 September 2022
(This article belongs to the Special Issue Pharmacokinetics and Risk Management of Drug Residues in Livestock)
Browse Figure
Review Reports Versions Notes

Abstract

:

Simple Summary

This review is a summary of published studies that contain drug residue depletion data for edible tissues and milk following treatment of sheep and goats. The information is separated by antibiotic class for ease of comparison between studies. This summary is useful for understanding medication residue depletion following extra-label drug use and can be used to help estimate withdrawal intervals in order to help protect the human food chain.

Abstract

This review provides a summary of extracted data from the published literature that contains drug residue depletion data for edible tissues and milk following treatment of sheep and goats. Out of 20,234 records obtained during the initial search, data from 177 records were included in this review. The data is separated by antibiotic class for ease of comparison between studies. Extracted data includes the active ingredient, dosing information, animal health status, analytical method and limits of detection, tolerance and maximum residue limit information, and time frames relative to residue absence or detection. This information is useful for understanding drug residue depletion profiles following extra-label use and for estimating withdrawal intervals, in order to protect the human food chain.

1. Introduction

Drinking water and availability of food for both humans and animals are affected by climate change that lowers rainfall and an increasing world population, especially in semi-arid climates [1]. Small ruminants present a unique opportunity for developing nations, specifically in developing nations that are in semi-arid climates, due to their multi-purpose use (meat, milk and fibers), lower production cost compared to large ruminants, and tolerance to low rainfall and hot climates [1].
According to data from the Food and Agriculture Organization of the United Nations (FAO), the number of sheep and goats worldwide has increased from approximately 1.4 billion head combined (1 billion sheep, ~400 million goats) in 1961 to approximately 2.3 billion head combined (~1.2 billion sheep, ~1.1 billion goats) in 2019 [2]. Between 2014 and 2019, the largest producers of sheep meat worldwide were China, Australia, New Zealand, Turkey and Algeria, whereas during this same time period, the largest producers of goat meat worldwide were China, India, Pakistan, Nigeria and Bangladesh.
In the United States, sheep and goats are considered minor species by the Food and Drug Administration (FDA) [3]; however, sheep are considered major species while goats are considered minor species by the European Medicines Agency (EMA) Committee for Medicinal Products for Veterinary Use [4]. In the United States, there is a “severe shortage of approved new animal drugs for use in minor species” [5].
The Food Animal Residue Avoidance and Depletion Program (FARAD) is a United States Department of Agriculture (USDA)-funded program with a mission to provide veterinary practitioners with scientifically based withdrawal interval recommendations following extra-label drug use or chemical/pesticide contamination in food-producing species. FARAD call submission data for small ruminants indicates a steady increase in the number of withdrawal interval request submissions from 2015 to 2019, with a steep increase in the number of submissions in 2020 (2015 = 435 submissions for sheep, 223 for goats; 2019 = 343 submissions for sheep, 710 for goats; 2020 = 595 submissions for sheep, 1401 for goats). The most commonly requested drug categories include antibiotics, anthelmintics, and non-steroidal anti-inflammatory drugs (NSAIDs). This data reflects the increasing numbers of backyard or hobby-farm environments, where the food-products are consumed by the family keeping the sheep or goats. Given the limited FDA-approved medications for use in sheep or goats, drugs are commonly prescribed in an extra-label manner which is legalized by the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) [6].
Given the importance of sheep and goats as commodity groups worldwide, the purpose of this review is to summarize research studies investigating antibiotic medication use in small ruminants with respect to the potential for drug residues to be present in small ruminant meat and milk products. Due to the large volume of published literature in small ruminants, this review only includes antibacterial medications; however, a second review will be completed incorporating anthelmintics and other medication classes not included here. It is important to note that residue depletion times referenced in the text are based on data from scientific studies. Normal industry practice to withdraw feed 8 to 12 h prior to processing the animals in order to minimize fecal contamination [7] may not have occurred in scientific research studies examining a zero day withdrawal. In addition, the residue depletion times listed in this manuscript are dependent on the sensitivity of the analytical method utilized in the study. Summaries of drug residue studies, drug approvals, tolerances (in the United States), and maximum residue limits (MRLs; in the European Union) have been provided in the tables for the reader’s convenience. If available, FDA-approved medications for use in sheep and goats should be utilized according to directions and labeled withdrawal times adhered to in order to guarantee human food safety.

2. Materials and Methods

2.1. Search Strategy

A systematic literature search was conducted using various databases and compared to publications included FARAD Program’s literature database. The aim of the search was to collect milk and edible tissue residue data for antibiotics that had been administered to small ruminants. Published literature between 1926 and 2021 was searched using PubMed, Cab Direct, Scopus, and Web of Science. Search terms and key words included: “sheep”, “goat(s)”, “small ruminants”, “caprine”, “ovine”, “drug absorption”, “clearance”, “drug residue(s)”, “pharmacokinetics”, “metabolic clearance rate”, “intestinal absorption”, “bioavailability”, “biological availability”, “metabolism”.

2.2. Screening Results

For systematic screening, search results were imported into the Covidence online platform (Covidence Systematic Review Software, Veritas Health Innovation, Melbourne, Australia) and duplicate results were removed by the Covidence software. Initially, the 20,234 “Titles and Abstracts” were screened by one reviewer (EDR or CED) for relevancy and categorized as ‘yes’, ‘no’, or ‘maybe’ using predetermined inclusion and exclusion criteria. The category of ‘maybe’ was used for trials that did not explicitly state the inclusion or exclusion criteria in the abstract and thus required further review of the full text. Inclusion criteria were as follows: in vivo sheep or goat drug trial; drug or metabolite concentration data and time point in tissue and/or milk; drug dose, route of administration, and dosing frequency stated. Exclusion criteria were as follows: any animal not a sheep or goat; in vitro study; concentration or residue data for non-drug substances (pesticide, toxin, vitamins) or drugs of abuse; drug plasma or serum concentrations only; dose of drug, route of administration, and dosing frequency missing. After initial screening for exclusion criteria, 1769 ‘yes’ and ‘maybe’ results moved to a ‘Full Text’ screening by one reviewer (EDR, KLM, or CED). These records were further excluded or included based on the above criteria and a reason was assigned. Records were excluded due to: not being a study (e.g., review, short communication, corrigendum; n = 128), not being able to verify text (e.g., full text not available from lenders worldwide, abstract only from proceedings, text unable to be translated; n = 141), being the wrong patient population/study design (e.g., not in live animals, in live animals other than small ruminants, etc.; n = 84), chemical product of study was a non-drug substance (n = 10), matrices under study did not consist of tissues or milk (n = 1076), and lack of specific concentration versus time presented in the paper (n = 60). A total of 270 records met the complete inclusion criteria. Figure 1 displays a flowchart representation of the screening process completed in this literature search.
For comparison, the FARAD database returned 832 records for both sheep and goats; however, 78 records were removed from the review due to incorrect matrices (i.e., plasma or serum data only). Ultimately, only 177 records met the complete inclusion criteria.

3. Data Extraction and Presentation (Antibiotic Drug Classes, Residue Detection, and Analytical Methods)

The published literature presenting tissue and milk residue data for antibiotics used in sheep and goats is presented in the Tables below and is categorized by antibiotic class. Tolerances or maximum residue limits are presented for FDA-approvals and EMA-approvals, respectively. The basic analytical method is described, with a focus on the limit of detection and limit of quantitation, alongside the dosing regimen for each study. Animal health status and additional information are also included, since variations in health- or lactation-status may affect drug residue depletion. Finally, two columns are included to indicate when residues were last detected. The column titled ‘Last sampling time point for which residues WERE detected (post-last treatment)’ refers the last sampling point when residues were detected based on the study sampling protocol. This is in contrast to the column titled ‘Sampling time point when NO residues were detected (post-last treatment)’ which refers to the last sampling point when residues were not detected based on the study sampling protocol. Instances where a greater than symbol (“>”) is utilized refers to situations where residues were still detected at the last sampling time point of the study protocol.
Data for the summarized studies includes analytical methods since it is important to consider how those methods impact the sensitivity of drug residue detection and how the analytical limits of detection compare to tolerances or MRLs. Newer analytical methods can detect drug residues at lower concentrations than historical microbiological bioassays or colorimetric testing, resulting in a greater number of days with detectable drug residues. In contrast, studies using less sensitive methods, having higher limits of detection, may have found shorter periods with detectable drug residues upon withdrawal of the drug. Readers are cautioned to keep the sensitivity of the analytical methods in mind when evaluating the data presented within this review, as well as the fact that most of the studies were completed in healthy animals. It is also important to note that US products approved for use in small ruminants should be used according to the FDA-approved label directions. The FDA-approved label withdrawal time should take precedent above any of the data summarized in this paper.
When considering antibiotic drug classes, it is important to remember that the World Health Organization (WHO) classifies antibiotics into categories based on their place in therapy for some infections in human medicine. These categories include critically important, highly important and important [8]. Some critically important antibiotics are then sub-divided by priority if they are considered sole or limited therapy for some infections in human medicine [8]. Some cephalosporins (third, fourth and fifth generations), quinolones, macrolides are classified as highest priority critically important antibiotics for human health. Aminoglycosides, some cephalosporins (first and second generations) are classified as high priority critically important antibiotics. Amphenicols, some penicillins (antipseudomonal, aminopenicillins with and without beta-lactamase inhibitors, amidinopenicillins, anti-staphylococcal, narrow spectrum), sulfonamides and tetracyclines are classified as highly important antibiotics for human health by the WHO.

3.1. Aminoglycosides

Aminoglycosides (amikacin, apramycin, dihydrostreptomycin, gentamicin, tobramycin, neomycin, streptomycin) are concentration dependent, bactericidal antibiotic agents produced from Streptomyces spp. and Micromonospora spp. Aminoglycosides act by irreversibly binding to the 30s subunit of the bacterial ribosome thereby inhibiting protein synthesis. Their spectrum of activity includes mostly Gram-negative bacteria, with some mycobacteria and staphylococci coverage. Transmission of Enterococcus spp., Enterobacteriaceae (including E. coli), and Mycobacterium spp. can occur from non-human sources and potentially result in human infection. Therefore, the appropriate use of aminoglycosides in food animal species is essential to maintain human safety.
Aminoglycosides are generally not well absorbed from the gastrointestinal tract [9], unless there is damage to the intestinal mucosa. When administered parenterally, aminoglycosides are rapidly and completely absorbed. Elimination of aminoglycosides is primarily renally, which may result in persistent residues in the kidneys. In most published studies in sheep and goats, residues in renal tissue exceeded the duration of the study [10,11,12,13,14,15,16,17]. In humans, aminoglycosides are poorly excreted into breastmilk [18]. This may also be the case for sheep and goats as a few studies have shown short duration of residue detection in milk following IV and IM administration [19,20,21,22,23,24,25,26].
In the United States, the only aminoglycoside FDA-approved for use in small ruminants is neomycin sulfate. However, the EMA has approved streptomycin/dihydrostreptomycin and kanamycin for sheep, while also extending MRLs from other species for gentamicin and neomycin. Table 1 shows the published literature that provides data for edible tissue or milk residues of aminoglycosides following treatment of sheep and goats.

3.2. Amphenicols

Amphenicols (chloramphenicol, florfenicol, thiamphenicol) are broad-spectrum antibiotics. These antibiotics are typically bacteriostatic agents that act by inhibiting microbial protein synthesis by binding to the 50s bacterial ribosomal subunit. Amphenicols are broad-spectrum against many aerobic and anaerobic Gram-positive and Gram-negative bacteria.
Little pharmacokinetic data is available following the use of amphenicols in sheep or goats. The limited data available in goats shows that florfenicol and thiamphenicol residues do enter the milk after intramuscular and intravenous administration, however tissue data was not available [35,36]. In one study, thiamphenicol concentrations were higher in the mammary gland that was frequently stripped compared to the gland that was not [35].
In the United States, there are no amphenicol products FDA-approved for use in sheep or goats. Chloramphenicol is prohibited from use in food producing animals in several countries including the United States, European Union, and Canada [6,37,38] due to the risk of blood dyscrasias, such as aplastic anemia and bone marrow suppression, in humans. Table 2 summarizes the published literature evaluating edible tissue or milk residues of amphenicols following treatment of sheep and goats.

3.3. Penicillin and Penicillin-Derivatives

Penicillins (penicillin G procaine, penicillin G benzathine) and penicillin-derivatives (amoxicillin, ampicillin, cloxacillin, dicloxacillin, nafcillin) are bactericidal antibiotics that act by inhibiting cell wall synthesis. These antibiotics display a broad spectrum of activity against many Gram-positive and Gram-negative bacteria, including anaerobic bacteria.
Amoxicillin and ampicillin show limited milk penetration or accumulation, even when the blood-milk barrier is altered in cases of mastitis [47,48]. However, beta-lactam products labeled for intramammary administration in cattle can result in very high antibiotic concentrations within the small ruminant udder due to the differences in both body and udder size [49,50]. Consequently, intramammary administration of cattle-labeled products to small ruminants can lead to persistent residues present in the milk and require extended withdrawal intervals beyond the labeled withdrawal times for cattle [49,51,52,53,54].In the United States, penicillin G procaine is FDA-approved for use in sheep via intramuscular administration. In the EU, MRLs have been extended from bovine species to all ruminants for nafcillin.
Due to the potential for allergic reactions to penicillin and penicillin-derivatives in humans, caution must be exhibited to ensure food-products from small ruminants do not contain traces of penicillins [55,56]. Table 3 summarizes the published literature evaluating edible tissue or milk residues of beta-lactams or penicillins following treatment of sheep and goats.

3.4. Cephalosporins

Cephalosporins (first-generation: cephapirin, cefacetrile, cephalothin, cephradine, cephalexin; second-generation: cefonicid; third-generation: ceftazidime, ceftiofur, ceftriaxone; fourth-generation: cefquinome, cefepime) are beta-lactam antibiotics divided into five ‘generations’ based on the spectrum of activity (first-generation cephalosporins are active against Gram-positive bacteria but not Gram-negative bacteria, while each consecutive generation has increased activity against Gram-negative bacteria with decreased Gram-positive activity). In the United States, cephalosporins are permitted to be used in an extra-label manner in minor species, such as sheep and goats, unlike major food producing species (cattle, swine, chickens & turkeys).
In general, cephalosporins have low penetration into milk [62,63,64,65,66] with variable pharmacokinetic parameters and slower milk depletion in mastitic animals [67,68]. Cephalexin exhibited a nearly double terminal serum elimination half-life in ewes compared to cattle, in addition to increased concentrations of cephalexin residues [69]. Cephapirin exhibited a longer presence of residues in goat samples compared to cattle when used for mastitis treatment [70].
Ceftiofur sodium (Naxcel®) is currently the only FDA-approved cephalosporin for use in sheep and goats with a 0 day meat and milk withdrawal time. Pharmacokinetic parameters of both intravenous and intramuscular ceftiofur sodium are found to be similar between sheep and goats when administered at the same dose [71]. Table 4 summarizes the published literature evaluating edible tissue or milk residues of cephalosporins following treatment of sheep and goats.

3.5. Fluoroquinolones/Quinolones

Fluoroquinolones (ciprofloxacin, danofloxacin, difloxacin, enrofloxacin, levofloxacin, marbofloxacin, moxifloxacin, norfloxacin, orbifloxacin, pefloxacin, sarafloxacin) are broad-spectrum antibiotics that exhibit concentration-dependent bactericidal activity via inhibition of DNA gyrase in bacterial cells. As a drug class, fluoroquinolones exhibit a high lipid solubility, low protein binding, high bioavailability (especially after parenteral administration) and large volumes of distribution in most species, including small ruminants [81,82,83,84,85,86,87,88,89,90,91,92,93,94,95]. Due to the importance of fluoroquinolones to human health, fluoroquinolones are prohibited from extra-label drug use in food-producing species in the United States.
Studies suggest that the pharmacokinetics of fluoroquinolones change during lactation due to the increased elimination of the drug from serum [88,96]. Additionally, multiple fluoroquinolones extensively penetrate into milk, with some drugs in the class exhibiting up to a 10× higher concentration in milk compared to plasma or serum [88,96,97,98]. This variation can be useful in mastitis cases since these drugs can accumulate in the milk at concentrations above the MIC for a sustained period of time [96,97,99].
In the United States, there are no fluoroquinolones FDA-approved for use in small ruminants, and due to the stipulations outlined by AMDUCA in the CFR, fluoroquinolones are prohibited from extra-label use in food-producing species [6]. In the European Union, flumequine is the only approved fluoroquinolone for use in sheep, while MRLs have been extended from bovine species to all food-producing species for enrofloxacin. Table 5 summarizes the published literature evaluating edible tissue or milk residues of quinolones following treatment of sheep and goats.

3.6. Macrolides

Marcolides (erythromycin, gamithromycin, spiramycin, tilmicosin, tulathromycin and tylosin) are a group of bacteriostatic compounds that bind to the 50S bacterial ribosomal subunit inhibiting bacterial protein synthesis and cell growth [110]. These antibiotics are effective against Mycoplasma spp. and Gram-positive organisms, and less effective against Gram-negative organisms.
Penetration into tissues, milk and blood are shown to be relatively quick with high systemic availability [111]. Macrolides show good penetration and distribution into the udder. In particular, tilmicosin and tulathromycin have been shown to have persistent drug residues in the milk [112,113,114,115,116,117], thus they are not recommended for use in lactating animals. Erythromycin, spiramycin and tylosin also exhibit good udder penetration, but result in shorter withdrawal intervals [29,60,111,118,119,120,121,122]. Some small ruminant macrolide pharmacokinetic parameters (absorption, volume of distribution and elimination) were found to be similar to those reported in cattle [111,112,116,123,124].
In the United States, the only FDA-approved macrolide for use in sheep is tilmicosin; however, this approval specifically excludes lactating sheep. Therefore, no tolerance has been established for milk. In the European Union, multiple macrolides are approved for use in small ruminants: gamithromycin and tilmicosin in sheep, and tulathromycin in both sheep and goats. Additionally, MRLs have been extended from other species for erythromycin, tilmicosin (in goats) and tylosin. Table 6 summarizes the published literature evaluating edible tissue or milk residues of macrolides following treatment of sheep and goats.

3.7. Sulfonamides

Sulfonamides (sulfadiazine, sulfadimethoxine, sulfamethoxazole, sulfachlorpyrazine) are bacteriostatic antibacterial medications that complete with para-aminobenzoic acid disrupting folic acid synthesis. They are active against Gram-positive and Gram-negative bacteria and protozoa.
One study administered sulfonamides in both normal and mastitic ewes. Sulfonamide concentrations were found to be much higher in the mastitic ewe milk, which the authors attributed in part to the increase in milk pH of mastitic milk [131]. Another study found that some sulfonamides are found in the milk in higher concentrations than blood, whereas others (sulfathiazole, sulfadimidine, sulfadiazine and sulfacetamide) are found in the milk in lower concentrations than blood [132].
Due to the potential for allergic reactions to sulfonamides, caution must be exhibited to ensure food-products from small ruminants do not contain traces of sulfonamides [133,134]. In the US, extra-label use of sulfonamides is prohibited in dairy cattle 20 months of age and older, due to allergic potential of affected milk and increased violative residues.
In the United States, there are no sulfonamide products FDA-approved for use in small ruminants, whereas there are some sulfonamide active ingredients with established milk MRLs for small ruminants in the EU. Table 7 summarizes the published literature evaluating edible tissue or milk residues of sulfonamides following treatment of sheep and goats.

3.8. Tetracyclines

Tetracyclines (chlortetracycline, doxycycline oxytetracycline, tetracycline) are broad-spectrum antibiotics that act by inhibiting the 30S bacterial ribosomal subunit thus inhibiting protein synthesis. They are active against Gram-positive and Gram-negative bacteria, as well as some atypical mycobacteria and protozoa [144,145,146].
In oxytetracycline- and chlortetracycline-treated animals, milk production decreased 15% [147]. Infusion of drug into one half of the udder resulted in diffusion of low concentrations into the untreated udder half [147].
Following intramammary infusion of chlortetracycline, residues were detected for a shorter time in goat milk compared to cow milk; however, parenteral chlortetracycline administration results in similar milk residue depletion between goats and cows [122].
In the United States, there are multiple tetracycline approvals for both sheep and goats: chlortetracycline (medicated feed for sheep), oxytetracycline (sheep) and tetracycline (sheep and goats; only topical administration for goats). In the EU, MRLs have been determined for chlortetracycline, oxytetracycline and tetracycline in all food-producing species. Table 8 summarizes the published literature evaluating edible tissue or milk residues of tetracyclines following treatment of sheep and goats.

4. Conclusions

The judicious use of medications and drug residue avoidance is an important topic in animal agriculture and for veterinarians treating animals that provide food for humans. Although there are numerous published studies that describe drug residues in sheep and goat meat and milk, they are scattered throughout the primary literature. In this review, these studies are compiled, and data extracted for easy reference to help facilitate a comprehensive overview of the scientific data, with respect to drug residues in edible tissues and milk from sheep and goats for antibiotics used in small ruminant practice.

Author Contributions

Conceptualization, L.A.T.; methodology, L.A.T.; visualization, M.O.C.; writing—original draft preparation, E.D.R. and L.A.T.; writing—review and editing, K.L.M. and C.E.D.; project administration, L.A.T. All authors have read and agreed to the published version of the manuscript.

Funding

This project was supported by United States Department of Agriculture, National Institute of Food and Agriculture, Food Animal Residue Avoidance and Depletion Program grant numbers 2020-41480-32518 and 2021-41480-35268.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in this review are included in the main manuscript and included tables. Further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

AMDUCAAnimal Medicinal Drug Use Clarification Act of 1994
CFRCode of Federal Regulations
EMAEuropean Medicines Agency
FAOFood and Agriculture Organization of the United Nations
FARADFood Animal Residue Avoidance and Depletion Program
FDAFood and Drug Administration
MICMinimum inhibitory concentration
MRLMaximum residue limit
NSAIDsNon-steroidal anti-inflammatory drugs
USDAUnited States Department of Agriculture
WHOWorld Health Organization

References

  1. Akinmoladun, O.F.; Muchenje, V.; Fon, F.N.; Mpendulo, C.T. Small Ruminants: Farmers’ Hope in a World Threatened by Water Scarcity. Animals 2019, 9, 456. [Google Scholar] [CrossRef] [PubMed]
  2. Food and Agriculture Organization of the United Nations. FAOSTAT. 2022. Available online: https://www.fao.org/faostat/en/#compare (accessed on 22 November 2021).
  3. Food and Drug Administration. Minor Use/Minor Species; Food and Drug Administration: Spring, MD, USA, 2022.
  4. European Medicines Agency. Guideline on Safety and Residue Data Requirements for the Establishment of Maximum Residue Limits in Minor Species; European Medicines Agency: Amsterdam, The Netherlands, 2022. [Google Scholar]
  5. Congress of the United States. Minor Use and Minor Species Animal Health Act of 2004; Congress of the United States: Washington, DC, USA, 2004.
  6. Food and Drug Administration. Title 21, Chapter I, Subchapter E, Part 530: Extralabel Drug Use in Animals; Food and Drug Administration: Silver Spring, MD, USA, 2022.
  7. Northcutt, J.K. Preslaughter factors affecting poultry meat quality. In Poultry Meat Processing; Woodhead Publishing: Cambridge, UK, 2000. [Google Scholar]
  8. World Health Organization. Critically Important Antimicrobials for Human Medicine 6th Revision; World Health Organization: Geneva, Switzerland, 2018. [Google Scholar]
  9. Riviere, J.E.; Craigmill, A.L.; Sundlof, S.F. Aminoglycosides. In Handbook of Comparative Pharmacokinetics and Residues of Veterinary Antimicrobials; CRC Press: Boca Raton, FL, USA, 1991. [Google Scholar]
  10. European Medicines Agency Committee for Veterinary Medicinal Products. Apramycin Summary Report (2); European Medicines Agency Committee for Veterinary Medicinal Products: Amsterdam, The Netherlands, 1999; Volume 526, pp. 1–8. [Google Scholar]
  11. Heitzman, R. Dihydrostreptomycin Streptomycin. Residues Some Vet. Drugs Anim. Foods 1995, 41, 17–29. [Google Scholar]
  12. Brown, S.; Riviere, J.; Coppoc, G.; Hinsman, E.; Carlton, W.; Steckel, R. Single intravenous and multiple intramuscular dose pharmacokinetics and tissue residue profile of gentamicin in sheep. Am. J. Vet. Res. 1985, 46, 69–74. [Google Scholar] [PubMed]
  13. Brown, S.; Coppoc, G.; Riviere, J. Effects of dose and duration of therapy on gentamicin tissue residues in sheep. Am. J. Vet. Res. 1986, 47, 2373–2379. [Google Scholar] [PubMed]
  14. Brown, S.; Baird, A. Evaluation of renal gentamicin depletion kinetic properties in sheep, using serial percutaneous biopsies. Am. J. Vet. Res. 1988, 49, 2056–2059. [Google Scholar]
  15. The Upjohn Company. NADA 011-315 Neomycin 325/Neomix Ag 325 Soluble Powder—Supplemental Approval (Date of Approval: 3 April 1996); FOI—Neomix- NADA 011-315; The Upjohn Company: Hastings, MI, USA, 1996; pp. 1–3. [Google Scholar]
  16. European Medicines Agency Committee for Veterinary Medicinal Products. Neomycin Summary Report (2); EMEA/MRL/730/00-Final; European Medicines Agency Committee for Veterinary Medicinal Products: Amsterdam, The Netherlands, 2000; Volume 730, pp. 1–8. [Google Scholar]
  17. Livingston, R.C. Neomycin. Residues Some Vet. Drugs Anim. Foods 1995, 41, 57–67. [Google Scholar]
  18. National Library of Medicine. Drugs and Lactation Database (LactMed); National Library of Medicine: Bethesda, MD, USA, 2006. [Google Scholar]
  19. El-Sooud, K.A. Pharmacokinetics of amikacin in lactating goats. Zent. Vet. A 1999, 46, 239–246. [Google Scholar] [CrossRef]
  20. Agrawal, A.; Singh, S.; Jayachandran, C. Pharmacokinetics of amikacin in goats after single intramuscular administration. Indian J. Pharmacol. 2001, 33, 374. [Google Scholar]
  21. Haritova, A.; Lashev, L. Pharmacokinetics of amikacin in lactating sheep. Vet. Res. Commun. 2004, 28, 429–435. [Google Scholar] [CrossRef]
  22. Ziv, G.; Kurtz, B.; Risenberg, R.; Glickman, A. Serum and milk concentrations of apramycin in lactating cows, ewes and goats. J. Vet. Pharmacol. Ther. 1995, 18, 346–351. [Google Scholar] [CrossRef]
  23. El-Gendi, A.Y.; Amer, A.M.; Azooz, H.A. Disposition kinetics and milk residues of apramycin in goats. In Proceedings of the European Association of Veterinary Pharmacology and Toxicology 8th Congress, Jerusalem, Israel, 30 July–3 August 2000. [Google Scholar]
  24. Ziv, G.; Bogin, E.; Shani, J.; Sulman, F.G. Distribution and blood-to-milk transfer of labeled antibiotics. Antimicrob. Agents Chemother. 1973, 3, 607–613. [Google Scholar] [CrossRef]
  25. European Medicines Agency Committee for Veterinary Medicinal Products. Dihydrostreptomycin (Extrapolation to All Ruminants) Summary Report (4); EMEA/CVMP/211249/2005-Final; European Medicines Agency Committee for Veterinary Medicinal Products: Amsterdam, The Netherlands, 2005; Volume 211249, pp. 1–5. [Google Scholar]
  26. Friedlander, L.G.; Stephany, R.W. Dihydrostreptomycin and Streptomycin Addendum. Residues Some Vet. Drugs Anim. Foods 2002, 41, 37–41. [Google Scholar]
  27. Lohuis, J.; Poutrel, B.; Cremoux, R.; Parez, V.; Aguer, D. Milk residues of penicillin, nafcillin and dihydrostreptomycin in dairy goats postpartum treated with Nafpenzal N8 at drying-off. In Proceedings of the Residues of Antimicrobial Drugs and Other Inhibitors in Milk, Kiel, Germany, 28–31 August 1995. [Google Scholar]
  28. Lohuis, J.; Berthelot, X.; Cester, C.; Parez, V.; Aguer, D. Pharmacokinetics and milk residues of penicillin, nafcillin and dihydrostreptomycin in dairy sheep treated with nafpenzal DC at drying-off. In Proceedings of the Residues of Antimicrobial Drugs and Other Inhibitors in Milk, Kiel, Germany, 28–31 August 1995. [Google Scholar]
  29. Ziv, G.; Bogin, E.; Shani, J.; Sulman, F. Penetration of radioactive-labeled antibiotics from blood serum into milk in normal and mastitic ewes. Ann. Rech. Vét. 1974, 5, 15–28. [Google Scholar]
  30. European Medicines Agency Committee for Veterinary Medicinal Products. Streptomycin and Dihydrostreptomycin Summary Report (2); EMEA/MRL/728/00-Final; European Medicines Agency Committee for Veterinary Medicinal Products: Amsterdam, The Netherlands, 2000; Volume 728, pp. 1–7. [Google Scholar]
  31. Heitzman, R.J. Dihydrostreptomycin/Streptomycin Addendum. Residues Some Vet. Drugs Anim. Foods 1998, 41, 39–44. [Google Scholar]
  32. Toutain, P.; De Pomyers, H.; Larrieu, G.; Periquet, B.; More, J. An in vivo model for pharmacokinetic studies in the kidney. J. Pharmacol. Methods 1985, 14, 1–11. [Google Scholar] [CrossRef]
  33. Andreini, G.; Pignattelli, P. Kanamycin blood levels and residues in domestic animals. Vet. Milano 1972, 21, 51–72. [Google Scholar]
  34. Pfizer, Inc. ANADA 200-046 Neomycin Sulfate Soluble Powder 325 g/lb—Supplemental Approval (3 April 1996); FOI—Neomycin ANADA 200-046; Pfizer: New York, NY, USA, 1996; pp. 1–3. [Google Scholar]
  35. Lavy, E.; Ziv, G.; Glickman, A. Single-dose pharmacokinetics of thiamphenicol in lactating goats. Acta Vet. Scand. Suppl. 1991, 87, 99–102. [Google Scholar]
  36. Lavy, E.; Ziv, G.; Soback, S.; Glickman, A.; Winkler, M. Clinical pharmacology of florfenicol in lactating goats. Acta Vet. Scand. Suppl. 1991, 87, 133–136. [Google Scholar]
  37. Government of Canada. Questions and Answers on Health Canada’s Policy on Extra-Label Drug Use (ELDU) in Food-Producing Animals; Government of Canada: Ottowa, ON, Canada, 2009.
  38. European Food Safety Authority. Scientific Opinion on Chloramphenicol in Food and Feed; European Food Safety Authority: Parma, Italy, 2014. [Google Scholar] [CrossRef]
  39. Ziv, G.; Bogin, E.; Sulman, F. Blood and milk levels of chloramphenicol in normal and mastitic cows and ewes after intramuscular administration of chloramphenicol and chloramphenicol sodium succinate. Zent. Vet. Reihe A 1973, 20, 801–811. [Google Scholar] [CrossRef]
  40. Dagorn, M.; Guillot, P.; Sanders, P. Pharmacokinetics of chloramphenicol in sheep after intravenous, intramuscular and subcutaneous administration. Vet. Q. 1990, 12, 166–174. [Google Scholar] [CrossRef]
  41. Ziv, G. Pharmacokinetics of antimycoplasma antibiotics in dairy cows and ewes. In Proceedings of the 8th International Meeting of Diseases in Cattle, Milan, Italy, 9–13 September 1974; pp. 80–92. [Google Scholar]
  42. Wetzlich, S.E.; Lane, V.M.; Craigmill, A.L. Tissue residue depletion after multiple subcutaneous administration of florfenicol to sheep. In Proceedings of the European Association of Veterinary Pharmacology and Toxicology 10th Congress, Turin, Italy, 17–22 September 2006; Volume 29, pp. 154–155. [Google Scholar]
  43. Lane, V.M.; Villarroel, A.; Wetzlich, S.; Clifford, A.; Taylor, I.; Craigmill, A. Tissue residues of florfenicol in sheep. J. Vet. Pharmacol. Ther. 2008, 31, 178–180. [Google Scholar] [CrossRef]
  44. Wells, R.J. Thiamphenicol; Addendum to the thiamphenicol residue monograph prepared by the 47th meeting of the Committee and published in FAO Food and Nutrition Paper 41/9, Rome 1996. Residues Some Vet. Drugs Anim. Foods 2000, 41, 119–128. [Google Scholar]
  45. Roy, B.; Banerjee, N. Distribution of chloramphenicol in goat blood and milk after intramuscular administration. Indian J. Anim. Sci. 1983, 53, 847–849. [Google Scholar]
  46. Wal, J.-M.; Peleran, J.-C.; Bories, G.F. High performance liquid chromatographic determination of chloramphenicol in milk. J. Assoc. Off. Anal. Chem. 1980, 63, 1044–1048. [Google Scholar] [CrossRef]
  47. Ziv, G.; Nouws, J. Serum and milk concentrations of ampicillin and amoxycillin in ruminants. Refuah Vet. 1979, 36, 104–110. [Google Scholar]
  48. Ramos, F.; Boison, J.; Friedlander, L.G. Amoxicillin. Residues Some Vet. Drugs Anim. Foods 2012, 1–35. Available online: https://www.fao.org/fileadmin/user_upload/vetdrug/docs/12-2012-amoxicillin.pdf (accessed on 7 August 2022).
  49. Buswell, J.; Knight, C.; Barber, D. Antibiotic persistence and tolerance in the lactating goat following intramammary therapy. Vet. Rec. 1989, 125, 301–303. [Google Scholar] [CrossRef]
  50. Roncada, P.; Tomasi, L.; Stracciari, G.; Ermini, L.; Strocchia, A. Milk depletion of dicloxacillin residues in cows and sheep following intramammary administration. J. Vet. Pharmacol. Ther. 2000, 23, 237–241. [Google Scholar] [CrossRef] [PubMed]
  51. Buswell, J.; Barber, D. Antibiotic persistence and tolerance in the lactating sheep following a course of intramammary therapy. Br. Vet. J. 1989, 145, 552–557. [Google Scholar] [CrossRef]
  52. Pengov, A.; Kirbis, A. Risks of antibiotic residues in milk following intramammary and intramuscular treatments in dairy sheep. Anal. Chim. Acta 2009, 637, 13–17. [Google Scholar] [CrossRef] [PubMed]
  53. Hill, B.; Jagusch, K.; Rajan, L.; Kidd, G. Antibiotic residues in goats milk following intramammary treatment. N. Z. Vet. J. 1984, 32, 130–131. [Google Scholar] [CrossRef]
  54. Ferrini, A.M.; Trenta, S.; Mannoni, V.; Rosati, R.; Coni, E. Depletion of long-acting ampicillin in goat milk following intramuscular administration. J. Agric. Food Chem. 2010, 58, 12199–12203. [Google Scholar] [CrossRef]
  55. Boatto, G.; Cerri, R.; Pau, A.; Palomba, M.; Pintore, G.; Denti, M.G. Monitoring of benzylpenicillin in ovine milk by HPLC. J. Pharm. Biomed. Anal. 1998, 17, 733–738. [Google Scholar] [CrossRef]
  56. Gee, H.-E.; Ho, K.-B.; Toothill, J. Liquid chromatographic determination of benzylpenicillin and cloxacillin in animal tissues and its application to a study of the stability at –20 °C of spiked and incurred residues of benzylpenicillin in ovine liver. J. AOAC Int. 1996, 79, 640–644. [Google Scholar] [CrossRef]
  57. Longo, F.; Cozzani, R.; Santis, L.d.; Boselli, C.; Rosati, R.; Fagiolo, A.; Cinquina, A. Amoxicillin detection in milk using screening tests and liquid chromatography after administration to lactating sheep. Riv. Sci. Dell’alimentazione 2002, 31, 313–319. [Google Scholar]
  58. Chaleva, E.; Dincheva, E. Ampicillin tolerance and content in the mammary gland of lactating cows and sheep. Vet. Med. Nauk. 1977, 14, 73–78. [Google Scholar]
  59. Edwards, S. Penicillin levels in the milk following intramuscular injection. Vet. Rec. 1966, 78, 583–585. [Google Scholar] [CrossRef]
  60. Long, P.; Heavner, J.; Ziv, G.; Geleta, J.; Nepote, K. Depletion of antibiotics from the mammary gland of goats. J. Dairy Sci. 1984, 67, 707–712. [Google Scholar] [CrossRef]
  61. Norbrook Laboratories, Ltd. Freedom of Information Summary, Supplemental New Animal Drug Application, NADA 065-010. Norocillin (Penecillin G Procaine Injectable Suspension) Cattle, Sheep, Swine, and Horses; To Revise the Currently Approved Formulation to Include Lecithin as a Surfactant; FOI—Norocillin NADA 065-010; Norbrook Laboratories, Ltd.: Newry, UK, 2010; pp. 1–27. [Google Scholar]
  62. Rule, R.; Lacchini, R.; Mordujovich, P.; Antonini, A. Evaluation of cefepime kinetic variables and milk production volume in goats. Arq. Bras. Med. Vet. Zootec. 2004, 56, 116–118. [Google Scholar] [CrossRef]
  63. Badillo, E.; Escudero, E.; Hernandis, V.; Galecio, J.S.; Marín, P. Pharmacokinetics of cefonicid in lactating goats after intravenous, intramuscular and subcutaneous administration, and after a long-acting formulation for subcutaneous administration. J. Vet. Pharmacol. Ther. 2020, 43, 50–56. [Google Scholar] [CrossRef]
  64. Yadav, K.; Jayachandran, C.; Singh, M.; Jha, H.; Sinha, S. Kinetics of intravenously administered ceftriaxone in lactating goat. Indian J. Anim. Sci. 2013, 70, 163–165. [Google Scholar]
  65. Ismail, M. Pharmacokinetics, urinary and mammary excretion of ceftriaxone in lactating goats. J. Vet. Med. Ser. A 2005, 52, 354–358. [Google Scholar] [CrossRef]
  66. Ziv, G.; Nouws, J. Clinical pharmacology of cephacetrile in ruminants. Zent. Vet. Reihe B 1977, 24, 798–811. [Google Scholar] [CrossRef]
  67. El Badawy, S.; Amer, A.; Kamel, G.; Eldeib, K.; Constable, P. Comparative pharmacokinetics using a microbiological assay and high performance liquid chromatography following intravenous administration of cefquinome in lactating goats with and without experimentally induced Staphylococcus aureus mastitis. Small Rumin. Res. 2015, 133, 67–76. [Google Scholar] [CrossRef]
  68. El Badawy, S.A.; Amer, A.M.; Kamel, G.M.; Eldeib, K.M.; Constable, P.D. Pharmacokinetics and pharmacodynamics of intramammary cefquinome in lactating goats with and without experimentally induced Staphylococcus aureus mastitis. J. Vet. Pharmacol. Ther. 2019, 42, 452–460. [Google Scholar] [CrossRef]
  69. Soback, S.; Ziv, G.; Bor, A.; Shapira, M. Pharmacokinetics of cephalexin glycinate in lactating cows and ewes. Zent. Vet. Reihe A 1988, 35, 755–760. [Google Scholar]
  70. Wetzel, R.K.; Stayer, P.A.; Wildman, E.E.; Randy, H.A. Depletion of cephapirin in goat’s milk following intramammary infusion. J. Dairy Sci. 1986, 69, 245. [Google Scholar]
  71. Courtin, F.; Wetzlich, S.; Gustafson, C.; Craigmill, A. Pharmacokinetics and milk residues of ceftiofur and metabolites in dairy goats. In Proceedings of the European Association of Veterinary Pharmacology and Toxicology 6th Congress, Edinburgh, UK, 7–11 August 1994; pp. 81–82. [Google Scholar]
  72. El-Rabbat, N.A.; Abdel-Wadood, H.M.; Sayed, M.; Mousa, H.S. High-performance liquid chromatographic determination and pharmacokinetic study of cefepime in goat plasma and milk after pre-column derivatization with Hg (I). J. Sep. Sci. 2010, 33, 2599–2609. [Google Scholar] [CrossRef]
  73. Rule, R.; Villagra, S.; Barrena, P.; Lacchini, R.; Reynaldni, F.J. Pharmacokinetics of ceftazidime administered to lactating and non-lactating goats. J. S. Afr. Vet. Assoc. 2011, 82, 219–223. [Google Scholar] [CrossRef]
  74. European Medicines Agency Committee for Veterinary Medicinal Products. Ceftiofur (Extension to Ovine and Extrapolation to All Mammalian Species) Summary Report (4); European Medicines Agency Committee for Veterinary Medicinal Products: Amsterdam, The Netherlands, 2006; Volume 80785, pp. 1–3. [Google Scholar]
  75. Garrett, E.; Dirikolu, L.; Grover, G. Milk and serum concentration of ceftiofur following intramammary infusion in goats. J. Vet. Pharmacol. Ther. 2015, 38, 569–574. [Google Scholar] [CrossRef]
  76. Goudah, A.; Shin, H.; Shim, J.; El-Aty, A.A. Characterization of the relationship between serum and milk residue disposition of ceftriaxone in lactating ewes. J. Vet. Pharmacol. Ther. 2006, 29, 307–312. [Google Scholar] [CrossRef] [PubMed]
  77. Rageh, A.H.; Abdel-Rahim, S.A.; Askal, H.F.; Saleh, G.A. Hydrophilic-interaction planar chromatography in ultra-sensitive determination of α-aminocephalosporin antibiotics. Application to analysis of cefalexin in goat milk samples using modified QuEChERS extraction technique. J. Pharm. Biomed. Anal. 2019, 166, 421–434. [Google Scholar] [CrossRef] [PubMed]
  78. Rule, R.; Cordiviola, C.; Vita, M.; Lacchini, R. Correlations between milk production and kinetic variables in milk of cephalothin administered to lactating goats. Vet. Med. 2004, 49, 370. [Google Scholar] [CrossRef]
  79. Rule, R.; Lacchini, R.; Román, A.G.; Antonini, A.; de Buschiazzo, P. Influence of feed type on the pharmacokinetics of cephalothin administered to lactating goats. Arch. Zootec. 2007, 56, 807–815. [Google Scholar]
  80. El-Sayed, M.; Atef, M.; El-Komy, A. Disposition kinetics of cephradine in normal and Escherichia coli infected goats. Dtsch. Tierarztl. Wochenschr. 1994, 101, 56–60. [Google Scholar]
  81. Singh, C.S.; Singh, S.D.; Singh, M.K.; Jayachandran, C. Disposition kinetics and distribution of ciprofloxacin in biological fluids of goats after intravenous administration. Indian J. Anim. Sci. 2001, 71, 635–637. [Google Scholar]
  82. El-Banna, H.; El-Sooud, K.A. Disposition kinetics of ciprofloxacin in lactating goats. Dtsch. Tierarztl. Wochenschr. 1998, 105, 35–38. [Google Scholar]
  83. Escudero, E.; Cárceles, C.; Fernandez-Varon, E.; Marin, P.; Benchaoui, H. Pharmacokinetics of danofloxacin 18% in lactating sheep and goats. J. Vet. Pharmacol. Ther. 2007, 30, 572–577. [Google Scholar] [CrossRef]
  84. Escudero, E.; Marín, P.; Cárceles, C.M.; Ramírez, M.J.; Fernández-Varón, E. Pharmacokinetic and milk penetration of a difloxacin long-acting poloxamer gel formulation with carboxy-methylcellulose in lactating goats. Vet. J. 2011, 188, 92–95. [Google Scholar] [CrossRef]
  85. El-Sooud, K.A. Influence of albendazole on the disposition kinetics and milk antimicrobial equivalent activity of enrofloxacin in lactating goats. Pharmacol. Res. 2003, 48, 389–395. [Google Scholar] [CrossRef]
  86. Marin, P.; Escudero, E.; Fernandez-Varon, E.; Espuny, A.; Titos, J.; Hernandis, V.; Carceles, C. Pharmacokinetics and milk penetration of an enrofloxacin long-acting poloxamer 407 gel formulation in lactating goats. J. Vet. Pharamcol. Ther. 2009, 32, 195–196. [Google Scholar]
  87. Narayan, J.P.; Kumar, N.; Jha, H.; Jayachandran, C. Effect of probenecid on kinetics of enrofloxacin in lactating goats after subcutaneous administration. Indian J. Exp. Biol. 2009, 47, 53–56. [Google Scholar]
  88. Haritova, A.; Lashev, L.; Pashov, D. Pharmacokinetics of enrofloxacin in lactating sheep. Res. Vet. Sci. 2003, 74, 241–245. [Google Scholar] [CrossRef]
  89. Marín, P.; Cárceles, C.M.; Escudero, E.; Fernández-Varón, E. Pharmacokinetics and milk penetration of ibafloxacin after intravenous administration to lactating goats. Can. J. Vet. Res. 2007, 71, 74. [Google Scholar]
  90. Goudah, A.; Abo-El-Sooud, K. Pharmacokinetics, urinary excretion and milk penetration of levofloxacin in lactating goats. J. Vet. Pharmacol. Ther. 2009, 32, 101–104. [Google Scholar] [CrossRef]
  91. Lorenzutti, A.; Litterio, N.; Himelfarb, M.; Zarazaga, M.D.P.; Andrés, M.S.; De Lucas, J. Pharmacokinetics, milk penetration and PK/PD analysis by Monte Carlo simulation of marbofloxacin, after intravenous and intramuscular administration to lactating goats. J. Vet. Pharmacol. Ther. 2017, 40, 629–640. [Google Scholar] [CrossRef]
  92. Shem-Tov, M.; Ziv, G.; Glickman, A.; Saran, A. Pharmacokinetics and penetration of marbofloxacin from blood into the milk of cows and ewes. J. Vet. Med. Ser. A 1997, 44, 511–519. [Google Scholar] [CrossRef]
  93. Fernández-Varón, E.; Villamayor, L.; Escudero, E.; Espuny, A.; Cárceles, C.M. Pharmacokinetics and milk penetration of moxifloxacin after intravenous and subcutaneous administration to lactating goats. Vet. J. 2006, 172, 302–307. [Google Scholar] [CrossRef]
  94. Goudah, A.; Cho, H.J.; Shin, H.C.; Shim, J.H.; Regmi, N.L.; Shimoda, M.; Abd El-Aty, A.M. Pharmacokinetics and milk distribution characteristics of orbifloxacin following intravenous and intramuscular injection in lactating ewes. J. Vet. Pharmacol. Ther. 2009, 32, 338–344. [Google Scholar] [CrossRef]
  95. El-Aty, A.M.A.; Goudah, A. Some pharmacokinetic parameters of pefloxacin in lactating goats. Vet. Res. Commun. 2002, 26, 553–561. [Google Scholar] [CrossRef]
  96. Real, R.; Egido, E.; Pérez, M.; Gonzalez-Lobato, L.; Barrera, B.; Prieto, J.; Alvarez, A.; Merino, G. Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: Interaction with ivermectin. J. Vet. Pharmacol. Ther. 2011, 34, 313–321. [Google Scholar] [CrossRef] [PubMed]
  97. Perez, M.; Otero, J.A.; Barrera, B.; Prieto, J.G.; Merino, G.; Alvarez, A.I. Inhibition of ABCG2/BCRP transporter by soy isoflavones genistein and daidzein: Effect on plasma and milk levels of danofloxacin in sheep. Vet. J. 2013, 196, 203–208. [Google Scholar] [CrossRef] [PubMed]
  98. Pulido, M.M.; Molina, A.J.; Merino, G.; Mendoza, G.; Prieto, J.G.; Alvarez, A.I. Interaction of enrofloxacin with breast cancer resistance protein (BCRP/ABCG2): Influence of flavonoids and role in milk secretion in sheep. J. Vet. Pharmacol. Ther. 2006, 29, 279–287. [Google Scholar] [CrossRef] [PubMed]
  99. Shem-Tov, M.; Ziv, G.; Glickman, A.; Saran, A. Pharmacokinetics and penetration of danofloxacin from the blood into the milk of ewes. Vet. Res. 1997, 28, 571–579. [Google Scholar]
  100. Barrera, B.; González-Lobato, L.; Otero, J.A.; Real, R.; Prieto, J.G.; Álvarez, A.I.; Merino, G. Effects of triclabendazole on secretion of danofloxacin and moxidectin into the milk of sheep: Role of triclabendazole metabolites as inhibitors of the ruminant ABCG2 transporter. Vet. J. 2013, 198, 429–436. [Google Scholar] [CrossRef]
  101. Otero, J.A.; García-Mateos, D.; Alvarez-Fernández, I.; García-Villalba, R.; Espín, J.C.; Álvarez, A.I.; Merino, G. Flaxseed-enriched diets change milk concentration of the antimicrobial danofloxacin in sheep. BMC Vet. Res. 2018, 14, 14. [Google Scholar] [CrossRef] [Green Version]
  102. Marín, P.; Escudero, E.; Fernández-Varón, E.; Ramírez, M.; Cárceles, C. Pharmacokinetics and milk penetration of difloxacin after a long-acting formulation for subcutaneous administration to lactating goats. J. Dairy Sci. 2010, 93, 3056–3064. [Google Scholar] [CrossRef]
  103. Fernandez-Varon, E.; Escudero, E.; Marin, P.; Titos, J.; Espuny, A.; Carceles, C. Pharmacokinetics and milk penetration of enrofloxacin and its metabolite ciprofloxacin after subcutaneous administration to lactating goats. J. Vet. Pharmacol. Ther. 2009, 32, 196–197. [Google Scholar]
  104. European Medicines Agency Committee for Veterinary Medicinal Products. Enrofloxacin (Extension to Sheep, Rabbits and Lactating Cows) Summary Report (3); EMEA/MRL/389/98-Final; European Medicines Agency Committee for Veterinary Medicinal Products: Amsterdam, The Netherlands, 1998; Volume 389, pp. 1–5. [Google Scholar]
  105. Cárceles, C.M.; Villamayor, L.; Escudero, E.; Marín, P.; Fernández-Varón, E. Pharmacokinetics and milk penetration of moxifloxacin after intramuscular administration to lactating goats. Vet. J. 2007, 173, 452–455. [Google Scholar] [CrossRef]
  106. Soback, S.; Gips, M.; Bialer, M.; Bor, A. Effect of lactation on single-dose pharmacokinetics of norfloxacin nicotinate in ewes. Antimicrob. Agents Chemother. 1994, 38, 2336–2339. [Google Scholar] [CrossRef]
  107. Marín, P.; Escudero, E.; Fernández-Varón, E.; Cárceles, C. Pharmacokinetics and milk penetration of orbifloxacin after intravenous, subcutaneous, and intramuscular administration to lactating goats. J. Dairy Sci. 2007, 90, 4219–4225. [Google Scholar] [CrossRef]
  108. Delmas, J.; Chapel, A.; Gaudin, V.; Sanders, P. Pharmacokinetics of flumequine in sheep after intravenous and intramuscular administration: Bioavailability and tissue residue studies. J. Vet. Pharmacol. Ther. 1997, 20, 249–257. [Google Scholar] [CrossRef]
  109. Francis, P.G.; Wells, R.J. Flumequine. Residues Some Vet. Drugs Anim. Foods 1998, 41, 59–70. [Google Scholar]
  110. European Medicines Agency Committee for Veterinary Medicinal Products. Erythromycin Summary Report (2); EMEA/MRL/720/99-Final; European Medicines Agency Committee for Veterinary Medicinal Products: Amsterdam, The Netherlands, 2000; Volume 720, pp. 1–8. [Google Scholar]
  111. Goudah, A.; Sher Shah, S.; Shin, H.; Shim, J.; Abd El-Aty, A. Pharmacokinetics and mammary residual depletion of erythromycin in healthy lactating ewes. J. Vet. Med. Ser. A 2007, 54, 607–611. [Google Scholar] [CrossRef]
  112. Ramadan, A. Pharmacokinetics of tilmicosin in serum and milk of goats. Res. Vet. Sci. 1997, 62, 48–50. [Google Scholar] [CrossRef]
  113. MacNeil, J.D. Tilmicosin. Residues Some Vet. Drugs Anim. Foods 1997, 41, 106–118. [Google Scholar]
  114. Xu, S.; Arnold, D. Tilmicosin: Addendum to tho monographs prepared by the 47th meeting of the Committee and published in the FAO Food and Nutrition paper 41/9. Residues Some Vet. Drugs Anim. Foods 2008, 41, 1–37. [Google Scholar]
  115. Grismer, B.; Rowe, J.D.; Carlson, J.; Wetzlich, S.; Tell, L.A. Pharmacokinetics of tulathromycin in plasma and milk samples after a single subcutaneous injection in lactating goats (C apra hircus). J. Vet. Pharmacol. Ther. 2014, 37, 205–208. [Google Scholar] [CrossRef]
  116. Amer, A.; Constable, P.; Goudah, A.; El Badawy, S. Pharmacokinetics of tulathromycin in lactating goats. Small Rumin. Res. 2012, 108, 137–143. [Google Scholar] [CrossRef]
  117. Lin, Z.; Cuneo, M.; Rowe, J.D.; Li, M.; Tell, L.A.; Allison, S.; Carlson, J.; Riviere, J.E.; Gehring, R. Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach. BMC Vet. Res. 2016, 12, 258. [Google Scholar] [CrossRef] [Green Version]
  118. Atef, M.; Youssef, S.; Atta, A.; El-Maaz, A. Disposition of tylosin in goats. Dtsch. Tierarztl. Wochenschr. 1991, 98, 451–453. [Google Scholar] [CrossRef]
  119. Ziv, G.; Sulman, F.G. Serum and milk concentrations of spectinomycin and tylosin in cows and ewes. Am. J. Vet. Res. 1973, 34, 329–333. [Google Scholar]
  120. Nagy, J.; Popelka, P.; Sokol, J.; Turek, P.; Neuschl, J. The excretion of tylosin residues in ewes milk after its experimental administration. Folia Vet. 2001, 45, 196–198. [Google Scholar]
  121. Ambros, L.; Montoya, L.; Kreil, V.; Waxman, S.; Albarellos, G.; Rebuelto, M.; Hallu, R.; Andres, M.S. Pharmacokinetics of erythromycin in nonlactating and lactating goats after intravenous and intramuscular administration. J. Vet. Pharmacol. Ther. 2007, 30, 80–85. [Google Scholar] [CrossRef]
  122. Ziv, G. Concentrations and residues of antibiotics in the milk of goats after parenteral and intramammary administration. In Proceedings of the Symposium Internacional de Ordeno Mecanico de Pequenos Rumiantes, Valladolid, Spain; 1984; pp. 513–528. [Google Scholar]
  123. Romanet, J.; Smith, G.W.; Leavens, T.L.; Baynes, R.E.; Wetzlich, S.E.; Riviere, J.E.; Tell, L.A. Pharmacokinetics and tissue elimination of tulathromycin following subcutaneous administration in meat goats. Am. J. Vet. Res. 2012, 73, 1634–1640. [Google Scholar] [CrossRef]
  124. Clothier, K.A.; Leavens, T.; Griffith, R.W.; Wetzlich, S.E.; Baynes, R.E.; Riviere, J.E.; Tell, L.A. Tulathromycin assay validation and tissue residues after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus). J. Vet. Pharmacol. Ther. 2012, 35, 113–120. [Google Scholar] [CrossRef]
  125. Kellermann, M.; Huang, R.A.; Forbes, A.B.; Rehbein, S. Gamithromycin plasma and skin pharmacokinetics in sheep. Res. Vet. Sci. 2014, 97, 199–203. [Google Scholar] [CrossRef]
  126. European Medicines Agency Committee for Veterinary Medicinal Products. European Public MRL Assessment Report (EPMAR) Gamithromycin (All Ruminants Except Bovine Species.)12 December 2016; EMA/CVMP/454092/2016; European Medicines Agency Committee for Veterinary Medicinal Products EPMAR: Amsterdam, The Netherlands, 2016; Volume 454092, pp. 1–11. [Google Scholar]
  127. Atef, M.; El-Sooud, K.A.; Nahed, E.; Tawfik, M. Elimination of tilmicosin in lactating ewes. Dtsch. Tierarztl. Wochenschr. 1999, 106, 291–294. [Google Scholar]
  128. Parker, R.; Patel, R.; Mclaren, I.; Francis, P. Residues of tilmicosin in milk of sheep after subcutaneous administration. In Proceedings of the European Association for Veterinary Pharmacology and Toxicology, Edinburgh, UK, 7–11 August 1994; pp. 226–227. [Google Scholar]
  129. Elanco Animal Health. Freedom of Information Summary; Micotil 300 Injection (tilmicosin phosphate); Supplement to NADA 140-929; Date of Approval: 4 September 2002; FOI—Micotil NADA 140-929; Elanco Animal Health: Greenfield, IN, USA, 2002; pp. 1–14. [Google Scholar]
  130. European Medicines Agency Committee for Veterinary Medicinal Products. European Public MRL Assessment Report (EPMAR) Tulathromycin (Ovine and Caprine Species) 23 February 2015; EMA/CVMP/131462/2014; European Medicines Agency Committee for Veterinary Medicinal Products EPMAR: Amsterdam, The Netherlands, 2015; Volume 131462, pp. 1–11. [Google Scholar]
  131. Tunnicliff, E.; Swingle, K. Sulfonamide concentrations in milk and plasma from normal and mastitic ewes treated with sulfamethazine. Am. J. Vet. Res. 1965, 26, 920–927. [Google Scholar]
  132. Rasmussen, F. Mammary excretion of sulphonamides. Acta Pharmacol. Toxicol. 1958, 15, 139–148. [Google Scholar] [CrossRef]
  133. Akogwu, E.; Saganuwan, S.; Onyeyili, P. Effects of piroxicam on tissue distribution of sulfadimidine in west African dwarf male and female goats. Hum. Exp. Toxicol. 2018, 37, 61–68. [Google Scholar] [CrossRef] [PubMed]
  134. Bevill, R.; Sharma, R.; Meachum, S.; Wozniak, S.; Bourne, D.; Dittert, L. Disposition of sulfonamides in food-producing animals: Concentrations of sulfamethazine and its metabolites in plasma, urine, and tissues of lambs following intravenous administration. Am. J. Vet. Res. 1977, 38, 973–977. [Google Scholar] [PubMed]
  135. Jha, H.; Banerjee, N. A note on distribution of sulphadimethoxine in blood, milk and urine of goats. Indian J. Anim. Sci. 1977, 47, 496–497. [Google Scholar]
  136. Yndestad, M.; Underdal, B. Residues of Sulfadimidine/Sulfanilamide and Sulfamethoxypyridazine in Sheep Tissue. Acta Vet. Scand. 1977, 18, 15–22. [Google Scholar] [CrossRef] [PubMed]
  137. Bevill, R.F.; Koritz, G.D.; Dittert, L.W.; Bobrne, D.W. Disposition of sulfonamides in food-producing animals V: Disposition of sulfathiazole in tissue, urine, and plasma of sheep following intravenous administration. J. Pharm. Sci. 1977, 66, 1297–1300. [Google Scholar] [CrossRef]
  138. Righter, H.F.; Worthington, J.M.; Mercer, H.D. Tissue residue depletion of sulfamerazine in sheep. J. Agric. Food Chem. 1972, 20, 876–878. [Google Scholar] [CrossRef]
  139. Atef, M. Half-life, volume of distribution and acetylation of sulphamerazine in sheep. Zent. Vet. Reihe A 1978, 25, 585–591. [Google Scholar] [CrossRef]
  140. Bulgin, M.; Lane, V.M.; Archer, T.; Baggot, J.; Craigmill, A. Pharmacokinetics, safety and tissue residues of sustained-release sulfamethazine in sheep. J. Vet. Pharmacol. Ther. 1991, 14, 36–45. [Google Scholar] [CrossRef]
  141. Bevill, R.F. Application of Pharamcokinetics to the Study of Sulfonamide Behavior in Cattle, Sheep, and Swine. In Proceedings of the Symposium of Veterinary Pharmacology and Therapeutics, Baton Rouge, LA, USA, 13–15 March 1978; pp. 75–101. [Google Scholar]
  142. Paulson, G.; Struble, C.; Mitchell, A. Comparative metabolism of sulfamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl) benzenesulfonamide] in the rat, chicken, pig and sheep. In Mode of Action, Metabolism and Toxicology; Elsevier: Amsterdam, The Netherlands, 1983; pp. 375–380. [Google Scholar]
  143. Hashem, M.; Tayeb, F.; El-Mekkawi, T. The level of some sulphonamide preparations in tissues and blood of cocks and sheep. J. Egypt. Vet. Med. Assoc. 1980, 40, 5–11. [Google Scholar]
  144. Attaie, R.; Bsharat, M.; Mora-Gutierrez, A.; Woldesenbet, S. Short communication: Determination of withdrawal time for oxytetracycline in different types of goats for milk consumption. J. Dairy Sci. 2015, 98, 4370–4376. [Google Scholar] [CrossRef]
  145. Payne, M.; Babish, J.; Bulgin, M.; Lane, M.; Wetzlich, S.; Craigmill, A. Serum pharmacokinetics and tissue and milk residues of oxytetracycline in goats following a single intramuscular injection of a long-acting preparation and milk residues following a single subcutaneous injection. J. Vet. Pharmacol. Ther. 2002, 25, 25–32. [Google Scholar] [CrossRef]
  146. Fletouris, D.; Papapanagiotou, E. Tissue residue depletion of oxytetracycline after repeated intramuscular administration of Oxysentin 100 in sheep. J. Vet. Pharmacol. Ther. 2009, 32, 56–61. [Google Scholar] [CrossRef]
  147. Anifantakis, E.M. Excretion rates of antibiotics in milk of sheep and their effect on yogurt production. J. Dairy Sci. 1982, 65, 426–429. [Google Scholar] [CrossRef]
  148. Wells, R.J. Chlortetracycline. Residues Some Vet. Drugs Anim. Foods 1996, 41, 31–66. [Google Scholar]
  149. Jha, V.; Jayachandran, C.; Singh, M.; Singh, S. Pharmacokinetic data on doxycycline and its distribution in different biological fluids in female goats. Vet. Res. Commun. 1989, 13, 11–16. [Google Scholar] [CrossRef]
  150. Jayachandran, C.; Singh, M.; Singh, S.; Jha, H. Pharmacokinetics and distribution of minocydine in different biological fluids of goats after intravenous administration. Indian J. Anim. Sci. 2012, 69, 304–306. [Google Scholar]
  151. Immelman, A.; Ziv, G. Serum and milk concentrations of oxytetracycline after the administration of a long-acting formulation to sheep. J. S. Afr. Vet. Assoc. 1982, 53, 199–200. [Google Scholar]
  152. Arndt, T.; Robinson, D.; Holland, R.; Wetzlich, S.; Craigmill, A. Oxytetracycline residues in sheep following im dosing with a long-acting formulation. J. Vet. Pharmacol. Ther. 1997, 20, 314–315. [Google Scholar]
  153. Boatto, G.; Pau, A.; Palomba, M.; Arenare, L.; Cerri, R. Monitoring of oxytetracycline in ovine milk by high-performance liquid chromatography. J. Pharm. Biomed. Anal. 1999, 20, 321–326. [Google Scholar] [CrossRef]
  154. Craigmill, A.; Holland, R.; Robinson, D.; Wetzlich, S.; Arndt, T. Serum pharmacokinetics of oxytetracycline in sheep and calves and tissue residues in sheep following a single intramuscular injection of a long-acting preparation. J. Vet. Pharmacol. Ther. 2000, 23, 345–352. [Google Scholar] [CrossRef]
  155. Fletouris, D.J.; Papapanagiotou, E.P. A new liquid chromatographic method for routine determination of oxytetracycline marker residue in the edible tissues of farm animals. Anal. Bioanal. Chem. 2008, 391, 1189–1198. [Google Scholar] [CrossRef] [PubMed]
  156. Fletouris, D.J.; Papapanagiotou, E.P.; Nakos, D.S. Liquid chromatographic determination and depletion profile of oxytetracycline in milk after repeated intramuscular administration in sheep. J. Chromatogr. B 2008, 876, 148–152. [Google Scholar] [CrossRef] [PubMed]
  157. Cinquina, A.L.; Longo, F.; Barchi, D.; Fagiolo, A.; Rosati, R.; Cozzani, R. Comparative pharmacokinetics of oxytetracycline in goat and sheep milk. Residues of Veterinary Drugs in Food. In Proceedings of the European Residue Conference IV, Veldhoven, The Netherlands, 8–10 May 2000; pp. 285–290. [Google Scholar]
  158. Hassan, S.A.A.; Shaddad, S.A.I.; El-Tayeb, L.B.; Omer, M.A.; Al-Nazawi, M.H.; Homeida, A.M. Detection of long-acting oxytetracycline residue levels in tissue of desert sheep following intramuscular injection. Int. J. Pharmacol. 2007, 3, 299–301. [Google Scholar]
  159. Reja, A.; Gonzalez, R.; Serrano, J.M.; Santiago, D.; Guimera, M.E.; Cano, M. Oxytetracycline and tetracycline residues in goat milk. In Proceedings of the European Associations of Veterinary Pharmacology and Toxicology 6th Congress, Edinburgh, UK, 7–11 August 1994. [Google Scholar]
  160. Reja Sanchez, A.; Gonzalez Pedrajas, R.; Serrano Caballero, J.M.; Santiago Laguna, D. Experimental determination of occurrence of tetracycline and oxytetracycline residues in goat milk. Blood/milk transference rates. Rev. Toxicol. 1995, 12, 29–34. [Google Scholar]
  161. Cinquina, A.L.; Gianetti, L.; Barchi, D.; Lanzi, S.; Longo, F.; Coresi, A.; Fagiolo, A.; Cozzani, R. Oxytetracycline residues in goat milk. Obiettivi Doc. Vet. 2002, 23, 37–40. [Google Scholar]
  162. Rule, R.; Moreno, L.; Serrano, J.M.; Garcia Roman, A.; Moyano, R.; Garcia, J. Pharmacokinetics and residues in milk of oxytetracyclines administered parenterally to dairy goats. Aust. Vet. J. 2001, 79, 492–496. [Google Scholar] [CrossRef]
Animals 12 02607 g001 550
Figure 1. Schematic diagram of the process for three independent evaluators to assess published manuscripts and the numerical outcome of each step. The ultimate goal was to curate manuscripts with tissue and milk residue data from live sheep and goat antibacterial drug studies.
Figure 1. Schematic diagram of the process for three independent evaluators to assess published manuscripts and the numerical outcome of each step. The ultimate goal was to curate manuscripts with tissue and milk residue data from live sheep and goat antibacterial drug studies.
Animals 12 02607 g001
Table
Table 1. Aminoglycoside residues in milk or edible tissue samples from sheep or goats following treatment.
Table 1. Aminoglycoside residues in milk or edible tissue samples from sheep or goats following treatment.
AnalyteSpecies; Breed; Age;
# of Animals per Time Point		Tolerance/
MRL		Analytical MethodLODLOQRoute of Admin-istrationDose & Active Ingredient# of DosesMatrixLast Sampling Time Point (Post-Last Treatment) When Residues WERE DetectedSampling Time Point When NO Residues Were Detected (Post-Last Treatment) *Health StatusAdditional InformationSource/Year
AmikacinGoat; Baladi;
2–3 years;
n = 5		US Tol: Not established.
EMA MRL: Not established.		BioassayNS0.2 ppmIV7.5 mg/kg Amikacin sulfate1Milk4 h (0.22 ppm)6 hHealthyMid- lactation; Milked 2×[19] 1999
IM7.5 mg/kg Amikacin sulfate1Milk6 h (0.21 ppm)8 h
AmikacinGoat; NS;
1.5–2 years;
n = 6		US Tol: Not established.
EMA MRL: Not established.		Bioassay0.1 ppmNSIM10 mg/kg Amikacin sulfate1Milk5 h (NS)6 hHealthyLactating[20] 2001
AmikacinSheep; crossbred; 2–4 years; n = 6US Tol: Not established.
EMA MRL: Not established		BioassayNS0.19 ppmIV7.5 mg/kg Amikacin sulfate1Milk9.5 h (0.85 ppm §)>1 dayHealthyLactating;
Milked 2×/day		[21] 2004
IM7.5 mg/kg Amikacin sulfate1Milk9.5 h (0.21 ppm §)>1 day
ApramycinGoat; Saanen; adult; n = 10US Tol: Not established.
EMA MRL: Not established.		BioassayNS0.1 ppmIV20 mg/kg Apramycin sulfate1Milk10 h (0.12 ppm §)>10 hHealthyEarly Lactation[22] 1995
ApramycinSheep; Awassi; adult; n = 6US Tol: Not established.
EMA MRL: Not established.		BioassayNS0.1 ppmIM10 mg/kg Apramycin sulfate1Milk720 min (0.15 ppm §)1440 minDiseased-MastitisMid-lactation[22] 1995
ApramycinSheep; Awassi; adult; n = 10US Tol: Not established.
EMA MRL: Not established.		BioassayNS0.1 ppmIV20 mg/kg Apramycin sulfate1Milk6 h (0.11 ppm §)8 hHealthyMid-lactation[22] 1995
ApramycinSheep; NS; Lambs;
n = 12 study;
n = 3/time pt		US Tol: Not established.
EMA MRL: Not established.		Bioassay500 ppbNSPO10 mg/kg Apramycin daily3LiverND@1 day1 dayHealthyNS[10] 1999
Kidney21 days (1730 ppb)35 days
MuscleND@1 day1 day
Fat21 days (960 ppb)28 days
NS; Lambs;
n = 20 study;
n = 4/time pt		HPLCLiver: 368 ppbLiver: 2500 ppbPO10 mg/kg Apramycin daily5Liver30 days (700 ppb)>30 days
Kidney: 394 ppbKidney: 2500 ppbKidney30 days (1700 ppb)>30 days
Muscle: 124 ppbMuscle: 500 ppbMuscleND @ 6 days6 days
Fat: 42 ppbFat: 500 ppbFatND @ 6 days6 days
ApramycinGoat; NS; Adult; NSUS Tol: Not established.
EMA MRL: Not established.		NSNSNSIM20 mg/kg Apramycin1Milk10 h (NS)12 hNSNS[23] 2000
IV20 mg/kg Apramycin1Milk12 h (NS)>12 h
Dihydro-
strepto-mycin		Goat; NS; Adults; n = 220US Tol: Not established.
EMA MRL: Not established.		Bioassay0.13 ppm0.15 ppmIMM300,000 IU Procaine benzyl-penicillin; 100 mg dihydro-strepto-mycin; 100 mg nafcillin1Milk6 days post kidding
(≥0.2 ppm)		7 days post kiddingHealthyDry off period (mean 61.0 ± 4.3 days SD (range 23–156 days); 1 tube per gland before drying off. Sample collected after kidding[27] 1995
Dihydro-strepto-mycinSheep; Lacaune; adult; n = 8US Tol: Not established.
EMA established MRL: 200 ppb (milk).		Bioassay0.02 ppmNSIMM300,000 IU Procaine benzyl-penicillin; 100 mg dihydro-streptomycin; 100 mg nafcillin1Milk3 days (0.02 ppm §)4 daysHealthyDry off period (mean 112 days (range 85–223 days); 1 tube per gland before drying off. Sample collected after lambing[28] 1995
Dihydro-strepto-mycinSheep; Awassi; adult; n = 3US Tol: Not established.
EMA established MRL: 200 ppb (milk).		BioassayNSNSIV20 mg/kg Dihydro-streptomycin (radio-labeled) then 10 mg/kg for 4 doses 45 min interval5Milk24 h (0.20 ppm §)36 hHealthyLactating;
Milked 2×/day		[24] 1973
Radio-activityNSNSIV5Milk8 h (1.83 ppm §)10 h
Dihydro-strepto-mycinSheep; NS; NS;
n = 22 study
n = 4/time pt		US Tol: Not established.
EMA established MRL: 500 ppb (liver, muscle, fat); 1000 ppb (kidney).		Bioassay0.5 ppmNSIM10 mg/kg Dihydro-streptomycin combined w/ 10,000 IU procaine penicillin-G daily5Kidney28 days (0.8 ppm)>28 daysHealthyNS[11] 1995
Muscle14 days (0.07 ppm)21 days
Inj. Site28 days (0.2 ppm)>28 days
Dihydro-strepto-mycinSheep; Awassi; Adult; n = 2US Tol: Not established.
EMA established MRL: 200 ppb (milk).		BioassayNSNSIM20 mg/kg Dihydro-streptomycin (radio-labeled)1Milk12 h (0.22 ppm §)24 hHealthyLactating[29] 1974
Milk48 h (0.11 ppm §)56 hDisease-mastitis
Radio-activityNSNSIMMilk48 h (0.75 ppm §)>48 hHealthy
Milk12 h (0.42 ppm §)24 hDisease-mastitis
Dihydro-strepto-mycinSheep; NS; NS;
n = 12 study;
n = 4/ time pt
NS; Adult;
n = 8		US Tol: Not established.
EMA established MRL: 500 ppb (liver, muscle, fat); 1000 ppb (kidney); 200 ppb (milk).		NSNSNSIM10 mg/kg Dihydro-streptomycin combined with benzyl-penicillin daily3Liver<400 ppb @ 14 days14 daysHealthyNS[25] 2005
Kidney<400 ppb @ 14 days14 days
Muscle<400 ppb @ 14 days14 days
Fat<400 ppb @ 14 days14 days
Inj. Site18 days (0.58 ppm)28 days
HPLCNS50 ppbIM10 mg/kg Dihydro-streptomycin sulfate combined with 10 mg/kg streptomycin daily3Milk48 h (0.06 ppm)60 hHealthyLactating
Dihydro-strepto-mycinSheep; Suffolk & Suffolk/Cheviot; adult; n = 8US Tol: Not established.
EMA established MRL: 200 ppb (milk).		HPLC0.02 ppm0.05 ppmIM10 mg/kg Dihydro-streptomycin combined with 10 mg/kg streptomycin daily3Milk48 h (0.06 ppm)60 hHealthyLactating;
Milked 2×/day		[26] 2002
Dihydro-strepto-mycinSheep; NS; NS;
n = 12 study;
n = 4/time pt		US Tol: Not established.
EMA established MRL: 500 ppb (liver, muscle, fat); 1000 ppb (kidney).		NSNS400 ppbIM10 mg/kg Dihydro-streptomycin combined w/ benzyl-penicillin daily3Liver<LOQ @ 14 days14 daysHealthyNS[30] 2000
Kidney<LOQ @ 14 days14 days
Muscle<LOQ @ 14 days14 days
Fat<LOQ @ 14 days14 days
Inj. Site18 days (0.584 ppm)28 days
Dihydro-strepto-mycinSheep; NS; NS;
n = 12 study;
n = 4/time pt		US Tol: Not established.
EMA established MRL: 500 ppb (liver, muscle, fat); 1000 ppb (kidney).		HPLCNS400 ppbIM10 mg/kg Dihydro-streptomycin combined w/ procaine penicillin daily3Liver<LOQ @ 14 days14 daysHealthyNS[31] 1998
Kidney<LOQ @ 14 days14 days
Muscle<LOQ @ 14 days14 days
Fat<LOQ @ 14 days14 days
Inj. Site18 days (0.584 ppm)28 days
GentamicinSheep; mixed breed; adult;
n = 7		US Tol: Not established.
EMA established MRL in all mammalian food producing species: 750 ppb (kidney).		BioassayNSNSIV4 mg/kg Gentamicin1Kidney *biopsy28 days (9.9 ppm)35 daysHealthyNS[32] 1985
GentamicinSheep; Suffolk; adult; n = 9 study;
n = 3/time pt		US Tol: Not established.
EMA established MRL in all mammalian food producing species: 750 ppb (kidney); 50 ppb (muscle).		Immuno-assay0.01 ppmNSIM3 mg/kg Gentamicin sulfate at 8 h intervals2Kidney15 days (20.0 ppm §)>15 daysHealthyNS[12] 1985
Muscle15 days (0.21 ppm §)>15 days
Heart15 days (0.64 ppm §)>15 days
GentamicinSheep; Suffolk; adult;
n = 12 study;
n = 3/time pt		US Tol: Not established.
EMA Established MRL in all mammalian food producing species: 200 ppb (liver); 750 ppb (kidney); 50 ppb (muscle, fat).		Immuno-assay0.01 ppmNSIM2 mg/kg Gentamicin sulfate1Liver12 days (0.31 ppt)>12 daysHealthyNS[13] 1986
Kidney12 days (2.74 ppt)>12 days
Muscle12 days (0.2 ppt)>12 days
Inj. Site12 days (0.15 ppt)>12 days
6 mg/kg Gentamicin sulfate1Liver12 days (1.5 ppt)>12 days
Kidney12 days (5.15 ppt)>12 days
Muscle12 days (0.002 ppt)>12 days
Inj. Site12 days (0.02 ppt)>12 days
18 mg/kg Gentamicin sulfate1Liver12 days (4.0 ppt)>12 days
Kidney12 days (9.23 ppt)>12 days
Muscle12 days (0.14 ppt)>12 days
Inj. Site12 days (0.53 ppt)>12 days
2 mg/kg Gentamicin sulfate at 8 h intervals9Liver12 days (4.02 ppt)>12 days
Kidney12 days (9.74 ppt)>12 days
Muscle12 days (0.04 ppt)>12 days
Inj. Site12 days (2.49 ppt)>12 days
6 mg/kg Gentamicin sulfate daily3Liver12 days (3.12 ppt)>12 days
Kidney12 days (10.0 ppt)>12 days
Muscle12 days (0.14 ppt)>12 days
Inj. Site12 days (5.03 ppt)>12 days
GentamicinSheep; western range; adult;
n = 4		US Tol: Not established.
EMA established MRL in all mammalian food producing species: 750 ppb (kidney).		Immuno-assay0.04 ppmNSIM3 mg/kg Gentamicin sulfate at 12 h intervals20Kidney (biopsy)77 days (9.71 ppm)>77 daysNSNS[14] 1988
KanamycinSheep; Bergamo; adult;
n = 12 study;
n = 3/time pt		US Tol: Not established.
EMA established MRL: 600 ppb (liver);
2500 ppb (kidney); 100 ppb (muscle).		BioassayNSNSIM20 mg/kg Kanamycin1Liver3 days (2.2 ppm)6 daysNSNS[33] 1991
Kidney10 days (8.31 ppm)14 days
MuscleND @ 3 days3 days
NeomycinGoat; NS; NS;
n = 18 study;
n = 4/ time pt		US Tol: 3600 ppb (liver); 7200 ppb (kidney);1200 ppb (muscle); 7200 ppb (fat).
EMA MRL extrapolated to all food producing species: 5500 ppb (liver); 9000 ppb (kidney); 500 ppb (muscle, fat).		BioassayNS0.5 ppmPOMW22 mg/kg Neomycin sulfate daily14LiverND @ 12 h12 hHealthyNS[15] 1996
Kidney96 h (0.6 ppm)>96 h
MuscleND @ 12 h12 h
FatND @ 12 h12 h
NeomycinGoat; NS; NS;
n = 20 study;
n = 5/time pt		US Tol: 3600 ppb (liver); 7200 ppb (kidney); 1200 ppb (muscle); 7200 ppb (fat).
EMA MRL extrapolated to all food producing species: 5500 ppb (liver); 9000 ppb (kidney); 500 ppb (muscle, fat).		BioassayNS500 ppbPOMW20 mg/kg Neomycin sulfate daily14LiverND @ 12 h12 hHealthyNS[16] 2000
Kidney96 h (700 ppb)>96 h
MuscleND @ 12 h12 h
FatND @ 12 h12 h
NeomycinGoat; NS; NS;
n = 20 study,
n = 4/time pt		US Tol: 3600 ppb (liver); 7200 ppb (kidney); 1200 ppb (muscle); 7200 ppb (fat).
EMA MRL extrapolated to all food producing species: 5500 ppb (liver); 9000 ppb (kidney); 500 ppb (muscle, fat).		BioassayNS0.5 ppmPO22 mg/kg Neomycin sulfate daily14LiverND @ 12 h12 hHealthyNS[17] 1995
Kidney96 h (0.7 ppm)>96 h
MuscleND @ 12 h12 h
FatND @ 12 h12 h
NeomycinGoat; NS; NS;
n = 20 study,
n = 4/time pt		US Tol: 3600 ppb (liver); 7200 ppb (kidney); 1200 ppb (muscle); 7200 ppb (fat).
EMA MRL extrapolated to all food producing species: 5500 ppb (liver); 9000 ppb (kidney); 500 ppb (muscle, fat).		NSNS0.5 ppmPOMW22 mg/kg Neomycin sulfate daily14LiverND @ 12 h12 hHealthyNS[34] 1996
Kidney96 h (0.57 ppm)>96 h
MuscleND @ 12 h12 h
FatND @ 12 h12 h
NeomycinSheep; NS; NS;
n = 18 study;
n = 4/time pt		US Tol: 3600 ppb (liver); 7200 ppb (kidney); 1200 ppb (muscle); 7200 ppb (fat).
EMA MRL extrapolated to all food producing species: 5500 ppb (liver); 9000 ppb (lidney); 500 ppb (muscle, fat).		BioassayNS0.5 ppmPOMW22 mg/kg Neomycin sulfate daily14LiverND @ 1 day1 dayHealthyNS[15] 1996
Kidney1 day (female) (1.28 ppm)3 days (female)
Kidney3 days (male) (0.45 ppm)7 days (male)
MuscleND @ 1 day1 day
FatND @ 1 day1 day
NeomycinSheep; NS; NS;
n = 20 study;
n = 5/time pt		US Tol: 3600 ppb (liver); 7200 ppb (kidney); 1200 ppb (muscle); 7200 ppb (fat).
EMA MRL extrapolated to all food producing species: 5500 ppb (liver); 9000 ppb (kidney); 500 ppb (muscle, fat).		BioassayNS500 ppbPOMW20 mg/kg Neomycin sulfate daily14LiverND @ 1 day1 dayHealthyNS[16] 2000
Kidney3 days (522 ppb)7 days
MuscleND @ 1 day1 day
FatND @ 1 day1 day
NeomycinSheep; NS; NS;
n = 20 study,
n = 4/time pt		US Tol: 3600 ppb (liver); 7200 ppb (kidney); 1200 ppb (muscle); 7200 ppb (fat).
EMA MRL extrapolated to all food producing species: 5500 ppb (liver); 9000 ppb (kidney); 500 ppb (muscle, fat).		BioassayNS0.5 ppmPO22 mg/kg Neomycin sulfate daily14LiverND @ 1 day1 dayHealthyNS[17] 1995
Kidney3 days (522 ppb)7 days
MuscleND @ 1 day1 day
FatND @ 1 day1 day
NeomycinSheep; NS; NS;
n = 20 study,
n = 4/time pt		US Tol: 3600 ppb (liver); 7200 ppb (kidney); 1200 ppb (muscle); 7200 ppb (fat).
EMA MRL extrapolated to all food producing species: 5500 ppb (liver); 9000 ppb (kidney); 500 ppb (muscle, fat).		NSNS0.5 ppmPOMW22 mg/kg Neomycin sulfate daily14LiverND @ 1 day1 dayHealthyNS[34] 1996
Kidney1 day (female) (1.28 ppm)3 days (female)
Kidney3 days (male) (0.45 ppm)7 days (male)
MuscleND @ 1 day1 day
FatND @ 1 day1 day
Strepto-mycinSheep; NS; NS;
n = 4		US Tol: Not established.
EMA established MRL: 200 ppb (milk).		HPLCNS50 ppbIM10 mg/kg Streptomycin combined w/ dihydro-streptomycin daily3Milk48 h (0.07 ppm)60 hHealthyLactating,
Milked 2×/day		[25] 2005
Strepto-mycinSheep; Suffolk & Suffolk/Cheviot; adult; n = 8US Tol: Not established.
EMA established MRL: 200 ppb (milk).		HPLC0.02 ppm0.05 ppb († 0.05 ppm)IM10 mg/kg Streptomycin combined w/ dihydro-streptomycin daily3Milk48 h (0.07 ppm)60 hHealthyMilked 2×/day[26] 2002
Strepto-mycinSheep; NS; NS; NSUS Tol: Not established.
EMA established MRL: 500 ppb (liver, muscle, fat); 1000 ppb (kidney).		HPLCNS200 ppbIM10 mg/kg Streptomycin daily3Liver2 days (655 ppb)>2 daysHealthyNS[30] 2000
Kidney2 days (914 ppb)>2 days
MuscleND @ 2 days2 days
FatND @ 2 days2 days
Inj. Site2 days (1373 ppb)>2 days
† Manuscript states limit of quantitation as 0.05 ppb; however, the limit of detection is in parts per million, therefore it is likely an error and should be interpreted as 0.05 parts per million. # = number. * Projected time for which residues could still be detected based on study protocol for sample collection time points and sample concentration results. Authors caution readers to critically evaluate these publications to estimate when full residue depletion might occur. Abbreviations: 2×/day: twice daily. LOD: Limit of detection. LOQ: Limit of quantification. EMA: European Medicines Agency. MRL: Maximum residue limit. ND: Not detected. NS: Not specified. Routes of Administration: IMM = intramammary, IM = intramuscular, IV = intravenous, PO = per os, POMF = per os as medicated feed, POMW = per os as medicated water, SC = subcutaneous. § Data points manually extracted use scanning software (Webplot digitizer or UnScanIt 7.0). Units: s = seconds, min = minutes, h = hours, ppt = parts per trillion, ppb = parts per billion, ppm = parts per million.
Table
Table 2. Amphenicol residues in milk or edible tissue samples from sheep or goats following treatment.
Table 2. Amphenicol residues in milk or edible tissue samples from sheep or goats following treatment.
AnalyteSpecies; Breed; Age;
# of Animals per Time Point		Tolerance/
MRL		Analytical MethodLODLOQRoute of Admin-istrationDose & Active Ingredient# of DosesMatrixLast Sampling Time Point (Post-Last Treatment) When Residues WERE DetectedSampling Time Point When NO Residues Were Detected (Post-Last Treatment) *Health StatusAdditional InformationSource/ Year
Chloram-phenicolSheep; Awassi; adult; n = 2US Tol: Not established.
EMA MRL: Not established.		ChemicallyNSNSIM50 mg/kg Chloramphenicol1Milk26 h (1.68 ppm §)>26 hHealthyLactating[39] 1973
Milk26 h (1.82 ppm §)>26 hDiseased-mastitis
BioassayNSNSIM50 mg/kg Chloramphenicol1Milk26 h (1.02 ppm §)>26 hHealthy
Milk26 h (1.54 ppm §)>26 hDiseased-mastitis
Radio-activityNSNSIM50 mg/kg Chloramphenicol (radiolabeled)1Milk13 h (NS)>13 hHealthy
Milk13 h (NS)>13 hDiseased-mastitis
ChloramphenicolSheep; Awassi; adult; n = 1US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIV50 mg/kg Chloramphenicol sodium succinate then 12.5 mg/kg for 2 doses at 90 min interval3Milk24 h (0.65 ppm §)36 hHealthyLactating; Milked 2x/day[24] 1973
Radio-activityNSNSIV50 mg/kg Chloramphenicol (radiolabeled) then 12.5 mg/kg for 2 doses at 90 min interval3Milk48 h (0.81 ppm §)60 h
Chloram-phenicolSheep; Awassi; Adult; n = 2US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIM50 mg/kg Chloramphenicol1Milk56 h (0.85 ppm §)>56 hHealthyLactating; Milked 2×/day[29] 1974
Milk56 h (1.28 ppm §)>56 hDiseased-mastitis
Radio-activityNSNSIM50 mg/kg Chloramphenicol (radiolabeled)1Milk56 h (0.2 ppm §)>56 hHealthy
Milk56 h (0.18 ppm §)>56 hDiseased-mastitis
Chloram-phenicolSheep; Rouge de L’Ouest; adult;
n = 11 study; n = 3 & 2/time pt		US Tol: Not established.
EMA MRL: Not established.		HPLC2 ppbNSIM30 mg/kg Chloramphenicol1Liver24 h (0.35 ppb §)336 hNSNS[40] 1990
Kidney336 h (0.76 ppb §)>336 h
Muscle336 h (2.13 ppb §)>336 h
Inj. Site336 h (4.18 ppb §)>336 h
Chloram-phenicolSheep; Awassi; adult; n = 2US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIV50 mg/kg Chloramphenicol sodium succinate1MilkNSNSHealthyLactating; Milked 2×/day[41] 1975
Florfenicol amineSheep; Polypay; NS; n = 25 study;
n = 5/time pt		US Tol: Not established.
EMA MRL by extension from bovine to ovine: 3000 ppb (liver);
300 ppb (kidney);
200 ppb (muscle).		HPLCNSNSSC40 mg/kg Florfenicol daily3Liver40 days (1.99 ppm)>40 daysNSNS[42] 2006
Kidney40 days (0.17 ppm)>40 days
Muscle40 days (0.08 ppm)>40 days
Fat40 days (0.01 ppm)>40 days
Inj. Site40 days (0.15 ppm)>40 days
Florfenicol amineSheep; mixed breed; 6–7 months; n = 26 study;
n = 5/time pt		US Tol: Not established.
EMA MRL by extension from bovine to ovine: 3000 ppb (liver);
300 ppb (kidney);
200 ppb (muscle).		HPLCNSLiver: 0.32 ppmSC40 mg/kg Florfenicol daily3Liver40 days (NS)>40 daysHealthyNS[43] 2008
Kidney: 0.1 ppmKidney40 days (NS)>40 days
Muscle: 0.05 ppmMuscle40 days (NS)>40 days
Fat: 0.04 ppmFat40 days (NS)>40 days
Inj. Site: 0.05 ppmInj. Site40 days (NS)>40 days
Thiam-phenicolSheep; crossbred; adult; n = 16 study;
n = 4/time pt.		US Tol: Not established.
EMA MRL by extension from bovine to ovine: 50 ppb (liver, kidney, muscle, fat, milk).		HPLC5 ppb21 ppbIM30 mg/kg Thiamphenicol daily5LiverND @ 4 days4 daysHealthyNS[44] 2000
Kidney4 days (40.2 ppb)8 days
Muscle<LOD @ 4 days4 days
Fat4 days (342.5 ppb)8 days
Chloram-phenicolGoat; Desi; 9–12 months; n = NSUS Tol: Not established.
EMA MRL: Not established.		ColorimetricNSNSIM10 mg/kg Chloramphenicol1Milk24 h (2.16 ppm)2 daysHealthyLactating[45] 1983
IM30 mg/kg Chloramphenicol1Milk96 h (3.33 ppm)>4 daysHealthy
Chloram-phenicolGoat; NS; Adult; n = 2US Tol: Not established.
EMA MRL: Not established.		HPLC5 ppbNSIM600 mg Chloram-phenicol1Milk8 h (0.077 ppm)1 dayHealthyLactating[46] 1980
IMM600 mg Chloram-phenicol1Milk24 h (0.026 ppm)32 hHealthy
Thiam-phenicolGoat; Saanen & crossbred; adult; n = 6US Tol: Not established.
EMA MRL by extension from bovine to ovine: 50 ppb (liver, kidney, muscle, fat, milk).		HPLCNSNSIV50 mg/kg Thiamphenicol1Milk12 h (4.92 ppm §)>12 hHealthyLate
lactation		[35] 1991
IM50 mg/kg Thiamphenicol1Milk12 h (4.90 ppm §)>12 hHealthy
FlorfenicolGoat; Saanen & crossbred; adult; n = 10US Tol: Not established.
EMA MRL: Not established.		HPLCNSNSIV25 mg/kg Florfenicol1Milk8 h (0.21 ppm §)>8 hHealthyMid-lactation[36] 1991
IM25 mg/kg Florfenicol1Milk8 h (0.11 ppm §)>8 hHealthy
§ Data points manually extracted use scanning software (Webplot digitizer or UnScanIt 7.0). # = number. * Projected time for which residues could still be detected based on study protocol for sample collection time points and sample concentration results. Authors caution readers to critically evaluate these publications to estimate when full residue depletion might occur. Abbreviations: 2×/day: twice daily. LOD: Limit of detection. LOQ: Limit of quantification. EMA: European Medicines Agency. MRL: Maximum residue limit. ND: Not detected. NS: Not specified. Routes of Administration: IMM = intramammary, IM = intramuscular, IV = intravenous, PO = per os, POMF = per os as medicated feed, SC = subcutaneous. Units: s = seconds, min = minutes, h = hours, ppb = parts per billion, ppm = parts per million.
Table
Table 3. Penicillin and penicillin-derivative residues in milk or edible tissue samples from sheep or goats following treatment.
Table 3. Penicillin and penicillin-derivative residues in milk or edible tissue samples from sheep or goats following treatment.
AnalyteSpecies; Breed; Age;
# of Animals		Tolerance/MRLAnalytical MethodLODLOQRoute of Admin-istrationDose & Active Ingredient# of DosesMatrixLast Sampling Time Point (Post-Last Treatment) When Residues WERE DetectedSampling Time Point When NO Residues Were Detected (Post-Last Treatment) *Health StatusAdditional InformationSource/ Year
AmoxicillinSheep; Texel; adult; n = 12US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIM10 mg/kg Amoxicillin sodium1Milk500 min (0.03 ppm §)>500 minHealthy &
Diseased- mastitis		Lactating[47] 1979
AmoxicillinGoats; Saanen; adult; n = 6US Tol: Not established.
EMA MRL: Not established.		Bioassay0.001 ppmNSIMM200 mg Amoxicillin trihydrate; 50 mg potassium clavulanate; 10 mg prednisolone combo product at 8 h intervals3Milk5 days (0.07 ppm §)>5 daysHealthyLactating;
Milked 2×/day;
1 syringe/ gland		[49] 1989
AmoxicillinSheep; Texel; adult; n = 12US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIM10 mg/kg Amoxicillin trihydrate1Milk500 min (0.06 ppm §)>500 minHealthy &
Diseased- mastitis		Lactating[47] 1979
AmoxicillinSheep; Friesland; adult; n = 6US Tol: Not established.
EMA MRL: Not established.		Bioassay0.001 ppmNSIMM200 mg Amoxicillin trihydrate; 50 mg potassium clavulanate; 10 mg prednisolone combo product at 8 h intervals3Milk7 days (0.003 ppm §)>7 daysHealthyLactating;
Milked 2×/day;
1 syringe/ gland		[51] 1989
AmoxicillinSheep; Comisana; adult; n = 10US Tol: Not established.
EMA MRL: Not established.		HPLC1.5 ppb2.5 ppbIM12.5 mg/kg Amoxicillin trihydrate
(long acting)		1Milk132 h (1.5 ppb)6 daysHealthyLactating;
Milked 2×/day		[57] 2002
AmoxicillinSheep; domestic dairy breed; adult;
n = 10		US Tol: Not established.
EMA MRL: Not established.		Bioassay3 ppb4 ppbIMM w/
IM		200 mg Amoxicillin trihydrate, 50 mg potassium clavulanate, 10 mg prednisolone combination product (IMM) at 12 h intervals
co-administered with 140 mg/35 mg per mL amoxicillin trihydrate/ clavulanic acid (IM) at 24 h intervals		5 (IMM); 2(IM)Milk192 h (4.5 ppb)>192 hDiseased- mastitisLactating; 1 syringe/gland[52] 2009
AmoxicillinSheep; crossbred; NS; n = 36 study;
n = 4/time pt
Dairy type; adult; n = 20		US Tol: Not established.
EMA MRL: Not established.		LC-MS5.8 ppb25.6 ppbIM7 mg/kg
Amoxicilllin † daily		5LiverNS48 hHealthyNS[48] 2012
KidneyNS48 h
MuscleNS48 h
FatNS48 h
Inj. Site64 days (25.6 ppb)>64 days
NSNSNSIM7 mg/kg
Amoxicilllin † daily		5Milk120 h (2.09 ppb)>120 hHealthyLactating;
Milked 2×/day
AmpicillinSheep; Texel; adult; n = 12US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIM10 mg/kg Ampicillin sodium1Milk8 h (0.03 §)>8 hHealthyLactating[47] 1979
10 h (0.03 §)>10 hDiseased- mastitis
AmpicillinGoats; Saanen; adult; n = 24 studyUS Tol: Not established.
EMA MRL: Not established.		HLPC1.5 ppb2.2 ppbIM15 mg/kg Amoxicilllin † (long acting) at 72 h interval2Milk168 h (6.0 ppb)180 hHealthyMid-lactation;
Milked 2×/day		[54] 2010
AmpicillinSheep; Texel; adult; n = 12US Tol: Not established
EMA MRL: Not established.		BioassayNSNSIM10 mg/kg Ampicillin trihydrate1Milk12 h (0.04 ppm §)>12 hHealthyLactating[47] 1979
12 h (0.1 ppm §)>12 hDiseased- mastitis
AmpicillinSheep; NS; adult; n = 4US Tol: Not established.
EMA MRL: Not established.		NSNSNSIMM250,000 IU Ampicillin trihydrate1Milk72 h (0.11 ppm)96 hNSLactating; Half syringe per gland[58] 1977
CloxacillinGoats; Saanen; adult; n = 8US Tol: Not established.
EMA MRL: Not established.		Bioassay0.02 ppmNSIMM200 mg Cloxacillin at 48 h intervals3Milk13 h (0.15 ppm§)>13 hHealthyLate lactation;
Milked 2×/day. Only one half/gland treated.		[53] 1984
Diclox-acillinSheep; Sarda; 2–3.5 years;
n = 4		US Tol: Not established.
EMA MRL: Not established.		HPLCNS0.02 ppmIMM100 mg/half Dicloxacillin at 12 h intervals.3Milk60 h (0.029 ppm)72 hHealthyLactating, High production;
Milked 2x/day		[50] 2000
72 h (0.026 ppm)84 hHealthyLactating, Low production;
Milked 2×/day
NafcillinGoats; NS; Adults; n = 220US Tol: Not established.
EU MRL by extension from bovine to all ruminants: 30 ppb (milk).		Bioassay0.012 ppm0.015 ppmIMM300,000 IU Procaine benzylpenicillin;
100 mg dihydro-streptomycin; 100 mg nafcillin		1MilkNS3 daysHealthyDry off period (mean 61.0 ± 14.3 days SD (range 23–156 days); 1 tube per gland before drying off. Sample collected after kidding[27] 1995
NafcillinSheep; Lacaune; adult; n = 8US Tol: Not established.
EMA MRL by extension from bovine to all ruminants: 30 ppb (milk).		Bioassay0.02 ppmNSIMM300,000 IU Procaine benzylpenicillin; 100 mg dihydrostreptomycin; 100 mg nafcillin1MilkND2 daysHealthyDry off period (mean 112 days (range 85–223 days); 1 tube per gland before drying off. Sample collected after lambing[28] 1995
Pen-ethamateGoats; NS; Adult; n = 2US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIM200,000 IU Penethamate (oil)
200,000 IU Penethamate (aqueous)		1Milk1 day (0.004 U/mL)>1 dayNSLactating[59] 1966
Milk12 h (0.075 U/mL)1 day
IM500,000 IU Penethamate (oil)
500,000 IU Penethamate (aqueous)		1Milk1 day (0.04 U/mL)>1 day
Milk1 day (0.2 U/mL)>1 day
PenicillinSheep; Awassi; Adult; n = 2US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIM20 mg/kg Penicillin †1Milk12 h (0.02 ppm §)1 dayHealthyLactating[29] 1974
RadioactivityNSNS Milk56 h (0.03 ppm §)>56 hDiseased- mastitis
BioassayNSNSIM20 mg/kg Benzylpenicillin-14C1Milk48 h (0.01 ppm §)56 hHealthy
RadioactivityNSNS Milk12 h (0.02 ppm §)1 dayDiseased- mastitis
PenicillinGoats; NS; Adult; n = 2US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIM200,000 IU Procaine penicillin (oil)1

1		Milk1 day (0.008 U/mL)>1 dayNSLactating[59] 1966
200,000 IU Procaine penicillin (aqueous)Milk12 h (0.012 U/mL)1 day
IM500,000 IU Procaine penicillin (oil)Milk1 day (0.07 U/mL)>1 day
500,000 IU Procaine penicillin (aqueous)Milk1 day (0.02 U/mL)>1 day
PenicillinGoats; NS; Adults; n = 217US Tol: Not established.
EMA MRL: Not established.		Bioassay0.002 IU/mL0.004 IU/mLIMM300,000 IU Procaine benzylpenicillin; 100 mg dihydro-streptomycin; 100 mg nafcillin combo product1MilkNS7 daysHealthyDry off period (mean 61.0 ± 14.3 days SD (range 23–156 days). 1 tube per gland before drying off. Sample collected after kidding[27] 1995
PenicillinGoats; dairy type; 2–7 years; n = 10US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIMM100,000 IU Penicillin G procaine at 12 h intervals3Milk60 h (0.49 ppm §)>60 hHealthyEarly & mid-lactation; Milked 2x/day; 1 syringe per gland[60] 1984
PenicillinSheep; NS; NS; n = 2US Tol: Zero.
EMA MRL: Not established.		LC-MS0.005 ppmNSIM1500 mg Benzylpenicillin daily3Liver2 days (0.24 ppm)>2 daysNSNS[56] 1996
Kidney2 days (0.87 ppm)>2 days
Muscle2 days (0.02 ppm)>2 days
PenicillinSheep; Lacaune; adult; n = 8US Tol: Zero.
EMA MRL: Not established.		Bioassay0.006 ppmNSIMM300,000 IU Procaine benzylpenicillin; 100 mg dihydro-streptomycin; 100 mg nafcillin1Milk3 days (0.01 ppm §)4 daysHealthyDry off period (mean 112 days (range 85–223 days); 1 tube per gland before drying off. Sample collected after lambing[28] 1995
PenicillinSheep; NS; 14–17 months;
n = 10 study;
n = 10/time pt		US Tol: Zero.
EMA MRL: Not established.		Bioassay0.0125 ppmNSIM3000 IU/lb Penicillin G procaine daily4LiverNS9 daysHealthyNS[61] 2010
KidneyNS9 days
MuscleNS9 days
FatNS9 days
Inj. SiteNS9 days
PenicillinSheep; Awassi; adult; n = 3US Tol: Zero.
EMA MRL: Not established.		BioassayNSNSIV20 mg/kg Penicillin †, then 10 mg/kg for 4 doses 45 min interval5Milk36 h (0.01 ppm §)48 hHealthyLactating;
Milked 2×/day		[24] 1973
RadioactivityNSNSIV20 mg/kg Penicillin † (radiolabeled) then 10 mg/kg for 4 doses 45 min interval5Milk8 h (0.08 ppm §)10 h
PenicillinSheep; Sardinian; Adult; n = 5US Tol: Zero.
EMA MRL: Not established.		HPLC2.6 ppb8.8 ppbIM24 mg/kg Penicillin G sodium1Milk8 days (0.01 ppm)
> 8 daysNSLactating;
Milked 2×/day		[55] 1998
IMM24 mg/kg Penicillin G sodium1Milk7 days (0.001 ppm)8 days
PenicillinSheep; domestic dairy breed; adult;
n = 10		US Tol: Zero.
EMA MRL: Not established.		Bioassay3 ppb4 ppbIMM co-admin w/IM1,000,000 IU Benzylpenicillin (IMM) daily co- administered with 250,000 IU benzylpenicillin (IM) at 24 h intervals.5 (IMM)
2 (IM)		Milk192 h (9.9 ppb)>192 hDiseasedLactating;
1 syringe/gland		[52] 2009
† Salt form unclear or not stated in article. # = number. * Projected time for which residues could still be detected based on study protocol for sample collection time points and sample concentration results. Authors caution readers to critically evaluate these publications to estimate when full residue depletion might occur. § Data points manually extracted use scanning software (Webplot digitizer or UnScanIt 7.0). Abbreviations: 2×/day: twice daily. LOD: Limit of detection. LOQ: Limit of quantification. EMA: European Medicines Agency. MRL: Maximum residue limit. ND: Not detected. NS: Not specified. Routes of Administration: IMM = intramammary, IM = intramuscular, IV = intravenous, PO = per os, POMF = per os as medicated feed, SC = subcutaneous. Units: s = seconds, min = minutes, h = hours, ppb = parts per billion, ppm = parts per million, mL = milliliter.
Table
Table 4. Cephalosporin residues in milk or edible tissue samples from sheep or goats following treatment.
Table 4. Cephalosporin residues in milk or edible tissue samples from sheep or goats following treatment.
AnalyteSpecies; Breed; Age; # of AnimalsTolerance/MRLAnalytical MethodLODLOQRoute of Admini-strationDose & Active Ingredient# of DosesMatrixLast Sampling Time Point (Post-Last Treatment) When Residues WERE DetectedSampling Time Point When NO Residues Were Detected (Post-Last Treatment) *Health StatusAdditional InformationSource/Year
CefepimeGoat; NS; Adult;
n = 10		US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIV20 mg/kg Cefepime1Milk12 h (0.17 ppm)>12 hHealthyLactating;
Milked 2×/day		[62] 2004
IM20 mg/kg Cefepime1Milk12 h (0.25 ppm)>12 h
CefepimeGoat; NS; 1 year;
n = 5		US Tol: Not established.
EMA MRL: Not established.		HPLC1.15 ppb3.49 ppmIM50 mg/kg Cefepime1Milk4 h (5.14 ppm§)> 4 hHealthyLactating[72] 2010
CefonicidGoat; Muriano-Granadina; 2–4 years; n = 6US Tol: Not established.
EMA MRL: Not established.		HPLC500 ppb750 ppbIV10 mg/kg Cefonicid sodium1Milk<LOQ @ 1 h1 hHealthyLactating;
Milked 1×/day		[63] 2020
IM10 mg/kg Cefonicid sodium1Milk<LOQ @ 1 h1 h
SC10 mg/kg Cefonicid sodium1Milk<LOQ @ 1 h1 h
SC20 mg/kg Cefonicid sodium1Milk<LOQ @ 1 h1 h
Cef-quinomeGoat; Zaraibi; 30–36 months; n = 5US Tol: Not established.
EMA MRL: Not established.		Bioassay0.009 ppm0.027 ppmIV3 mg/kg Cefquinome sulfate1Milk48 h (0.02 ppm §)>2 daysHealthyLactating;
Milked 1×/day		[67] 2015
HPLC0.006 ppm0.017 ppmMilk48 h (0.01 ppm §)>2 days
Bioassay0.009 ppm0.027 ppmIV3 mg/kg Cefquinome sulfate1Milk48 h (0.02 ppm §)>2 daysDiseased-Mastitis
HPLC0.006 ppm0.017 ppmMilk48 h (0.02 ppm §)>2 days
Cef-quinomeGoat; Zaraibi; 30–36 months; n = 5US Tol: Not established.
EMA MRL: Not established.		HPLC0.006 ppm0.018 ppmIMM75 mg Cefquinome sulfate1Milk120 h (0.01 ppm §)>120 hHealthyEarly & mid-lactating; 1 full tube per gland
1 full tube into single infected udder half		[68] 2019
IMM75 mg Cefquinome sulfate1Milk96 h (0.01 ppm §)120 hDiseased-Mastitis
Cef-tazidimeGoat; Creole; Adult; n = 6US Tol: Not established.
EMA MRL: Not established.		Bioassay0.125 ppm0.3 ppmIV10 mg/kg Ceftazidime1Milk12 h (0.52 ppm §)>12 hHealthyLactating;
Milked 2x/day		[73] 2011
IM10 mg/kg Ceftazidime1Milk12 h (0.54 ppm §)>12 h
CeftiofurGoat; Alpine & Alpine-Saanen;
4 years; n = 6		US Tol: 100 ppb (milk).
EMA MRL extrapolated from bovine to all mammalian species: 100 ppb (milk).		HPLCNS0.05 ppmIV2.2 mg/kg Ceftiofur sodium1Milk24 h (NS)2 daysHealthyLactating;
Milked 2×/day		[71] 1994
IM2.2 mg/kg Ceftiofur sodium daily5Milk24 h (NS)2 days
CeftiofurSheep; NS; Adult; n = 9US Tol: 100 ppb (milk).
EMA MRL by extension from bovine to ovine: 100 ppb (milk).		HPLCNSNSIM2 mg/kg Ceftiofur sodium daily5Milk<LOQ @ 12 h12 hHealthyLactating[74] 2006
CeftiofurGoat; mixed dairy type; 28 months;
n = 5		US Tol: 100 ppb (milk).
EMA MRL extrapolated from bovine to all mammalian species: 100 ppb (milk).		LC-MSNS20 ppbIMM125 mg Ceftiofur hydrochloride daily2Milk72 h (37 ppb)4 daysHealthyMid- & late lactation;
Milked 2×/day. Left udder half infused.		[75] 2015
CeftriaxoneGoat; Dairy type; 1.5–2 years; n = 6US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIV20 mg/kg Ceftriaxone sodium1Milk2 h (0.11 ppm)2.5 hHealthyLactating[64] 2013
CeftriaxoneGoat; NS; 2–2.5 years; n = 10US Tol: Not established.
EMA MRL: Not established.		BioassayNS0.2 ppmIV20 mg/kg Ceftriaxone1Milk8 h (0.36 ppm)10 hHealthyLactating[65] 2005
IM20 mg/kg Ceftriaxone1Milk10 h (0.26 ppm)12 h
CeftriaxoneSheep; native breed; 2–3 years;
n = 6		US Tol: Not established.
EMA MRL: Not established.		BioassayNS0.1 ppmIV10 mg/kg Ceftriaxone1Milk10 h (0.22 ppm)12 hHealthyLactating;
Milked 2×/day		[76] 2006
IM10 mg/kg Ceftriaxone1Milk12 h (0.19 (ppm)24 h
Ceph-acetrileSheep; Texel; adult; n = 6US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIM12 mg/kg Benzathine cephacetrile1Milk24 h (NS)>1 dayHealthyLactating[66] 1977
CephalexinGoat; NS; 1 year;
n = 2		US Tol: Not established.
EMA MRL: Not established.		HPLC0.165 ppmNSIM10 mg/kg Cephalexin1Milk72 h (0.07 ppm §)>3 daysNSLactating[77] 2019
CephalexinSheep; Awassi; adult; n = 10US Tol: Not established.
EMA MRL: Not established.		Bioassay0.1 ppmNSIM10 mg/kg Cephalexin1Milk8 h (0.46 ppm §)>8 hHealthyLate lactation[69] 1988
Ceph-alothinGoat; Creole; adult; n = 20US Tol: Not established.
EMA MRL: Not established.		HPLC0.01 ppmNSIV10 mg/kg Cephalothin1Milk12 h (0.31 ppm §)>12 hHealthyLactating;
Milked 2x/day		[78] 2004
Ceph-alothinGoat; Creole; adult; n = 22 study; groups of 8, 8 and 6US Tol: Not established.
EMA MRL: Not established.		HPLC0.01 ppmNSIV20 mg/kg Cephalothin1Milk6 h (0.08 ppm §)8 hHealthyEarly lactation; Restricted diet[79] 2007
IV20 mg/kg Cephalothin1Milk8 h (0.28 ppm §)10 hEarly lactation; Restricted diet + additional energy
IV20 mg/kg Cephalothin1Milk12 h (0.12 ppm §)14 hEarly lactation; Balanced diet
CephapirinGoat; French Alpine; 1–7 years; n = 20US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIMM200 mg Cephapirin at 12 h intervals2MilkND @ 192 h8 daysHealthyMid-lactation; 1 full tube into R half udder[70] 1986
IMM200 mg Cephapirin at 12 h intervals3MilkND @ 192 h8 days
CephapirinGoat; dairy type; 2–7 years; n = 10US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIMM200 mg Sodium cephapirin at 12 h intervals2Milk48 h (0.03 ppm §)60 hHealthyEarly & mid- lactation; Milked 2×/day; 1 full tube into each gland[60] 1984
CephradineGoat; NS; adult;
n = 4		US Tol: Not established.
EMA MRL: Not established.		Spectrophoto-metrically0.2 ppmNSIM10 mg/kg Cephradine1Milk8 h (1.55 ppm)12 hHealthy and DiseasedLactating[80] 1994
IM10 mg/kg Cephradine at 12 h intervals3Milk8 h (1.28 ppm)12 h
IM10 mg/kg Cephradine at 12 h intervals5Milk8 h (3.02 ppm)12 h
IM10 mg/kg Cephradine at 12 h intervals7Milk8 h (2.78 ppm)12 h
IM10 mg/kg Cephradine at 12 h intervals9Milk8 h (3.02 ppm)12 h
§ Data points manually extracted use scanning software (Webplot digitizer or UnScanIt 7.0). # = number. * Projected time for which residues could still be detected based on study protocol for sample collection time points and sample concentration results. Authors caution readers to critically evaluate these publications to estimate when full residue depletion might occur. Abbreviations: 1×/day: once daily. 2×/day: twice daily. LOD: Limit of detection. LOQ: Limit of quantification. EMA: European Medicines Agency. MRL: Maximum residue limit. ND: Not detected. NS: Not specified. Routes of Administration: IMM = intramammary, IM = intramuscular, IV = intravenous, SC = subcutaneous. Units: s = seconds, min = minutes, h = hours, ppb = parts per billion, ppm = parts per million.
Table
Table 5. Fluoroquinolone residues in milk or edible tissue samples from sheep or goats following treatment.
Table 5. Fluoroquinolone residues in milk or edible tissue samples from sheep or goats following treatment.
AnalyteSpecies; Breed; Age; # of AnimalsTolerance/ MRLAnalytical MethodLODLOQRoute of Admini-strationDose & Active Ingredient# of DosesMatrixLast Sampling Time Point (Post-Last Treatment) When Residues WERE DetectedSampling Time Point When NO Residues Were Detected (Post-Last Treatment) *Health StatusAdditional InformationSource/ Year
CiprofloxacinGoats; NS; adult;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		Bioassay0.05 ppmNSIV4 mg/kg Ciprofloxacin1Milk24 h (0.07 ppm)30 hHealthyLactating[81] 2014
CiprofloxacinGoats; Baladi; 30–36 months; n = 5US Tol: Prohibited.
EMA MRL: Not established.		Bioassay0.01 ppmNSIV5 mg/kg Ciprofloxacin1Milk10 h (0.11 ppm)18 hHealthyLactating[82] 1998
IM5 mg/kg Ciprofloxacin1Milk10 h (0.07 ppm)18 h
IM5 mg/kg Ciprofloxacin daily5Milk3 days (0.07 ppm)4 days
DanofloxacinGoats; Murciano-Granadina; 1.5–3 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		HPLC0.005 ppm0.015 ppmSC6 mg/kg Danofloxacin1Milk36 h (0.01 ppm §)48 hHealthyMid-lactation; Milked 2×/day[83] 2007
DanofloxacinSheep; Manchega;
2–4 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		HPLC0.005 ppm0.015 ppmSC6 mg/kg Danofloxacin1Milk36 h (0.02 ppm §)48 hHealthyMid-lactation; Milked 2×/day[83] 2007
DanofloxacinSheep; Assaf; adult; n = 12US Tol: Prohibited.
EMA MRL: Not established.		Bioassay0.04 ppmNSIV1.25 mg/kg Danofloxacin1Milk24 h (0.1 ppm §)>1 dayHealthyMid-lactation[99] 1997
IM1.25 mg/kg Danofloxacin1Milk24 h (0.07 ppm §)>1 day
DanofloxacinSheep; Assaf; 2–3 years;
n = 5		US Tol: Prohibited.
EMA MRL: Not established.		HPLC4 ppb5 ppbIM1.25 mg/kg1Milk24 h (0.07 ppm §)>24 hHealthyMid-lactation; Milked 2×/day[96] 2011
IM1.25 mg/kg co-administered with 0.2 mg/kg ivermectin1Milk24 h (0.09 ppm §)>24 h
DanofloxacinSheep; Assaf; 2–3 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		HPLC4 ppb5 ppbIM1.25 mg/kg Danofloxacin1Milk24 h (0.08 ppm §)>24 hHealthyMid-lactation; Milked 2×/day[97] 2013
IM1.25 mg/kg Danofloxacin + soy diet1Milk24 h (0.1 ppm §)>24 h
IM1.25 mg/kg Danofloxacin + Gen-daid (isoflavones)1Milk24 h (0.03 ppm §)>24 h
DanofloxacinSheep; Assaf; 2–3 years;
n = 6		US Tol: Prohibited
EMA MRL: Not established.		HPLCNS100 ppbIM1.25 mg/kg Danofloxacin1Milk24 h (0.03 ppm §)>24 hHealthyMid-lactation; Milked 2×/day[100] 2013
IM1.25 mg/kg Danofloxacin co-administered with 1 mg/kg IV triclabendazole1Milk24 h (0.25 ppm §)>24 h
DanofloxacinSheep; Assaf; adult; n = 6US Tol: Prohibited.
EMA MRL: Not established.		HPLCNS19 ppbIM1.25 mg/kg Danofloxacin standard diet1Milk24 h (0.05 ppm §)> 24 hHealthyMid-lactation; Milked 2×/day[101] 2018
IM1.25 mg/kg Danofloxacin w/ 10% flaxseed diet1Milk24 h (0.04 ppm §)>24 hr
IM1.25 mg/kg Danofloxacin w/ 15% flaxseed diet1Milk24 h (0.05 ppm §)> 24 h
DifloxacinGoats; Murciano-Granadina;
4–5 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		HPLCNS10 ppbIV5 mg/kg Difloxacin1Milk48 h (0.02 ppm §)72 hHealthyLactating; Milked 1×/day[102] 2010
SC5 mg/kg Difloxacin1Milk36 h (0.02 ppm §)48 h
SC15 mg/kg Difloxacin (long acting)1Milk144 h (0.59 ppm §)>144 h
DifloxacinGoats; Murciano-Granadina;
4–5 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established		HPLCNS10 ppbSC15 mg/kg Difloxacin (long acting)1Milk144 h (0.07 ppm §)>144 hHealthyLactating; Milked 1x/day[84] 2011
EnrofloxacinGoats; Sham;
2–3 years;
n = 10		US Tol: Prohibited.
EMA MRL extension from bovine to all food producing species: 100 ppb (milk).		BioassayNS0.02 ppmIV5 mg/kg Enrofloxacin1Milk24 h (0.06 ppm)36 hHealthyMid-lactation; Milked 2x/day[85] 2003
IV5 mg/kg Enrofloxacin co-administered with 7.5 mg/kg albendazole PO1Milk12 h (0.11 ppm)24 h
IM5 mg/kg Enrofloxacin1Milk36 h (0.08 ppm)48 h
IM5 mg/kg Enrofloxacin co-administered with 7.5 mg/kg albendazole PO1Milk24 h (0.16 ppm)36 h
EnrofloxacinGoats; Murciano-Granadina;
2.5–3.5 years; n = 6		US Tol: Prohibited.
EMA MRL extension from bovine to all food producing species: 100 ppb (milk).		HPLCNSNSSC5 mg/kg Enrofloxacin1MilkNSNS †HealthyLactating[103] 2009
Ciprofloxacin
EnrofloxacinGoats; Murciano-Granadina;
2.5–3.5 years; n = 6		US Tol: Prohibited.
EMA MRL extension from bovine to all food producing species: 100 ppb (milk).		HPLCNSNSIV5 mg/kg Enrofloxacin1MilkNSNS ‡HealthyLactating[86] 2009
SC5 mg/kg Enrofloxacin
(long acting)		1MilkNSNS Ϙ
EnrofloxacinGoats; NS;
1.5–2 years;
n = 6		US Tol: Prohibited.
EMA MRL extension from bovine to all food producing species: 100 ppb (milk).		Bioassay0.01 ppmNSSC5 mg/kg Enrofloxacin1Milk30 h (0.08 ppm)36 hHealthyLactating[87] 2009
SC5 mg/kg Enrofloxacin SC, pretreated with 70 mg/kg probenecid PO1Milk36 h (0.02 ppm)48 h
EnrofloxacinSheep; NS; Neo-natalUS Tol: Prohibited.
EMA MRL by extension from bovine to ovine: 300 ppb (liver); 200 ppb (kidney); 100 ppb (muscle, fat).		HPLCNS10 ppbPO7.5 mg/kg Enrofloxacin1LiverNSEnro ∼: 16 daysHealthyNS[104] 1998
Cipro ≈: 16 days
KidneyNSEnro ∼: 16 days
Cipro ≈: 16 days
CiprofloxacinMuscleNSEnro ∼: 16 days
Cipro ≈: 16 days
FatNSEnro ∼: 16 days
Cipro ≈: 16 days
EnrofloxacinSheep; crossbred;
2–4 years;
n = 6		US Tol: Prohibited.
EMA MRL extension from bovine to all food producing species: 100 ppb (milk).		BioassayNS0.018 ppmIV2.5 mg/kg Enrofloxacin1Milk24 h (0.13 ppm §)>24 hHealthyLactating; Milked 2×/day[88] 2003
IM2.5 mg/kg Enrofloxacin1Milk24 h (0.15 ppm §)>24 h
EnrofloxacinSheep; Assaf; 2–3 years;
n = 12		US Tol: Prohibited.
EMA MRL extension from bovine to all food producing species: 100 ppb (milk).		HPLCNSNSIV2.5 mg/kg Enrofloxacin1Milk24 h (0.09 ppm §)> 24 hHealthyMid-lactation; Milked 2×/day[98] 2006
IV2.5 mg/kg Enrofloxacin co-administered with 0.8 mg/kg genistein IM1Milk24 h (0.05 ppm §)> 24 h
IV2.5 mg/kg Enrofloxacin co-administered with 2 mg/kg albendazole IV1Milk24 h (0.06 ppm §)> 24 h
IbafloxacinGoats; Murciano-Granadina;
3–4 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		HPLCNS10 ppbIV15 mg/kg Ibafloxacin1Milk6 h (0.05 ppm §)12 hHealthyLactating[89] 2007
LevofloxacinGoats; NS;
3–5 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		BioassayNS0.05 ppmIV4 mg/kg Levofloxacin hemihydrate1Milk36 h (0.04 ppm §)48 hHealthyLactating[90] 2009
IM4 mg/kg Levofloxacin hemihydrate1Milk36 h (0.06 ppm §)48 h
Marbo-floxacinGoats; Anglo-nubian;
3–5 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		HPLCNS0.025 ppmIV5 mg/kg Marbofloxacin1Milk36 h (0.06 ppm §)48 hHealthyLactating[91] 2017
IM5 mg/kg Marbofloxacin1Milk36 h (0.07 ppm §)48 h
Marbo-floxacinSheep; Assaf; adult; n = 15US Tol: Prohibited.
EMA MRL: Not established.		Bioassay0.05 ppm ^0.04 ppm ^IV2.5 mg/kg Marbofloxacin1Milk24 h (0.05 ppm §)>24 hHealthyMid-lactation[92] 1997
IM2.5 mg/kg Marbofloxacin1Milk24 h (0.23 ppm §)> 24 h
MoxifloxacinGoats; Murciano-Granadina;
3–4 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		HPLCNS10 ppbIV5 mg/kg Moxifloxacin1Milk32 h (0.01 ppm §)48 hHealthyLactating[93] 2006
SC5 mg/kg Moxifloxacin1Milk32 h (0.05 ppm §)48 h
MoxifloxacinGoats; Murciano-Granadina;
3–4 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		HPLCNS10 ppbIM5 mg/kg Moxifloxacin1Milk32 h (0.01 ppm §)48 hHealthyLactating[105] 2007
NorfloxacinSheep; crossbred; adult; n = 6US Tol: Prohibited.
EMA MRL: Not established.		HPLC0.07 ppmNSIV25 mg/kg Norfloxacin nicotinate1Milk24 h (10 ppm)>24 hHealthyLactating[106] 1994
OrbifloxacinGoats; Murciano-Granadina;
5–6 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		HPLC20 ppb25 ppbIV2.5 mg/kg Orbifloxacin1Milk12 h (0.04 ppm §)24 hHealthyLactating[107] 2007
SC2.5 mg/kg Orbifloxacin1Milk24 h (0.03 ppm §)36 h
IM2.5 mg/kg Orbifloxacin1Milk12 h (0.05 ppm §)24 h
OrbifloxacinSheep; Barky; 4–6 years;
n = 6		US Tol: Prohibited.
EMA MRL: Not established.		BioassayNS0.04 ppmIV2.5 mg/kg Orbifloxacin1Milk24 h (0.09 ppm §)30 hHealthyLactating[94] 2009
IM2.5 mg/kg Orbifloxacin1Milk30 h (0.06 ppm §)48 h
PefloxacinGoats; Egyptian; 2 years; n = 5US Tol: Prohibited.
EMA MRL: Not established.		BioassayNS0.078 ppmIV10 mg/kg Pefloxacin1Milk10 h (0.1 ppm)12 hHealthyLactating[95] 2002
IM10 mg/kg Pefloxacin1Milk10 h (0.1 ppm)12 h
FlumequineSheepUS Tol: Not established.
EMA established MRL:
100 ppb (liver);
300 ppb (kidney);
50 ppb (muscle, fat, skin).		HPLCNS100 ppbIM12 mg/kg Flumequine for first dose, then 6 mg/kg at 12 h intervals10LiverFlu: 78 h (13.8 ppb)Flu: >78 hNSNS[108] 1997
7-OH: 48 h(10.24 ppb)7-OH: 60 h
KidneyFlu: 78 h (38.6 ppb)Flu: >78 h
7-OH: 78 h (4.5 ppb)7-OH: >78 h
MuscleFlu: 78 h (9.0 ppb)Flu: >78 h
7-Hydroxy-flumequine7-OH: 18 h (15.3 ppb)7-OH: 30 h
FatFlu: 78 h (52.5 ppb)Flu: >78 h
7-OH: ND @ 18 h7-OH: 18 h
Inj. SiteFlu: 90 h (10 ppb)Flu: >90 h
7-OH: 30 h (13.5 ppb)7-OH: 42 h
FlumequineSheep; NS; NS;
n = 20 study;
n = 4/time pt		US Tol: Not established.
EMA established MRL:
100 ppb (liver);
300 ppb (kidney);
50 ppb (muscle, fat, skin).		HPLCNS5 ppbIM12 mg/kg Flumequine for first dose, then 6 mg/kg at 12 h intervals6Liver78 h (19.3 ppb)>78 hHealthyNS[109] 1998
Kidney78 h (62.5 ppb)>78 h
Muscle78 h (12.4 ppb)>78 h
Fat78 h (171.9 ppb)>78 h
§ Data points manually extracted use scanning software (Webplot digitizer or UnScanIt 7.0). # = number. † Enrofloxacin parent half-life reported = 2.74 h; Ciprofloxacin metabolite half-life = 4.79 h. ‡ Intravenous half-life reported= 5.39 h. Ϙ Subcutaneous half-life reported= 14.85 h. ∼ Enro: Enrofloxacin. ≈ Cipro: Ciprofloxacin. * Projected time for which residues could still be detected based on study protocol for sample collection time points and sample concentration results. Authors caution readers to critically evaluate these publications to estimate when full residue depletion might occur. ^ LOD and LOQ values should be confirmed with authors; however, they are reported as published. Abbreviations: 1×/day: once daily. 2×/day: twice daily. 7-OH: 7-hydroxyflumequine. LOD: Limit of detection. LOQ: Limit of quantification. EMA: European Medicines Agency. FLU: flumequine. MRL: Maximum residue limit. NS: Not specified. Routes of Administration: IM = intramuscular, IV = intravenous, PO = per os, SC = subcutaneous. Units: s = seconds, min = minutes, h = hours, ppb = parts per billion, ppm = parts per million.
Table
Table 6. Macrolide residues in milk or edible tissue samples from sheep or goats following treatment.
Table 6. Macrolide residues in milk or edible tissue samples from sheep or goats following treatment.
AnalyteSpecies; Breed Age;
# of Animals		Tolerance/
MRL		Analytical MethodLODLOQRoute of Admini-strationDose & Active Ingredient# of DosesMatrixLast Sampling Time Point (Post-Last Treatment) When Residues
WERE Detected		Sampling Time Point When
NO Residues Were Detected (Post-Last Treatment) *		Health StatusAdditional InformationSource/Year
Erythro-mycinGoat; dairy type; 2–7 years; n = 10US Tol: Not established.
EMA MRL by extension from bovine to all food producing species: 40 ppb (milk).		BioassayNSNSIMM300 mg Erythromycin at 12 h intervals3Milk24 h (0.05 ppm §)36 hHealthyEarly & mid-lactation; Milked 2x/day, Whole tube per gland[60] 1984
Erythro-mycinGoat; NS; adult;
n = 6		US Tol: Not established.
EMA MRL by extension from bovine to all food producing species: 40 ppb (milk).		BioassayNS0.024 ppmIV10 mg/kg Erythromycin1Milk12 h (0.14 ppm §)>12 hHealthyEarly lactation[121] 2007
IM15 mg/kg Erythromycin1Milk12 h (0.24 ppm §)>12 h
Erythro-mycinSheep; NS;
3–4 years; n = 6		US Tol: Not established.
EMA MRL by extension from bovine to all food producing species: 40 ppb (milk).		BioassayNS0.039 ppmIV10 mg/kg Erythromycin1Milk12 h (0.14 ppm §)24 hHealthyLactating[111] 2007
IM10 mg/kg Erythromycin1Milk12 h (0.16 ppm §)24 h
SC10 mg/kg Erythromycin1Milk24 h (0.05 ppm §)>24 h
Erythro-mycinSheep; NS; NS;
n = 20 study;
n = 4/time pt		US Tol: Not established.
EMA established MRL: 200 ppb (liver, kidney, muscle, fat).		BioassayNSLiver: 250 ppbIM10 mg/kg Erythromycin daily5Liver1 day (1.22 ppm)3 daysHealthyNS[110] 2000
Kidney: 250 ppbKidney1 days (0.77 ppm)3 days
Muscle: 200 ppbMuscle1 day (0.42 ppm)3 days
Fat: 200 ppbFatND1 day
Inj. Site: 200 ppbInj. Site15 days (0.37 ppm)>15 days
LS-MCNS100 ppbIM10 mg/kg Erythromycin daily5Liver1 days (0.41 ppm)3 daysHealthy
Kidney1 days (0.59 ppm)3 days
Muscle1 days (0.27 ppm)3 days
FatND1 day
Inj. Site6 days (0.46 ppm)9 days
Gamithro-mycinSheep; Merino;
5–6 months;
n = 9 study;
n = 3/time pt		US Tol: Not established.
EMA MRL: Not established.		LS-MCNS10 ppbSC6 mg/kg Gamithromycin1Skin10 days (276 ppb)>10 daysHealthyNS[125] 2014
Gamithro-mycinSheep; NS; 7 months;
n = 35 study;
n = 5/ time pt		US Tol: Not established.
EMA established MRL: 300 ppb (liver); 200 ppb (kidney); 50 ppb (muscle & fat).		LS-MCNSNSSC6 mg/kg Gamithromycin1LiverNS ‡NS ‡HealthyNS[126] 2016
KidneyNS ‡NS ‡
MuscleNS ‡NS ‡
FatNS ‡NS ‡
Inj. SiteNS ‡NS ‡
SpiramycinSheep; Awassi; adult; n = 1US Tol: Not established.
EMA MRL: Not established.		Bioassay
NSNSIV20 mg/kg Spiramycin adipate1Milk60 h (2.78 ppm §)>96 hHealthyLactating; Milked 2×/day[24] 1973
Radio-activityNSNSIV20 mg/kg Spiramycin (radiolabeled)1Milk60 h (3.61 ppm §)>96 h
SpiramycinSheep; Awassi; Adult; n = 2US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIM20 mg/kg Spiramycin adipate1Milk56 h (2.40 ppm §)>56 hHealthyLactating; Milked 2x/day[29] 1974
Radio-activityNSNSMilk56 h (3.61 ppm §)>56 h
BioassayNSNSIM20 mg/kg Spiramycin (radiolabeled)1Milk56 h (1.79 ppm §)>56 hDiseased- mastitis
Radio-activityNSNSMilk56 h (1.92 ppm §)>56 h
TilmicosinGoats; NS; 2.5–3 years; n = 5US Tol: Not established.
EMA MRL by extension from ovine to all food producing species: 40 ppb (milk).		Bioassay10 ppbNSSC10 mg/kg Tilmicosin1Milk11 days (0.16 ppm §)12 daysHealthyEarly lactation[112] 1997
TilmicosinSheep; Barki; 2–3 years; n = 5US Tol: Not established.
EMA established MRL: 40 ppb (milk).		BioassayNS0.1 ppmSC10 mg/kg Tilmicosin phosphate1Milk8 days (0.04 ppm §)>8 daysHealthyMid-lactation[127] 1999
TilmicosinSheep; Suffolk crossbred; adult; n = 4US Tol: Not established.
EMA established MRL: 40 ppb (milk).		HPLC50 ppbNSSC10 mg/kg Tilmicosin1Milk11 days (46 ppb)>11 daysNSEarly & mid-lactation; Milked 2x/day[128] 1994
TilmicosinSheep; Beulah Cross; 10–11 weeks; n = 14 study (slaughter 4 time pts)US Tol:
1200 ppb (liver);
100 ppb (muscle).
EMA established MRL: 1000 ppb (liver & kidney); 50 ppb (muscle & fat).		Radio-activityNSNSSC20 mg/kg Tilmicosin phosphate (radiolabeled)1Liver28 days (2.7 ppm)>28 daysHealthyNS[129] 2002
Kidney28 days (0.55 ppm)>28 days
Muscle28 days (1.35 ppm)>28 days
Fat28 days (0.26 ppm)>28 days
Inj. Site28 days (6.51 ppm)>28 days
NS; NS; n = 16 & 4 slaughter time ptsHPLC50 ppbNSSC20 mg/kg Tilmicosin phosphate1Liver28 days (160 ppb)>28 daysHealthy
Kidney28 days (73 ppb)>28 days
Muscle7 days (193.5 ppb)21 days
Fat3 days (73 ppb)7 days
Inj. Site28 days (121.8 ppb)>28 days
Scottish Blackface;
6 months;
n = 24 study;
n = 4/time pt		HPLCNS50 ppbSC30 mg/kg Tilmicosin phosphate1Liver56 days (81 ppb)>56 daysHealthy
Kidney42 days (51 ppb)56 days
Muscle<LOQ @ 14 days14 days
Fat<LOQ @ 14 days14 days
Inj. Site56 days (81 ppb)>56 days
Swaledale; NS;
n = 28 study;
n = 4/tme pt		HPLCNS50 ppbSC10 mg/kg Tilmicosin phosphate1Liver35 days (59 ppb)42 daysHealthy
Kidney21 days (73 ppb)28 days
Muscle<LOQ @ 14 days14 days
Fat<LOQ @ 14 days14 days
Inj. Site28 days (80 ppb)35 days
TilmicosinSheep; NS; lambs;
n = 12 study;
n = 3/time pt		US Tol:
1200 ppb (liver); 100 ppb (muscle).
EMA established MRL: 50 ppb (muscle & fat); 1000 ppb (liver & kidney).		Radio-activityNSNSSC20 mg/kg Tilmicosin phosphate (radiolabeled)1Liver28 days (2.7 ppm)>28 daysHealthyNS[113] 1997
Kidney28 days (0.55 ppm)>28 days
Muscle28 days(<0.26 ppm)>28 days
Fat28 days (<1.2 ppm)>28 days
NS; lambs;
n = 12 study;
n = 3/time pt		Inj. Site28 days (1.32 ppm)>28 days
HPLCNS0.05 ppmSC20 mg/kg Tilmicosin phosphate1Liver28 days (0.16 ppm)>28 daysHealthyNS
Kidney28 days (0.06 ppm)>28 days
Muscle7 days (0.19 ppm)21 days
Swaledale; NS;
n = 28 study;
n = 4/time pt		Fat7 days (<0.05 ppm)7 days
Inj. Site28 days (0.12 ppm)>28 days
LCNS0.05 ppmSC10 mg/kg Tilmicosin phosphate1Liver21 days (0.07 ppm)28 daysHealthyNS
Kidney21 days (0.07 ppm)28 days
NS; adult; n = 4MuscleND @ 14 days14 days
Fat<LOQ @ 14 days14 days
Inj. Site28 days (0.08 ppm)35 days
HPLC
NS0.05 ppmSC10 mg/kg Tilmicosin phosphate1Milk10 days (0.06 ppm)14 daysHealthyLactating
TilmicosinSheep; Suffolk crossbred; Adult; n = 4US Tol: Not established.
EMA established MRL: 50 ppb (milk).		HPLCNS50 ppbSC10 mg/kg Tilmicosin1Milk15 days (0.3 ppm §)>15 daysHealthyEarly lactation[114] 2008
Tulathro-mycinGoats; Boer; 5–7 months;
n = 16 study;
n = 4/time pt		US Tol: Not established.
EMA established MRL: 450 ppb (muscle);
250 ppb (fat); 5400 ppb (liver);1800 ppb (kidney).		UPLC0.7 ppb2 ppbSC2.5 mg/kg Tulathromycin at 7-day interval2Liver20 days (0.78 ppm))>20 daysHealthyNS[123] 2012
Kidney20 days (0.44 ppm)>20 days
Muscle5 days (0.46 ppm)10 days
Fat10 days (0.17 ppm)20 days
Tulathro-mycinGoats; Mixed; 7–8 weeks; n = 6US Tol: Not established.
EMA established MRL: 450 ppb (muscle);
250 ppb (fat); 5400 ppb (liver);
1800 ppb (kidney).		LC-MSLiver: 0.75 ppmLiver: 1.91 ppmSC2.5 mg/kg Tulathromycin1Liver<LOD @ 14 days14 daysHealthy JuvenilesNS[124] 2012
Kidney<LOD @ 14 days14 days
Kidney: 0.29 ppmKidney:
1.66 ppm		Muscle<<LOD @ 14 days14 days
Fat<LOD @ 14 days14 days
Muscle:
0.24 ppm		Muscle: 0.69 ppmInj. Site35 days (0.25 ppm)>35 days
Mixed; 5–6 months; n = 30 stdy; n = 6/time ptSC2.5 mg/kg Tulathromycin1Liver12 days (1.18 ppm)18 daysHealthy Market-age
Fat: 0.14 ppmFat: 0.61 ppmKidney48 days (0.31 ppm)>48 days
Muscle5 days (0.24 ppm)12 days
Inj. Site: 0.24 ppmInj. Site: 0.69 ppmFat12 days (0.15 ppm)18 days
Inj. Site18 days (1.27 ppm)27 days
Mixed; 2–3 weeks; n = 12 SC2.5 mg/kg Tulathromycin
at 7-day interval		3Liver7 days (0.7 ppm)>7 daysHealthy Juveniles
Kidney<LOD @ 7 days>7 days
Muscle<LOD @ 7 days>7 days
Fat<LOD @ 7 days>7 days
Inj. Site7 days (8.76 ppm)>7 days
SC7.5 mg/kg Tulathromycin
at 7-day interval		3Liver7 days (3.4 ppm)>7 daysHealthy Juveniles
Kidney7 days (1.65 ppm)>7 days
Muscle7 days (0.65 ppm)>7 days
Fat7 days (0.36 ppm)>7 days
Inj. Site7 days (17.9 ppm)>7 days
SC12.5 mg/kg Tulathromycin at 7-day interval3Liver7 days (4.87 ppm)>7 daysHealthy Juveniles
Kidney7 days (3.28 ppm)>7 days
Muscle7 days (1.33 ppm)>7 days
Fat7 days (0.65 ppm)>7 days
Inj. Site7 days (24.4 ppm)>7 days
Tulathro-mycinGoats; dairy type; 2–5 years; n = 8US Tol: Not established.
EMA MRL: Not established.		HPLC1.8 ppb5.0 ppbSC2.5 mg/kg Tulathromycin1Milk45 days (2 ppb)>45 daysHealthy,Lactating;
Milked 2×/day		[115] 2016
Tulathro-mycinGoats; NS; 30–36 months; n = 5US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIV2.5 mg/kg Tulathromycin1Milk19 days (0.08 ppm §)>19 daysHealthyLactating[116] 2012
IM2.5 mg/kg Tulathromycin1Milk19 days (0.1 ppm §)>19 days
Tulathro-mycinGoats; dairy type; 1–7 years; n = 8US Tol: Not established.
EMA MRL: Not established.		LS-MS1.8 ppb5.0 ppbSC2.5 mg/kg Tulathromycin at 7-day interval2Milk58 days (0.5 ppb)61 daysHealthyLactating; Milked 2×/day[117] 2016
Tulathro-mycinSheep; NS; NS;
n = 30 study;
n = 3/time pt		US Tol: Not established.
EMA established MRL: 450 ppb (muscle); 250 ppb (fat); 5400 ppb (liver);
1800 ppb (kidney).		LS-MCNSLiver: 300 ppbIM2.5 mg/kg Tulathromycin1Liver35 days (0.3 ppm)42 daysHealthyNS[130] 2015
Kidney: 200 ppb Kidney21 days (0.2 ppm)28 days
Muscle; 50 ppb Muscle21 days (0.05 ppm)28 days
Fat: 50 ppb Fat14 days (0.05 ppm)21 days
Inj. Site: 50 ppb Inj. Site49 days (0.15 ppm)>49 days
TylosinGoats; NS; adult; n = 5US Tol: Not established.
EMA MRL by extension from bovine to all food producing species: 50 ppb (milk).		BioassayNSNSIV15 mg/kg Tylosin tartrate1Milk24 h (0.6 ppm)>24 hHealthyLactating[118] 1991
IM15 mg/kg Tylosin tartrate1Milk24 h (1.7 ppm)>24 h
TylosinSheep; Awassi; adult; n = 3US Tol: Not established.
EMA MRL by extension from bovine to all food producing species: 50 ppb (milk).		BioassayNSNSIM20 mg/kg Tylosin1Milk26 h (1.80 ppm)>26 hHealthyLactating; Milked 2x/day[119] 1973
Milk26 h (0.67 ppm)>26 hDiseased- mastitis
TylosinSheep; Merino; adult; n = 7US Tol: Not established.
EMA MRL by extension from bovine to all food producing species: 50 ppb (milk).		HPLCNSNSIM10 mg/kg Tylosin5Milk36 h (30.9 ppb)48 hHealthyLactating; Milked 2×/day[120] 2001
§ Data points manually extracted use scanning software (Webplot digitizer or UnScanIt 7.0). # = number. ‡ Liver HL reported= 5.48 days; Kidney HL reported = 4.22 days; Muscle HL = 2.55 days; Fat HL reported = 2.82 days; Injection site core = 4.43 days; Injection site ring = 2.39 days. * Projected time for which residues could still be detected based on study protocol for sample collection time points and sample concentration results. Authors caution readers to critically evaluate these publications to estimate when full residue depletion might occur. Abbreviations: 2×/day: twice daily. LOD: Limit of detection. LOQ: Limit of quantification. EMA: European Medicines Agency. MRL: Maximum residue limit. ND: Not detected. NS: Not specified. Routes of Administration: IMM = intramammary, IM = intramuscular, IV = intravenous, SC = subcutaneous. Units: s = seconds, min = minutes, h = hours, ppb = parts per billion, ppm = parts per million.
Table
Table 7. Sulfonamide residues in milk or edible tissue samples from sheep or goats following treatment.
Table 7. Sulfonamide residues in milk or edible tissue samples from sheep or goats following treatment.
AnalyteSpecies; Breed; Age; # of AnimalsTolerance/MRLAnalytical MethodLODLOQRoute of Admini-strationDose & Active Ingredient# of DosesMatrixLast Sampling Time Point (Post-Last Treatment) When Residues WERE DetectedSampling Time Point When NO Residues Were Detected (Post-Last Treatment) *Health StatusAdditional InformationSource/Year
Sulfa-dimethoxineGoat; NS; adult; n = 5US Tol: Not established.
EMA MRL: Not established.		Color-imetricallyNSNSPO286 mg/kg sulfadimethoxine1Milk2 days
(NS)		3 daysHealthyLactating[135] 2016
Sulfa-nilamideGoat; NS; Adult; n = 1US Tol: Not established.
EMA established MRL: 100 ppb (milk).		Spectro-metricNSNSIMM1000 mg Sulfanilamide1Milk4 days (143 ppm)>4 daysHealthyLactating; Single gland[132] 1958
Sulfa-cetamideGoat; NS; Adult; n = 1US Tol: Not established.
EMA established MRL: 100 ppb (milk).		Spectro-metricNSNSIMM1000 mg Sulfacetamide1Milk4 days (2520 ppm)>4 daysHealthyLactating; Single gland[132] 1958
Sulfa-nilamideSheep; NS; adult;
n = 7		US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIV;
PO		150 mg/kg Sulfanilamide
IV once then 100 mg/kg sulfanilamide
PO at 12 h intervals		8Liver8 days (79 ppm)>8 daysHealthyNS[136] 1977
Kidney8 days (119 ppm)>8 days
Muscle8 days (50 ppm)>8 days
Sulfa-methoxy-pyridazineSheep; NS; adult;
n = 7		US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSPO35 mg/kg Sulfamethoxy-pyridazine once then 25 mg/kg Sulfamethoxy-pyridazine daily4Liver8 days (55 ppb)>8 daysHealthyNS[136] 1977
Kidney8 days (115 ppb)>8 days
Muscle8 days (41 ppb)>8 days
Sulf-athiazoleSheep; mixed; lambs; n = 15 study;
n = 3/time pt		US Tol: Not established.
EMA MRL: Not established.		SpectrometricNSNSIV72 mg/kg Sodium sulfathiazole1Liver1 day (0.12 ppm §)>1 dayHealthyNS[137] 1977
Kidney1 days (0.11 ppm §)>1 day
Muscle16 h (0.27 ppm §)1 day
Fat16 h (0.26 ppm §)1 day
Sulfa-merazineSheep; mixed; 22 months; n = 13 study; n = 3/time ptUS Tol: Not established.
EMA MRL: Not established.		HPLCNS0.1 ppmPO132 mg/kg Sulfamerazine once, then 66 mg/kg at 12 h intervals6Liver5 days (0.11 ppm)7 daysHealthyNS[138] 1972
Kidney5 days (0.07 ppm)7 days
Muscle7 days (0.12 ppm)10 days
Fat7 days (0.05 ppm)>7 days
Sulfa-merazineSheep; NS; adult;
n = 12		US Tol: Not established.
EMA established MRL: 100 ppb (milk).		Spectro-metricNSNSPO100 mg/kg Sulfamerazine1Milk2 days (3.7 ppm)>2 daysHealthyLactating; Full dose/ gland[139] 1978
IV
100 mg/kg Sulfamerazine1Milk1 day (5.0 ppm)2 days
IM
100 mg/kg Sulfamerazine1Milk1 days (4.2 ppm)2 days
IMM500 mg Sulfamerazine1Milk12 min (428 ppm)>12 min
Sulfa-methazine †Goat; West African Dwarf; 1 year;
n = 20 study;
n = 1/time point		US Tol: Not established.
EMA MRL: Not established.		Spectro-metric0.05 ppmNSIM100 mg/kg Sulfadimidine1Liver30 days (5.29 ppm)>30 daysHealthyNS[133] 2018
Kidney30 days (3.84 ppm)>30 days
Muscle30 days (2.01 ppm)>30 days
Fat30 days (4.84 ppm)>30 days
IM100 mg/kg Sulfadimidine co-admin w/5 mg/kg piroxicam1Liver30 days (5.33 ppm)>30 days
Kidney30 days (4.79 ppm)>30 days
Muscle30 days (1.38 ppm)>30 days
Fat30 days (4.53 ppm)>30 days
Sulfa-methazine †Sheep; Targhee/Rambouillet; lambs; n = 16 study;
n = 2/time pt		US Tol: Not established.
EMA MRL: Not established.		Spectro-metricNSNSIV107.25 mg/kg Sodium sulfamethazine1Liver4 days (0.11 ppm)>4 daysHealthyNS[134] 1977
Kidney4 days (0.14 ppm)>4 days
Muscle4 days (0.09 ppm)>4 days
Fat4 days (0.05 ppm)>4 days
Sulfa-methazine †Sheep; crossbred; 2–3 years; n = 25 study;
n = 5/time pt		US Tol: Not established.
EMA MRL: Not established.		HPLCNS0.1 ppmPO391 mg/kg Sulfamethazine1Liver4 days (0.3 ppm)8 daysHealthyNS[140] 1991
Kidney4 days (0.25 ppm)8 days
Muscle4 days (0.2 ppm)8 days
FatND4 days
Sulfa-methazine †Sheep; crossbred; adult; n = 10US Tol: Not established.
EMA Established MRL: 100 ppb (milk).		Spectro-metricNSNSPO15,000 mg Sulfamethazine1Milk1 day (NS)>1 dayHealthyLactating[131] 1965
PO15,000 mg Sulfamethazine at 12 h interval2Milk2 days
(NS)		>2 daysHealthy
PO15,000 mg Sulfamethazine at 16 h interval2Milk2 days
(NS)		>2 daysHealthy
PO15,000 mg Sulfamethazine at 22 h interval2Milk2 days
(NS)		>2 daysHealthy
PO15,000 mg Sulfamethazine at 24 h interval2Milk2 days
(NS)		>2 daysHealthy
PO15,000 mg Sulfamethazine at 25 h interval2Milk53 h
(NS)		>53 hDiseased- mastitis
PO15,000 mg Sulfamethazine first dose, 10,000 mg second dose at 24 h interval2Milk2 days
(NS)		>2 daysHealthy
PO15,000 mg Sulfamethazine first dose, 7000 mg second dose at 24 h interval3Milk2 days
(NS)		>2 daysHealthy
PO15,000 mg Sulfamethazine first dose, 7000 mg second dose at 22 h interval3Milk78 h
(NS)		>78 hDiseased- mastitis
PO15,000 mg Sulfamethazine first 2 doses at 13 h interval, 7000 mg third dose at 23 h interval3Milk74 h
(NS)		>74 hDiseased- mastitis
PO15,000 mg Sulfamethazine first 2 doses at 13 h interval, 7000 mg third dose at 22 h interval3Milk83 h
(NS)		>83 hDiseased- mastitis
PO18,000 mg first dose, 6000 mg second dose at 17 h interval then 19 h interval3Milk80 h
(NS)		>80 hDiseased- mastitis
PO18,000 mg Sulfamethazine first dose, 6000 mg at 24 h intervals4Milk96 h
(NS)		>96 hDiseased- mastitis
Sulfa-methazine †Sheep; NS; NS; NSUS Tol: Not established.
EMA MRL: Not established.		NSNSNSPO107.25 mg/kg Sulfamethazine1Liver2 days (0.1 ppm §)>2 daysHealthyNS[141] 1978
Kidney2 days (0.23 ppm §)>2 days
Muscle2 days (0.15 ppm §)>2 days
Fat36 h (0.16 ppm §)2 days
Sulfa-methazine †Sheep; Suffolk; NS;
n = 2;
n = 1/time pt		US Tol: Not established.
EMA MRL: Not established.		RadioactivityNSNSPO100 mg/kg Sulfamethazine (radiolabeled)1Liver2 days (10 ppm)>2 daysHealthyNS[142] 1983
Kidney2 days (22 ppm)>2 days
Muscle2 days (3 ppm)>2 days
Sulfa-methazine †Sheep; Balady; 2–4 years;
n = 9 study;
n = 3/time pt		US Tol: Not established.
EMA MRL: Not established.		NSNSNSIM0.1 mg/kg Sulfadimidine1Liver4 h (20 ppm)>4 hHealthyNS[143] 1980
Kidney4 h (198 ppm)>4 h
Muscle4 h (11 ppm)>4 h
SulfadiazineSheep; Balady; 2–4 years;
n = 9 study;
n = 3/time pt		US Tol: Not established.
EMA MRL: Not established.		NSNSNSIM0.1 mg/kg Sulfadiazine1Liver4 h (25 ppm)>4 hHealthyNS[143] 1980
Kidney4 h (40 ppm)>4 h
Muscle4 h (13 ppm)>4 h
§ Data points manually extracted use scanning software (Webplot digitizer or UnScanIt 7.0). # Number. † Sulfamethazine and sulfadimidine are the same chemical/active ingredient. * Projected time for which residues could still be detected based on study protocol for sample collection time points and sample concentration results. Authors caution readers to critically evaluate these publications to estimate when full residue depletion might occur. Abbreviations: LOD: Limit of detection. LOQ: Limit of quantification. EMA: European Medicines Agency. MRL: Maximum residue limit. NS: Not specified. Routes of Administration: IMM = intramammary, IM = intramuscular, IV = intravenous, PO = per os. Units: s = seconds, min = minutes, h = hours, ppb = parts per billion, ppm = parts per million.
Table
Table 8. Tetracycline residues in milk or edible tissue samples from sheep or goats following treatment.
Table 8. Tetracycline residues in milk or edible tissue samples from sheep or goats following treatment.
AnalyteSpecies;Breed; Age; # of AnimalsTolerance/MRLAnalytical MethodLODLOQRoute of Admini-strationDose & Active Ingredient# of DosesMatrixLast Sampling Time Point (Post-Last Treatmnet) When Residues WERE DetectedSampling Time Point When NO Residues Were Detected (Post-Last Treatment) *Health StatusAdditional InformationSource/Year
Chlortetra-cyclineSheep; Chios & Friesian; adult; n = 4US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		BioassayNSNSIM25 mg/kg Chlor-tetracycline hydrochloride1Milk72 h (0.1 ppm)
120 h (R udder) (0.28 ppm)		>72 h
>120 h (R udder)		HealthyLactating; Only right ½ of udder infused.[147] 1982
IMM426 mg Chlor-tetracycline hydrochloride
in right half of udder.		1Milk38 h (L udder) (0.09 ppm)48 h (L udder)
Chlortetra-cyclineSheep; NS; lambs; NSUS Tol: 6000 ppb (liver); 12,000 ppb (kidney, fat);
2000 ppb (muscle).
EMA established MRL for all food producing species: 300 ppb (liver);
600 ppb (kidney);
100 ppb (muscle).		NSNSLiver: 0.03 ppmPOMF50 mg/kg Chlor-tetracycline daily42Liver0 days (0.11 ppm)2 daysHealthyNS[148] 1996
Kidney: 0.028 ppmKidney2 days (0.06 ppm)4 days
Muscle: 0.027 ppmMuscle0 days (0.03 ppm)2 days
Fat: 0.025 ppmFatND0 days
Chlortetra-cyclineSheep; NS; lambs; NSUS Tol: 6000 ppb (liver); 12,000 ppb (kidney, fat);
2000 ppb (muscle).
EMA established MRL for all food producing species: 300 ppb (liver);
600 ppb (kidney);
100 ppb (muscle).		NSNSLiver: 0.03 ppmPOMF50 mg/kg Chlor-tetracycline co-admin with 50 mg/kg sulfamethazine daily42Liver0 days (0.21 ppm)4 daysHealthyNS[148] 1996
Kidney: 0.028 ppmKidney6 days (0.05 ppm)8 days
Muscle: 0.027 ppmMuscle0 days (0.04 ppm)4 days
Fat: 0.025 ppmFatND0 days
Doxy-cyclineGoat; NS; adult; n = 6US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIV5 mg/kg Doxycycline hydrochloride1Milk48 h (0.12 ppm §)>2 daysHealthyLactating[149] 1989
Mino-cyclineGoat; NS; 1.5–2 years; n = 6US Tol: Not established.
EMA MRL: Not established.		BioassayNSNSIV5 mg/kg Minocycline hydrochloride1Milk36 h (0.11 ppm)2 daysHealthyLactating[150] 1999
Oxytetra-cyclineSheep; Chios & Friesian; adult; n = 4US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		BioassayNSNSIM30 mg Oxytetracycline hydrochloride1Milk38 h (0.7 ppm)48 hHealthyLactating; Only right ½ of udder infused.[147] 1982
IMM420 mg Oxytetracycline hydrochloride in right half of udder1Milk110 h (R udder) (0.58 ppm)120 h (R udder)
14 h (L udder) (1.22 ppm24 h (L udder)
Oxytetra-cyclineSheep; Awassi; adult; n = 8US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		Bioassay0.5 ppmNSIM20 mg/kg Oxytetracycline1Milk72 h (NS)>3 daysHealthyEarly lactation[151] 1982
Oxytetra-cyclineSheep; mixed breed; NS;
n = 24 study;
n = 4/time pt		US Tol: 6000 ppb (liver); 12,000 ppb (kidney, fat);
2000 ppb (muscle).
EMA established MRL for all food producing species: 300 ppb (liver);
600 ppb (kidney);
100 ppb (muscle).		HPLCNSLiver: 85 ppbIM19.8 mg/kg Oxytetracycline (long acting)1LiverNS14 daysNSNS[152] 1997
Kidney: 42 ppbKidneyNS14 days
Muscle: 45 ppbMuscleNS14 days
Fat: 45 ppbFatNS14 days
Inj. SiteNS14 days
Oxytetra-cyclineSheep; Sardinian; adult; n = 5US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		HPLC5.2 ppb17.5 ppbIMM20 mg/kg Oxytetracycline1Milk
7 days (0.1 ppm §)>7 daysNSLactating; Milked 2×/day[153] 1999
IM20 mg/kg Oxytetracycline1Milk7 days (4.15 ppm §)>7 days
Oxytetra-cyclineSheep; mixed breed; NS;
n = 24 study;
n = 4/time pt		US Tol: 6000 ppb (liver);12,000 ppb (kidney, fat);
2000 ppb (muscle).
EMA established MRL for all food producing species: 300 ppb (liver);
600 ppb (kidney);
100 ppb (muscle).		HPLCNSLiver: 85 ppbIM20 mg/kg Oxytetracycline (long acting)1Liver7 days (52 ppb)14 daysHealthyNS[154] 2000
Kidney: 42 ppbKidney14 days (65 ppb)>14 days
Muscle: 45 ppb;Muscle7 days (49 ppb)14 days
Fat: 45 ppbFat7 days (88 ppb)14 days
Inj. Site14 days (59 pb)>14 days
Oxytetra-cyclineSheep; NS; 16 months;
n = 2 study;
n = 1/ time pt		US Tol: 6000 ppb (liver); 12,000 ppb (kidney, fat);
2000 ppb (muscle).
EMA established MRL for all food producing species: 300 ppb (liver);
600 ppb (kidney);
100 ppb (muscle).		LC-MSLiver Oxy: 15.3 ppbLiver Oxy: 50 ppbIM10 mg/kg Oxytetracycline daily5LiverOxy: 2 days (272.8 ppb)Oxy: >2 daysHealthyNS[155] 2008
Liver 4-Epi †:
16.6 ppb		Liver 4-Epi †:
50 ppb		4-Epi †: 4 h (217.8 ppb)4-Epi †: 2 days
Kidney Oxy: 15.7 ppbKidney Oxy: 50 ppbKidneyOxy: 2 days (1342.4 ppb)Oxy: >2 days
Kidney 4-Epi †:
17.5 ppb		Kidney 4-Epi †:
50 ppb		4-Epi †: 2 days (55 ppb)4-Epi †: >2 days
Muscle Oxy: 12.4 ppbMuscle Oxy: 50 ppbMuscleOxy: 2 days (73.6 ppb)Oxy: >2 days
4-epi-Oxytetra-cyclineMuscle 4-Epi †:
13.9 ppb		Muscle 4-Epi †:
30 ppb		4-Epi †: 4 h (34.2 ppb)4-Epi †: 2 days
Fat Oxy: 12.4 ppbFat Oxy: 50 ppbFatOxy: 4 h (3610.7 ppb)Oxy: 2 days
Fat 4-Epi †:
14.1 ppb		Fat 4-Epi †:
30 ppb		4-Epi †: <LOQ @ 4 h4-Epi †: 4 h
Inj. Site Oxy: 12.4 ppbInj. Site Oxy: 30 ppbInj. SiteOxy: 2 days (763.2 ppb)Oxy: >2 days
Inj. Site 4-Epi †:
13.9 ppb		Inj. Site 4-Epi †:
30 ppb		4-Epi†: 2 days (34.5 ppb)4-Epi †: >2 days
Oxytetra-cyclineSheep; Chios;
3 years; n = 20		US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		LC-MSNS20 ppbIM10 mg/kg Oxytetracycline daily5Milk7 days (33.2 ppb)8 daysHealthyLactating; Milked 2×/day[156] 2008
Oxytetra-cyclineSheep; Comisana; adult; n = 8US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		HPLCNSNSIM20 mg/kg Oxytetracycline (long acting)1Milk7.5 days (50 ppb)8 daysHealthyLactating; Milked 2×/day[157] 2000
Oxytetra-cyclineSheep; desert; 9–12 months;
n = 12/ study;
n = 4/time pt		US Tol: 6000 ppb (liver);12,000 ppb (kidney, fat);
2000 ppb (muscle).
EMA establsihed MRL for all food producing species: 300 ppb (liver);
600 ppb (kidney);
100 ppb (muscle).		BioassayNSNSIM5000 mg/kg Oxytetracycline (long acting) daily5Liver10 days (1.51 ppm)>10 daysNSNS[158] 2007
Kidney10 days (6.7 ppm)>10 days
Muscle10 days (70.87 ppm)>10 days
Inj. Site10 days (1227.7 ppm)>10 days
Oxytetra-cyclineSheep; Chios; 16 months;
n = 30 study;
n = 5/time pt		US Tol: 6000 ppb (liver); 12,000 ppb (kidney, fat);
2000 ppb (muscle).
EMA established MRL for all food producing species: 300 ppb (liver);
600 ppb (kidney);
100 ppb (muscle).		LC-MSNSLiver: 50 ppb
IM10 mg/kg Oxytetracycline daily5LiverOxy: 6 days (0.05 ppm)Oxy: 9 daysHealthyNS[146] 2009
4-Epi †: 2 days (0.05 ppm)4-Epi †: 4 days
Kidney: 50 ppbKidneyOxy: 9 days (0.08 ppm)Oxy: 12 days
4-Epi †: 4 days (0.05 ppm)4-Epi †: 6 days
Muscle: 30 ppbMuscleOxy: 4 days (0.04 ppm)Oxy: 6 days
4-epi-Oxytetra-cycline 4-Epi †: 2 days (0.04 ppm)4-Epi †: 4 days
Fat: 30 ppbFatOxy: 0 days (2.7 ppm)Oxy: 2 days
4-Epi †:<LOQ @ 0 days4-Epi †: 0 days
Inj. Site: 30 ppbInj. SiteOxy: 9 days (0.04 ppm)Oxy: 12 days
4-Epi †: 2 days (0.062 ppm)4-Epi †: 4 days
Oxytetra-cyclineGoat; Saanen; adult; n = 8US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		HPLCNSNSIM20 mg/kg Oxytetracycline (long acting)1Milk7.5 days (60 ppb)8 daysHealthyLactating; Milked 2×/day[157] 2000
Oxytetra-cyclineGoat; mixed breed; NS;
n = 32
Mixed breed; adult; n = 10		US Tol:
6000 ppb (liver); 12,000 ppb (kidney, fat); 2000 ppb (muscle); Not approved (milk).
EMA established MRL for all food producing species: 300 ppb (liver); 600 ppb (kidney);
100 ppb (muscle); 100 ppb (milk).		Bioassay0.1 ppmNSIM20 mg/kg Oxytetracycline (long acting)1Liver7 days (385 ppb)14 daysHealthyLactating; Milked 2×/day[145] 2002
Kidney7 days (376 ppb)14 days
Muscle7 days (246 ppb)14 days
Fat96 h (236 ppb)7 days
Inj. Site14 days (1129 ppb)>14 days
HPLC0.15 ppm IM20 mg/kg Oxytetracycline (long acting)1Milk178 h (0.03 ppm)>178 hHealthyLactating; Milked 2×/day
SC20 mg/kg Oxytetracycline (long acting)1Milk178 h (0.05 ppm)>178 h
Oxytetra-cyclineGoat; Saanen; adult; n = 8US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		Bioassay0.25 ppmNSIMM426 mg Oxytetracycline per half daily3Milk5 h (0.50 ppm §)>5 hHealthyLactating; Milked 2×/day[53] 1984
Oxytetra-cyclineGoat; NS; adult; NSUS Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		HPLCNSNSIM15 mg/kg Oxytetracycline daily4Milk100 h (0.46 ppm)>100 hHealthyLactating[159] 1994
Oxytetra-cyclineGoat; Canary Island; adult;
n = 5		US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		HPLCNSNSIM15 mg/kg Oxytetracycline4Milk96 h (0.46 ppm)>96 hHealthyLactating; Milked 2×/day[160] 1995
Oxytetra-cyclineGoat; Saanen; adult; n = 8US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		LC-MS15 ppb50 ppbIM20 mg/kg Oxytetracycline1Milk180 h (60 ppb)8 daysHealthyLactating; Milked 2×/day[161] 2002
Oxytetra-cyclineGoat; Nubian, Alpine &
LaMancha; adult; n = 15		US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		HPLCNSNSIM17.6 mg/kg Oxytetracycline at 48 h interval2Milk96 h (87 ppb)>96 hHealthyMid-lactation; Milked 2×/day[144] 2015
Oxytetra-cyclineGoat; Murciano-Granadina; adult; n = 5US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		HPLCNSNSIV20 mg/kg Oxytetracycline chlorhydrate1Milk2 days (0.25 ppm §)>2 daysHealthyLactating; Milked 1×/day[162] 2001
IM20 mg/kg Oxytetracycline chlorhydrate1Milk3 days (0.36 ppm §)>3 days
IM20 mg/kg Oxytetracycline dehydrate (Long Acting)1Milk3 days (0.27 ppm §)>3 days
Oxytetra-cyclineGoat; NS; 2–7 years; n = 10US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		BioassayNSNSIMM426 mg Oxytetracycline hydrochloride per half at 12 h intervals3Milk96 h (0.02 ppm §)108 hHealthyEarly & mid-lactation; Milked 2×/day;
1 tube/ mammary gland		[60] 1984
Tetra-cyclineSheep; Awassi; Adult; n = 2US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		BioassayNSNSIM20 mg/kg Tetracycline1Milk48 h (0.08 ppm §)>2 daysHealthyLactating; Milked 2×/day[29] 1974
48 h (0.04 ppm §)>2 daysDiseased- mastitis
Radio-activityNSNSIM20 mg/kg Tetracycline (radiolabeled)1Milk48 h (0.14 ppm §)>2 daysHealthy
48 h (0.2 ppm §)>2 daysDiseased- mastitis
Tetra-cyclineSheep; Awassi; adult; n = 4US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		BioassayNSNSIV20 mg/kg Tetracycline hydrochloride (radiolabeled), then 5 mg/kg for 2 doses at 90 min interval1Milk60 h (0.70 ppm §)4 daysHealthyLactating; Milked 2×/day[24] 1973
Radio-activityNSNS60 h (0.12 ppm §)4 days
Tetra-cyclineGoat; Canary Island; adult;
n = 5		US Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		HPLCNSNSIM15 mg/kg Tetracycline4Milk96 h (0.91 ppm)>96 hHealthyLactating; Milked 2×/day[160] 1995
Tetra-cyclineGoat; NS; adult; NSUS Tol: Not established.
EMA established MRL for all food producing species: 100 ppb (milk).		HPLCNSNSIM15 mg/kg Tetracycline daily4Milk100 h (0.91 ppm)>100 hHealthyLactating[159] 1994
§ Data points manually extracted use scanning software (Webplot digitizer or UnScanIt 7.0). # = number. † 4-epi-Oxytetracycline Metabolite. * Projected time for which residues could still be detected based on study protocol for sample collection time points and sample concentration results. Authors caution readers to critically evaluate these publications to estimate when full residue depletion might occur. Abbreviations: 2×/day: twice daily. LOD: Limit of detection. LOQ: Limit of quantification. EMA: European Medicines Agency. MRL: Maximum residue limit. ND: Not detected. NS: Not specified. Routes of Administration: IMM = intramammary, IM = intramuscular, IV = intravenous, PO = per os, POMF = per os as medicated feed, SC= subcutaneous. Units: s = seconds, min = minutes, h = hours, ppb = parts per billion, ppm = parts per million.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Richards, E.D.; Martin, K.L.; Donnell, C.E.; Clapham, M.O.; Tell, L.A. Antibacterial Drug Residues in Small Ruminant Edible Tissues and Milk: A Literature Review of Commonly Used Medications in Small Ruminants. Animals 2022, 12, 2607. https://doi.org/10.3390/ani12192607

AMA Style

Richards ED, Martin KL, Donnell CE, Clapham MO, Tell LA. Antibacterial Drug Residues in Small Ruminant Edible Tissues and Milk: A Literature Review of Commonly Used Medications in Small Ruminants. Animals. 2022; 12(19):2607. https://doi.org/10.3390/ani12192607

Chicago/Turabian Style

Richards, Emily D., Krysta L. Martin, Catherine E. Donnell, Maaike O. Clapham, and Lisa A. Tell. 2022. "Antibacterial Drug Residues in Small Ruminant Edible Tissues and Milk: A Literature Review of Commonly Used Medications in Small Ruminants" Animals 12, no. 19: 2607. https://doi.org/10.3390/ani12192607

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop