U-64,279A
Overview
Chemical Names
[6R-[6alpha,7BETA(Z)]]-7-[[(2-AMINO-4-THIAZOLYL)(METHOXYIMINO)ACETYL]AMINO]-3-[[2-FURANYLCARBONYL)THIO]METHYL]-8-OXO-5-THIA-1-AZABICYCLO[4.2.0]OCT-2-ENE-2- CARBOXYLIC ACID; CEFTIOFUR MONOHYDROCHLORIDE; (6R-7R)-7-[[2-AMINO-4-THIAZOLYL)-Z-(METHOXYIMINO)ACETYL]AMINO]-3-[[(2-FURANYLCARBONYL)THIO]METHYL]-8-OXO-5-THIA-1-AZABICYCLO[4.2.0]OCT-2-ENE-CARBOXYLIC ACID, MONOHYDROCHLORIDE
Synonyms
CEFTIOFUR SODIUM; Na CEFTIOFUR; CEFTIOFUR MONOHYDROCHLORIDE; TRADE NAMES: NAXCEL, EXCENEL
Functional Class
Veterinary Drug
ANTIMICROBIAL_AGENT
ANTIMICROBIAL_AGENT
Evaluations
Evaluation year: 1998
ADI:Upper limit temporary value: 0-0.05 mg/kg bw/d
ADI:
Upper limit temporary value: 0-0.05 mg/kg bw/d
Comments:
The Committee's evaluation of concluded that ceftiofur was of no concern for carcinogenicity, due to the following factors: no evidence of genotoxicity in a variety of assays, no chemical relation of the drug or its metabolites to known carcinogens, rapid metabolism of drug, and lack of neoplastic nor preneoplastic lesions in 90-day feeding studies in rats, dogs, monkeys, or in reproductive toxicity studies involving exposure for periods of up to 160 days. No reproductive or developmental toxicity was observed in rodents. The Committee concluded that most sensitive endpoint is toxicity to gut flora. Therefore, an ADI of 0-50 µg/kg bw/d (3000 µg/p/d for a 60-kg adult) was established, based on the lowest MIC50 value for desfuroylceftiofur cysteine disulfide of 2 µg/ml for Clostridium and Escherichia species, converted to an upper-limit temporary ADI value using the following formula: ADI (µg/kg bw) = Concentration without effect on gut flora (2 µg/ml) X Daily fecal bolus (150 g)/(Fraction of oral dose bioavailable (0.1) × Safety factor (1) × Weight of human (60 kg)). The total safety factor of 1 accounted for the following factors: the range of MICs needed to account for sensitive bacteria, anaerobic environment, bacterial density and pH; the fraction of the dose available to the gut microflora from PK studies of ceftiofur in humans; and variability among exposed individuals. On the basis of residue studies, the Committee recommended the following MRLs: 1000 µg/kg (muscle), 6000 µg/kg (kidney), and 2000 µg/kg (fat) in cattle & pigs. The Committee reaffirmed the MRL values of 2000 µg/kg (liver, cattle & pigs) & 100 µg/L (cow's milk). These MRLs would result in a maximum daily intake of 1050 µg/p/d.
MRL Comment:
MRLs (expressed as desfuroylceftiofur, in mg/kg tissue, mg/l milk): Muscle (cattle and pigs): 1; Liver and fat (cattle and pigs): 2; Kidney (cattle and pigs): 6; Milk (cattle): 0.1
MRL Code:
MRL
Intake:
From daily intake of all tissues at the MRL for each: 1050 µg/p/d
Meeting:
48
Report:
Tox Monograph:
Residues:
Toxicological study
Pivotal Study:
In vitro microbiological studies (Thurn et al., 1994; Zurenko & Yagi, 1990; Kennedy et al., 1991; Watts et al., 1991): 58 strains commonly isolated from the human GI tract were tested with ceftiofur and its metabolites. The MIC values were determined by agar dilution at both high and low inoculum densities. Generally, MIC values doubled with increasing inoculum density. Ceftiofur was always more active than its metabolites desfuroylceftiofur, desfuroylceftiofur disulfide, and desfuroylceftiofur cysteine disulfide. Streptococcus, Propionibacterium and Bifidobacterium were the most sensitive. Bacteroides sp., Enterococcus
faecium, Eubacterium sp., and Lactobacillus sp. were least sensitive to ceftiofur, with MIC50 values of 16 µg/ml, 128 µg/ml,
1 µg/ml, and 16 µg/ml, respectively.
Animal Specie:
Human gut flora, 58 strains
Effect:
Growth inhibition in vitro
Point of departure:
MIC50=2 µg/ml
Previous Years:
1995, TRS 864-JECFA 45/26, FNP 41/8-JECFA 45/9, FAS 36-JECFA 45/61. 0.05. MRLs (EXPRESSED AS DESFUROYLCEFTIOFUR): MUSCLE (CATTLE AND PIGS): 0.2; LIVER (CATTLE AND PIGS): 2; KIDNEY (CATTLE AND PIGS): 4; FAT (CATTLE AND PIGS): 0.6; MILK (CATTLE): 0.1. FU. M
1995, TRS 864-JECFA 45/26, FNP 41/8-JECFA 45/9, FAS 36-JECFA 45/61. 0.05. MRLs (EXPRESSED AS DESFUROYLCEFTIOFUR): MUSCLE (CATTLE AND PIGS): 0.2; LIVER (CATTLE AND PIGS): 2; KIDNEY (CATTLE AND PIGS): 4; FAT (CATTLE AND PIGS): 0.6; MILK (CATTLE): 0.1. FU. M