APURONE
Overview
Chemical Names
9-FLUORO-6,7-DIHYDRO-5-METHYL-1-OXO-1H,5H-BENZO[ij]-QUINOLIZINE-2-CARBOXYLIC ACID
Synonyms
R-802; APURONE
CAS number
42835-25-6
Functional Class
Veterinary Drug
ANTIMICROBIAL_AGENT
ANTIMICROBIAL_AGENT
Evaluations
Evaluation year: 2006
ADI:0-30 µg/kg bw
ADI:
0-30 µg/kg bw
Comments:
The Committee concluded that the available data support a non-genotoxic,threshold-based mechanism for tumour formation by flumequine in the mouse liver. The Committee therefore re-established the ADI of 0–30 µg/kg bw, based on the overall NOEL for hepatotoxicity of 25 mg/kg bw/day from a 13-week study in mice and a safety factor of 1000. A safety factor of 1000 was chosen to reflect the short duration of the study and the lack of histochemical characterization of the foci of altered hepatocytes.
MRL Comment:
MRLs (EXPRESSED AS FLUMEQUINE): MUSCLE AND LIVER (CATTLE, CHICKENS, PIGS AND SHEEP): 500 µg/kg; MUSCLE (BLACK TIGER SHRIMP (P. MONODON) AND SHRIMP): 500 µg/kg (TEMPORARY); MUSCLE INCLUDING NORMAL PROPORTIONS OF SKIN (TROUT): 500 µg/kg; KIDNEY (CATTLE, CHICKENS, PIGS, AND SHEEP): 3000 µg/kg; FAT (CATTLE, CHICKENS, PIGS, AND SHEEP): 1000 µg/kg The assignment of the temporary MRL for shrimp applies to all freshwater and marine shrimp.
MRL Code:
TMRL
Intake:
TMDI of flumequine residues: 27.6 µg/kg bw/d (92% of the ADI)
Meeting:
66
Report:
Tox Monograph:
Residues:
Toxicological study
Pivotal Study:
13-week GLP-compliant mouse study designed to investigate the hepatotoxic lesions and the activity of hepatic drug-metabolizing enzymes (Stewart, 1995): CD-1 mice (16/sex/group) were fed diets containing flumequine at concentrations providing doses of 0, 25, 50, 100, 400, or 800 mg/kg bw/d to males and 0, 100, 400, or 800 mg/kg bw/d to females. Plasma enzyme activities were measured after 12 weeks. Liver microsomes were prepared to test the activity of the xenobiotic-metabolizing enzyme system by measuring total protein and cytochrome P450 content, P450-dependent dealkylation of resorufin and coumarin derivatives, and 1-naphthol glucuronidation. Significant increases in the activities of alanine aminotransferase and alkaline phosphatase were noted at 400 and 800 mg/kg bw/d and in lactic dehydrogenase and aspartate aminotransferase at 800 mg/kg bw/d. Liver weights were increased at the two highest doses. Dose-dependent hepatocytic hypertrophy and fatty vacuolation (> 25 mg/kg bw/day (males) & > 100 mg/kg bw/day (females)), increased ploidy, intranuclear inclusions, and centrilobular necrosis (>100 mg/kg bw per day) were seen. Degeneration of hepatocytes with focal necrosis, accompanied by increased mitotic activity, was seen only in high dose males. The slight hypertrophic alterations of liver cells with minimal degenerative alterations in males at 50 and 100 mg/kg bw/d were regarded as signs of hepatotoxic lesions rather than metabolic overload. The NOEL was 25 mg/kg bw/d on the basis of hepatotoxic lesions in males.
Animal Specie:
Mice
Effect:
Hepatotoxic lesions (males)
NOEL:
25 mg/kg bw/day
Point of departure:
25 mg/kg bw/day
Previous Years:
2004, TRS 925-JECFA 62/18, FNP 41/15-JECFA 60/43 (2003), FAS 53-JECFA 62/93. 0-30 µg/kg bw. MRLs (EXPERSSED AS FLUMEQUINE): MUSCLE AND LIVER (CATTLE, CHICKENS, PIGS AND SHEEP): 500 µg/kg; MUCSLE (BLACK TIGER SHRIMP (P. MONODON)): 500 µg/kg (TEMPORARY); MU
2004, TRS 925-JECFA 62/18, FNP 41/15-JECFA 60/43 (2003), FAS 53-JECFA 62/93. 0-30 µg/kg bw. MRLs (EXPERSSED AS FLUMEQUINE): MUSCLE AND LIVER (CATTLE, CHICKENS, PIGS AND SHEEP): 500 µg/kg; MUCSLE (BLACK TIGER SHRIMP (P. MONODON)): 500 µg/kg (TEMPORARY); MU