DICLAZURIL

Overview

Chemical Names
(±)-2,6-DICHLORO-alpha-(4-CHLOROPHENYL)-4-(4,5-DIHYDRO-3,5-DIOXO-1,2,4-TRIAZIN-2(3H- YL)BENZENEACETONITRILE
Functional Class
Veterinary Drug
ANTIPROTOZOAL_AGENT

Evaluations

Evaluation year: 1999

ADI:
0-0.03 mg/kg bw

Comments:
The additional studies complied with the request of the Committee by showing enteric absorption and exposure of pregnant rabbits to diclazuril which was sufficient to enable the teratogenicity of the drug to be assessed. On the basis of these findings, the Committee considered the NOEL for diclazuril of 3 mg/kg bw/day in the two-year mouse study, based on histopathological changes in the lungs, as the most appropriate toxicological end-point for establishing an ADI. An ADI of 0-30 µg/kg bw was established by applying a 100-fold safety factor to the NOEL. This provides a margin of safety of at least 10 000 for the teratogenic effect of the compound in rabbits. The TMDI from the recommended MRLs is 0.6 mg/p/d.
MRL Comment:
MRLs (expressed as diclazuril, in mg/kg): Muscle (sheep, rabbits and poultry): 0.5: Liver (sheep, rabbits and poultry): 3; Kidney (sheep, rabbits and poultry): 2; Fat (sheep and rabbits): 1; Fat (poultry): 1 (fat/skin in normal proportions)
MRL Code:
TMRL
Intake:
TMDI: 0.6 mg/p/d
Meeting:
50
Report: 
TRS 888-JECFA 50/54
Tox Monograph: 
FAS 41-JECFA 50/87
Residues: 
FNP 41/11-JECFA 50/29

Toxicological study

Pivotal Study:
25-month combined long-term toxicity/carcinogenicity study (Verstraeten et al., 1989a): Swiss mice (50/sex/group) were administered doses of diclazuril of 0, 16, 63, 250 or 1000 mg/kg of feed (0, 3, 11, 47 or 190 mg/kg bw/d (males) and 0, 4, 14, 53 or 220 mg/kg bw/d (females)). High dose males showed reduced body-weight gain and food consumption and an increased incidence of cachexia. Increased incidences of hepatic parenchymal centrilobular swelling and presence of lipid vacuoles in the centrilobular hepatocytes and swollen sinusoidal cells were seen in males at > 3 mg/kg bw/day and in females at 220 mg/kg bw/day. The NOEL in this study was 16 mg/kg of feed, equal to 3 mg/kg bw/day.
Animal Specie:
Mouse
Effect:
Histopathology in lungs
NOEL:
3 mg/kg bw/day
LOEL:
11 mg/kg bw/d
Point of departure:
3 mg/kg bw/day
Previous Years:
1995, TRS 864-JECFA 45/40, FNP 41/8-JECFA 45/67, FAS 36-JECFA 45/119. 0-0.02 (TEMPORARY). MRLs (TEMPORARY; EXPRESSED AS PARENT DRUG): MUSCLE (SHEEP, RABBITS AND POULTRY): 0.5: LIVER (SHEEP, RABBITS AND POULTRY): 3; KIDNEY (SHEEP, RABBITS AND POULTRY): 2;
1995, TRS 864-JECFA 45/40, FNP 41/8-JECFA 45/67, FAS 36-JECFA 45/119. 0-0.02 (TEMPORARY). MRLs (TEMPORARY; EXPRESSED AS PARENT DRUG): MUSCLE (SHEEP, RABBITS AND POULTRY): 0.5: LIVER (SHEEP, RABBITS AND POULTRY): 3; KIDNEY (SHEEP, RABBITS AND POULTRY): 2;