Monepantel

Overview

Synonyms
AHC 2102225
CAS number
887148-69-8
JECFA number
85
Functional Class
Veterinary Drug
ANTHELMINTHIC_AGENT
Veterinary Drug

Evaluations

Evaluation year: 2017

ADI:
0–0.02 mg/kg bw

Comments:
Established by JECFA 75 (2011). ARfD: Unnecessary.
MRL Comment:
MRLs in cattle tissue: 300 μg/kg in muscle, 1000 μg/kg in kidney, 2000 μg/kg in liver and 7000 μg/kg in fat.
Intake:
13.7 μg/kg bw per day (general population) and 5.0 μg/kg bw per day (children) which represents respectively 25 and 22% of the upper bound of the ADI.
Report: 
JECFA 85 report

Evaluation year: 2013

ADI:
0–20 μg/kg bw
Comments:
An ADI of 0–20 μg/kg body weight was established by the Committee at its seventy-fifth meeting (WHO TRS No. 969, 2012).
MRL Comment:
Recommended maximum residue limits (MRLs) In sheep 13,000μg/kg (Fat), 1,700μg/kg (Kidney), 7,000μg/kg (Liver) 500μg/kg (Muscle) as moneantel( Monepantel sulfone) These MRLs are consistent with the shortest withdrawal time assigned in Member States with an approved use of monepantel.
Intake:
Using the model diet and marker residue to total residue ratios of 1.00 for muscle and 0.66 for fat, liver and kidney, and applying a correction factor of 0.94 to account for the mass difference between monepantel sulfone (the marker residue) and monepantel, the EDI is 446 μg/person per day, which represents approximately 37% of the upper bound of the ADI.
Meeting:
78
Report: 
TRS 988-JECFA 78/
Tox Monograph: 
FAS 69-JECFA 78/
Residues: 
FAO Monograph

Evaluation year: 2011

ADI:
0–20 μg/kg bw
Comments:
The Committee considered liver to be the primary target of toxicity for monepantel, as demonstrated by effects on relevant biochemical variables, absolute and relative liver weights and histological findings that were consistent across studies and species. The Committee established an ADI of 0–20 μg/kg bw based on a NOAEL of 1.8 mg/kg bw/d in a 78-week oral dosing study in mice, a safety factor of 100, and rounding to one significant figure. The Committee recommended MRLs for monepantel sulfone in sheep tissue of 300 μg/kg in muscle, 700 μg/kg in kidney, 3000 μg/kg in liver and 5500 μg/kg in fat. Using the food basket model diet and a ratio of marker residue to total residue of 100% for muscle and 66% for fat, liver and kidney, and applying a correction factor of 0.94 to account for the mass difference between monepantel sulfone (the marker residue) and monepantel, the EDI is 201 μg/p/day (17% of the ADI).
MRL Comment:
MRLs for monepantel sulfone in sheep: 300 μg/kg (muscle), 700 μg/kg (kidney), 3000 μg/kg (liver), 5500 μg/kg (fat).
Intake:
201 μg/p/day, based on food basket model diet, ratio of marker residue to total residue of 100% for muscle and 66% for fat, liver and kidney, correction factor of 0.94
Meeting:
75
Report: 
TRS 969/JECFA 75
Tox Monograph: 
Monepantel.pdf
Residues: 
FNP 12/12-JECFA 75

Toxicological study

Pivotal Study:
78-week GLP-compliant study (Fischer, 2008): CD-1, SPF mice (50/sex/group) administered monepantel in the diet at a concentration of 0, 10, 30, 120 or 500 ppm (0, 1.3, 4.2, 16.2 and 69.1 mg/kg bw/d (males) and 0, 1.8, 5.5, 22.8 and 91.7 mg/kg bw/day (females)). Increased incidences of fatty change were recorded at all doses. Although the effect did not reach statistical significance at 10 and 30 ppm, the effect in females at 30 ppm was considered toxicologically relevant. Increased incidences of hepatocellular hypertrophy was noted in all treated males and in all but high-dose females at all test item doses with the exception of the top dose without a dose–response relationship. The NOAEL was 10 ppm (1.8 mg/kg bw/day), based on increased incidence of fatty change in liver in females at 30 ppm (5.5 mg/kg bw/day) and supported by increased hepatocellular hypertrophy .
Animal Specie:
Mouse
Effect:
Increased incidences of fatty change & hypertrophy in hepatocytes
NOAEL:
1.8 mg/kg bw/day
LOAEL:
5.5 mg/kg bw/day
Point of departure:
1.8 mg/kg bw/day