Abstract
FSCJ conducted a risk assessment of monepantel (CAS No.887148-69-8), a parasiticide based on results from various studies. Data on pharmacokinetics (cattle) and residues (cattle) were newly submitted. Negative results were obtained in all genotoxicity and carcinogenicity studies. The no-observed-adverse-effect level (NOAEL) obtained in all studies was 100 ppm (equivalent to 3 mg/kg bw per day for both sexes). In the 52-week chronic toxicity study in dogs, FSCJ specified an ADI for monepantel at 0.03 mg/kg bw per day based on NOAEL of 3 mg/kg bw per day, by applying a safety factor of 100.
Conclusion in Brief1)
FSCJ conducted a risk assessment of monepantel (CAS No.887148-69-8), a parasiticide based on results from various studies. Data on pharmacokinetics (cattle) and residues (cattle) were newly submitted.
The data used in the assessment include pharmacokinetics (rats, dogs, sheep and cattle), residues (sheep and cattle), genotoxicity, acute toxicity (rats), subacute toxicity (mice, rats and dogs), chronic toxicity (rats and dogs), carcinogenicity (mice and rats), and reproductive and developmental toxicity (rats and rabbits) as well as data on general pharmacology.
Negative results were obtained in all genotoxicity studies. Therefore, it is possible to establish an acceptable daily intake (ADI) due to no genotoxicity relevant to humans. Monepantel did not show carcinogenicity in a 78-week carcinogenicity study in mice and a 104-week carcinogenicity study in rats.
Adverse effects observed at the lowest dose in various toxicological studies were shortened thromboplastin time, adrenal hypertrophy and histopathological changes in the liver of males, decreased albumin levels, decreased albumin/globulin ratio, increased alkaline phosphatase activity, and increased relative thyroid weight in females, at 300 ppm in a 52-week chronic toxicity study of dogs. The no-observed-adverse-effect level (NOAEL) in this study was 100 ppm (equivalent to 3 mg/kg bw per day for both sexes).
Consequently, FSCJ specified an ADI for monepantel at 0.03 mg/kg bw per day, based on NOAEL of 3 mg/kg bw per day in the 52-week chronic toxicity study in dogs, applying a safety factor of 100. (table 1)
Table 1. Levels relevant to toxicological evaluation of monepantel.
| Species | Study | Dose (mg/kg bw/day) |
NOAEL (mg/kg bw/day) |
| Mouse | 13-week subacute toxicity | M: 5, 18, 98, 959 F: 5, 22, 115, 1 213 |
5 Elevated AST levels |
| Mouse | 78-week carcinogenicity study | 1, 4, 16, 69 | 4 Increased incidence of fatty liver F: Increased absolute/relative liver weights Not carcinogenic |
| Rat | 4-week subacute toxicity study | M: 86, 346, 1 044 F: 90, 362, 1 017 |
M: 86 (LOAEL) F: 90 (LOAEL) Centrilobular hypertrophy of hepatocytes M: Diffuse hypertrophy of thyroid follicular cells F: Increase in T.Chol, PL and TG as well as increased absolute/relative liver weight |
| Rat | 90-day subacute toxicity | M: 4, 15, 74, 900 F: 4, 15, 81, 947 |
15 Increase in thromboplastin time F: Increase in T.Chol and PL, centrilobular hypertrophy of hepatocytes and increased absolute/relative liver weight |
| Rat | 52-week chronic toxicity study | M: 3, 11, 54, 656 F: 3, 14, 67, 778 |
14 Increased absolute/relative liver weight |
| Rat | 104-week carcinogenicity study | M: 5, 47, 578 F: 6, 57, 707 |
- Not carcinogenic |
| Rat | Two-generation reproductive toxicity study |
F0: prior to mating: 15.8, 119, 950 During pregnancy: 13.5, 103, 863 During lactation period: 32.3, 245, 2 055 F1: prior to mating: 18.6, 141, 1 109 During pregnancy: 15.1, 114, 918 During lactation period: 30.8, 241, 2 028 |
Parent: 13.5 ~ 32.3 Increased absolute/relative liver weight, centrilobular hypertrophy of hepatocytes, cortical cell hypertrophy of the zona glomerulosa in the adrenal glands Offspring: 13.5 ~ 32.3 (LOAEL) Increased absolute/relative liver weight |
| Rat | Teratogenicity study | 0, 100, 300, 1 000 | 1 000 Not teratogenic |
| Dog | 4-week subacute toxicity | M: 161, 566, 1 217 F: 184, 561, 1 472 |
M: 161 (LOAEL), F: 184 (LOAEL) Increase in ALP, decreased absolute/relative thymus weight and increased absolute/relative adrenal weight |
| Dog | 13-week subacute toxicity | M: 10, 107, 963 F: 11, 97, 1 176 |
(LOAEL) M: 10, F: 11 Small intestine (dilation of glands) F: Pancreas (increased apoptosis) |
| Dog | 52-week chronic toxicity | M: 3, 10, 99 F: 3, 8, 91 |
3 M: Decrease in thromboplastin time and histopathological findings in the liver F: Decrease in Alb and A/G ratio, increase in ALP as well as increased relative thyroid weight |
| Rabbit | Teratogenicity | 0, 100, 300, 1 000 | 1 000 Not teratogenic |
| Toxicological ADI (mg/kg bw/day) | 0.03 NOAEL: 3 Safety factor: 100 |
||
| The critical study for setting the ADI | 52-week chronic toxicity study in dogs | ||
| ADI (mg/kg bw/day) | 0.03 | ||
Acknowledgement
FSCJ wishes to thank the members of Expert Committee on Veterinary Medicinal Products for the preparation of the original full report.
Note
- 1).This is the second edition of the risk assessment report of Monepantel issued in September 2010. The Ministry of Health, Labour and Welfare requested an assessment of the veterinary medicinal product in association with an import tolerance application for cattle. The previous ADI, 0.001mg/kg bw per day was thus withdrawn.