Table B.1.
Examples of active substances (possibly) causing aneugenic effects that have previously been evaluated for the maximum residue limit (MRL) classification for use in food producing animals. Note that these are published examples and have not been re‐evaluated by EFSA for this guidance document
| Active substance | Genotoxicity | Experi‐mental evidence of aneu‐genicity | Carcinogenicity | Risk assessment | CR (EU) 37/2010 entry* | Reference** |
|---|---|---|---|---|---|---|
| Colchicine | Positive results in vivo and in vitro for gene and chromosome mutation. Aneugenic potential in vivo (1 mg/kg) and in vitro (0.006 μg/ml) | Yes | No data available | No ADI could be set up based on genotoxicity, teratogenicity, effects on fertility, no data on absorption after local treatment of cattle and horses) | Table 2 | EMEA/MRL/044/95‐FINAL |
| Benzimidazole derivatives | ||||||
| Albendazole | In vivo aneugens | Yes | No evidence in either rats or mice in suitable carcinogenicity bioassays | ADI of 0–0.005 mg/kg bw per day based on NOEL for teratogenicity of 5 mg/kg per day and a safety factor of 1,000 | Table 1 | MRL Summary Report (reference here) and EMEA/MRL/865/03‐FINAL |
| Albendazole oxide | Yes | No studies with albendazole oxide | ADI of 0–0.005 mg/kg bw per day based on albendazole data | Table 1 | EMEA/MRL/555/99‐FINAL February 1999 | |
| Netobimin | Yes | No studies with netobimin | ADI of 0–0.005 mg/kg bw per day based on albendazole data | Table 1 | EMEA/MRL/556/99‐FINAL April 1999 | |
| Mebendazole | Not a direct acting mutagen or clastogenic. Aneugenic in mammalian somatic cells. Not possible to identify an in vivo NOEL for aneugenicity, but a no‐effect concentration of 85 ng/ml was identified from in vitro FISH studies | Yes | No evidence of carcinogenicity in rats and mice but studies were considered inadequate | ADI of 0.0125 mg/kg bw per day based on NOEL of 2.5 mg/kg bw per day in a 13‐week study in dogs and in developmental toxicity studies in rats and mice using a safety factor of 200 | Table 1 | EMEA/MRL/625/99‐FINAL July 1999 and EMEA/MRL/781/01‐FINAL March 2001 |
| Thiabendazole | No gene mutation or structural chromosomal damage. Consistent evidence of aneugenicity in vitro. Negative in validated oral in vivo mutagenicity assays. Some reports of aneuploidy in bone marrow cells in vivo following intraperitoneal administration | Yes, but conclusion that negative in vivo with the oral route | No excess incidence of any type of tumour in mice. In rats, no increases in tumours except thyroid follicular adenomas, which was considered to be due to by a nongenotoxic mechanism related to liver enlargement | ADI of 0.1 mg/kg bw based on an overall toxicological NOEL of 10 mg/kg bw/day for a range of toxicological endpoints including effects on the liver, thyroid and bone marrow, spleen, effects on reproductive performance, teratogenicity in mice and fetotoxicity in rats. A safety factor of 100 was applied | Table 1 | EMEA/MRL/868/03‐FINAL June 2004 |
| Oxfendazole | Benzimidazole compound, which are known to be mitotic spindle poisons. The mutagenicity data available for febantel, fenbendazole and oxfendazole show no clear evidence of genotoxicity and although no specific tests for aneugenicity have been conducted, the clastogenicity studies that have been conducted are generally reassuring’ | No | No evidence of carcinogenicity in rats or mice | ADI of 7 μg/kg bw per day based on the NOEL of 0.65 mg/kg bw per day for hepatic vacuolation in a carcinogenicity study in rats with a safety factor of 100 to febantel, fenbendazole and oxfendazole share the same metabolism with oxfendazole being most toxic | Table 1 | EMEA/MRL/888/03‐FINAL June 2004 |
| Fenbendazole | Benzimidazole compound, which are known to be mitotic spindle poisons. The mutagenicity data available for febantel, fenbendazole and oxfendazole show no clear evidence of genotoxicity and although no specific tests for aneugenicity have been conducted, the clastogenicity studies that have been conducted are generally reassuring’ | No | No evidence of carcinogenicity in rats or mice | ADI of 7 μg/kg bw per day, based on toxicity data for oxfendazole | Table 1 | EMA/CVMP/914694/2011 |
| Febantel | Benzimidazole compound, which is known to be a mitotic spindle poison. The mutagenicity data available for febantel, fenbendazole and oxfendazole show no clear evidence of genotoxicity and although no specific tests for aneugenicity have been conducted, the clastogenicity studies that have been conducted are generally reassuring | No | No evidence of carcinogenicity in rats and mice | ADI of 7 μg/kg bw per day, based on toxicity data for oxfendazole | Table 1 | EMEA/MRL/192/97‐FINAL June 1997 |
| Benzimidazole derivatives without indication of aneugenicity in the MRL summary reports | ||||||
| Flubendazole | Negative for gene mutation, DNA damage, a sex‐linked recessive lethal assay in Drosophila melanogaster, a dominant lethal assay in mice and in vivo micronucleus tests in rats and mice | No | No evidence of carcinogenicity in rats and mice although both studies were marred by poor survival | ADI of 0–12 μg/kg bw per day based on the NOEL of 2.5 mg/kg bw per day in a 3‐month study in dogs, with a safety factor of 200 | Table 1 | EMEA/CVMP/33128/2006‐FINAL |
| Triclabendazole | Negative in a range of genotoxicity studies, including MN in hamster bone marrow | No | No evidence of carcinogenicity in rats and mice | ADI of 0.0015 mg/kg bw, based on a NOEL of 0.15 mg/kg bw/day for increased post‐partum mortality of the F2 generation in a two‐generation rat reproduction study and an UF of 100 | Table 1 | No reference number of CVMP's MRL Summary Report (1) available*** |
*
CR (EU) 37/2010: Use of active substances in veterinary medicinal products for food producing animals; Table 1 substances with numerical MRLs or ‘No MRL required’ classification, made it possible to be used in veterinary medicines; Table 2 – prohibited substances.