benzovindiflupyr (ISO); N-[9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide

Carcinogenicity

Description of key information

2 Year rat study NOAEL = 100 ppm (4.88 mg/kg/day).  Treatment related increase in thyroid follicular cell adenoma was observed in top dose (600 ppm) males.  
80 Week mouse study NOAEL = 60 ppm (7.55 mg/kg/day).  No treatment-related increase in tumour incidence

Justification for classification or non-classification

Mode of action studies are ongoing to investigate the human relevance of the thyroid tumours observed in rats. A final judgment on classification for carcinogenicity will be made once these studies are completed.

Carcinogenicity: Based on the available information the substance does not meet the criteria for classification as "carcinogen" under Regulation (EC) 1272/2008, Annex I, Part 3, 3.6.2; reason for non-classification: inconclusive.

Additional information

SYN545192 has been evaluated for carcinogenic potential in the rat and the mouse. 

In a 2 year combined chronic toxicity/carcinogenicity study in Wistar rats, SYN545192 was tested at dietary inclusion levels of 0, 25, 100 and 600 ppm (males) or 400 ppm (females). Significantly lower body weight gain, food consumption and food utilisation were observed in both sexes at the top dose. ALP, ALT and AST values were consistently lower than control values at the top dose. In males at 600 ppm, liver weight (covariate analysis with body weight) was statistically significantly increased. There were no other effects on organ weight. The incidence of centrilobular hypertrophy in the liver was statistically significantly higher in top dose males and females at 52 and 104 weeks. In males at 600 ppm, the incidence of eosinophilic cell foci in the liver was statistically significantly higher after 104 weeks and a higher incidence of hepatocyte vacuolation was seen after 104 weeks. A higher incidence of pigmented hepatocytes was observed in females at 400 ppm after 52 and 104 weeks. In males at 600 ppm, there was a treatment-related increase in the incidence of thyroid follicular cell adenomas. There were no other treatment-related neoplastic findings. A NOAEL was established at 100 ppm (4.88 mg/kg/day in males and 6.66 mg/kg/day in females).

In a carcinogenicity study in the mouse, groups of 50 male and 50 female CD-1 mice were fed diets containing 0, 20, 60 or 200 ppm of SYN545192 for a period of at least 80 weeks. Statistically significantly lower group mean body weight was observed in males treated with 200 ppm during the first 7 weeks of the study. This was associated with a statistically lower group mean body weight gain compared to the control animals over the first 4 weeks of the study.There was a higher incidence of simple mucosal hyperplasia in the large intestine (colon and caecum) at 200 ppm in males and females that was considered to be treatment related.  The effect was more pronounced in males based on incidence and severity. In the colon the incidences were 13/49 in males and 10/48 in females. These higher incidences attained statistical significance in both sexes when compared with controls. In the caecum the incidences were 4/50 in males and 2/48 in females. These micropathology findings provide clear evidence of systemic toxicity at 200 ppm. There was no effect on the large intestine at either 20 or 60 ppm. There were no treatment-related neoplastic findings in this study. Although there was a higher incidence of Harderian gland adenoma in the treated groups when compared with controls, this difference was considered to be incidental to treatment:

·        There was no dose-response relationship such that the Harderian gland tumour incidence at the low dose was higher than the historical control range whereas the incidence in the mid-dose was within the historical range

·        There was no statistical significance using pairwise tests and there was no statistically significant trend using the Peto trend test

·        There were no indications of any pre-neoplastic micropathology findings in the Harderian gland

·        There were no increases in the incidence of adenocarcinoma in the Harderian gland, and there was no indication of any increase in tumour incidence in the Harderian gland in the rat

·        The Harderian gland is a rodent specific structure with no anatomical equivalent in humans (Aldert et al 1986 the

Harderian Gland: Its tumours and its relevance to humans. Trans Am Ophthalmol 84; 321-341).

 The NOEL for the 80 week mouse study was established at 60 ppm, which is equivalent to 7.55 mg/kg/day in males and 8.67 mg/kg/day in females.