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

Endpoint summary

Description of key information

NO(A)EL (oral, dietary, 2-year, rat) at 100 ppm (males: 4.88 mg/kg bw/day, females: 6.66 mg/kg bw/day; see IUCLID section 7.7, Carcinogenicity)
NO(A)EL (dermal, 28-day, rat) at 1000 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

4.88 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Summary of the repeated dose data:

NO(A)EL (oral, dietary, 28-day, rat) at 100 ppm (males: 9 mg/kg bw/day, females: 9 mg/kg bw/day)

NO(A)EL (oral, dietary, 90-day, rat) at 100 ppm (males: 7.6 mg/kg bw/day, females: 8.2 mg/kg bw/day)

NO(A)EL (oral, dietary, 2-year, rat) at 100 ppm (males: 4.88 mg/kg bw/day, females: 6.66 mg/kg bw/day; see IUCLID section 7.7, Carcinogenicity)

NO(A)EL (oral, dietary, 28-day, mouse) at 100 ppm (males: 15.6 mg/kg bw/day, females: 19.0 mg/kg bw/day)

NO(A)EL (oral, dietary, 90-day, mouse) at 100 ppm (males: 17.0 mg/kg bw/day, females: 20.9 mg/kg bw/day)

NO(A)EL (oral, dietary, 80-week, mouse) at 60 ppm (males: 7.55 mg/kg bw/day, females: 8.67 mg/kg bw/day; see IUCLID section 7.7, Carcinogenicity)

NO(A)EL (oral, capsule, 13-week, dog) at 30 mg/kg bw/day

NO(A)EL (oral, capsule, 2-year, dog) at 250 mg/kg/day

NO(A)EL (dermal, 28-day, rat) at 1000 mg/kg bw/day

The repeated dose toxicity of SYN545192 has been evaluated by the oral route of administration in rats, dogs and mice and by the dermal route in a 28-day study in the rat. In rats the main effect observed after short-term administration of SYN545192 was a reduction in body weight gain, food consumption and food utilisation. There were some minor changes in the liver including increased liver wweight and centrilobular hypertrophy which were considered indicative of adaptive change. A minor pathological finding of minimal tubular basophilia in the kidney was noted in top dose females in the 28 day rat study, but this was not seen in males nor was it seen in the 90 day rat study or the 2-year rat study. In both studes the NO(A)EL was 100 ppm (8-9 mg/kg/day). The 2 year rat combined chronic toxicity/carcinogenicity study (see IUCLID Section 7.7, Carcinogenicity, for the corresponding robust study summary (endpoint study record)) was conducted 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 was statistically significantly increased. 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 the 28 day mouse study, SYN545192 caused initial body weight loss at doses of 300 and 500 ppm and tubulointerstitial nephritis was observed in the kidneys in both sexes at 500 ppm. In the 90 day study, which was conducted using the same dose levels as the 28 day study, there were no findings in the kidney. Initial body weight loss was observed in the 90 day study at 500 ppm and two males from the high dose satellite study group were terminated in extremis indicating that this dose level was too high to be used as a top dose level for the subsequent 80 week mouse carcinogenicity study. The other finding in the 90 day mouse study was the observation of hyperplasia in the colon and rectum which was observed in both sexes at 300 and 500 ppm. The NOAEL for the 28 and 90 day mouse studies was 100 ppm (16-17 mg/kg/day).

In the 90 day dog study, there were signs of general toxicity at the top dose of 750 mg/kg/day including salivation, slight initial body weight loss and reduced food consumption and reduced body weight gain. Slight initial body weight loss, reduced body weight gain and initial reduced food consumption were also observed at 375 mg/kg/day. Increased plasma triglycerides were seen in both sexes at 750 mg/kg/day. Decreased plasma calcium values were observed in males at 375 and 750 mg/kg/day. The NOEL was established at 30 mg/kg/day. In the 1 year dog study, salivation, vomiting of feed, fluid, capsule or mucus as well as feces containing mucus were observed in both sexes at 250 and 500 mg/kg/day and were considered a local effect of the test item, rather than a systemic effect. Reduced body weight gain was seen in males and females at 500 mg/kg/day. The NOAEL for systemic toxicity was 250 mg/kg/day. 

In a 28 day dermal toxicity study in the rat conducted up to the limit dose of 1000 mg/kg/day, there were no indications of local effects at the application site nor were there any signs of systemic toxicity. The NOEL was the top dose of 1000 mg/kg/day.

All studies are considered to be relevant, reliable and adequate for risk assessment, and adequate for classification purposes. The lowest NO(A)EL results for oral and dermal administration are carried forward for risk assessment purposes.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

Based on the available information the substance does not meet the criteria for classification as "specific target organ toxicity" – repeated exposure) under Regulation (EC) 1272/2008, Annex I, Part 3, 3.9.2; reason for non-classification: conclusive but not sufficient for classification.