6-Amino-5-chloro-2-cyclopyrimidine-4-carboxylic acid

Neurotoxicity

Description of key information

OECD 408 (rats): no adverse effects observed in neurobehavioral endpoints

OECD 409 (dogs): no adverse effects observed in neurobehavioral endpoints

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Effect on neurotoxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Neurotoxicity testing was included in a GLP-compliant sub-chronic feeding study in rats (exposure over 94 or 95 days in males and 96 or 97 days in females) (Crl:CD(SD)) according to OECD 408 (2011 g).

In this study, 15 rats per sex and dose level were fed with a diet containing 600, 2000, 6000 and 18000 ppm test substance (corresponding to 35, 114, 349 and 1045 mg/kg bw/day in males and 45, 146, 448 and 1425 mg/kg bw/day in females, respectively). Control animals received standard diet (Rodent Lab Diet^®5002). Neurobehavioral evaluations, consisting of functional observational battery (FOB) and motor activity, were conducted prior to study start and during weeks 4, 8, and 13 of exposure. The functional observational battery included investigations of the following parameters: forelimb and hindlimb grip strength, footsplay, rearing, body temperature and other functional observational battery (FOB) endpoints. After approximately 90 days, selected animals (5 rats/sex/group) were perfused for neuropathology.

There were no test substance-related changes in forelimb or hindlimb grip strength, hindlimb footsplay, body temperature, rearing, or any of the other behavioral parameters evaluated in the FOB in males or females administered any dietary concentration of the test substance. In addition, there were no test substance-related effects on duration of movement or number of movements in males or females administered any dietary concentration of the test substance. Furthermore, there were no test substance-related gross or microscopic effects observed in neuropathology.

 

In addition, neurotoxicity parameters were also investigated in a GLP compliant 90 Day feeding study in dogs according to OECD guideline 409 (2011 i). In this study, 4 Beagle dogs per dose and sex were fed diet containing test substance concentrations of 250, 1250, 5000 and 15,000 ppm (corresponding to 6.46, 33.31, 126.23 and 425.71 mg/kg bw/day in males and 7.02, 37.94, 124.12, and 387.53 mg/kg bw/day in females, respectively). Control animals received plain diet (Certified Canine Diet #5007). Neurobehavioral parameters were checked weekly (4 h after food removal). Examinations included changes in the level of activity, gait, posture, altered strength and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g., excessive grooming, repetitive circling) or bizarre behavior (e.g., self-mutilation). All observations were scaled when possible. Scores other than zero were observed for the following parameters: lacrimation, arousal, body tone and limp tone. However, all findings were either comparable to controls, without any dose-response or occurred only at selected time points and were thus not considered treatment-related or adverse.

 

In conclusion, the available data do not indicate neurotoxic effects in rats and dogs, and thus the target substance is not considered to exhibit neurotoxic properties.

Justification for classification or non-classification

The available data on neurotoxicity obtained for the test substance are conclusive but not sufficient for classification according to Regulation (EC) No. 1272/2008 (CLP).