Nitrapyrin

Neurotoxicity

Description of key information

NOEL (neurotoxicity) = 40 mg/kg/day; NOEL (neuropathology) = 120 mg/kg/day; 90-day - rat (male/female); EPA OPPTS 870.6200, OECD 424; Andrus et al. (2014)

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

40 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The study was conducted under GLP conditions and in accordance with standardised guidelines; it was therefore assigned a reliability score of 1 in line with the criteria of Klimisch et al. (1997). The overall quality of the database is good.

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

The neurotoxicity of the test material was investigated in a study which was conducted under GLP conditions and in accordance with the standardised guidelines EPA OPPTS 870.6200 and OECD 424.

During the study groups of 10 male and 10 female F344/DuCrl rats were exposed to 0, 10, 40 or 120 mg test material/kg/day, in the diet, for at least 90 days. These dose levels corresponded to actual time-weighted average doses of 0, 10.2, 40.6, or 122 mg/kg/day for males, and 0, 10.0, 40.2, or 121 mg/kg/day for females, respectively. Ten rats/sex/dose were evaluated pre-exposure and during 2, 4, 8, and 13 weeks of exposure using a functional observational battery (FOB), determinations of grip performance, rectal temperature, landing foot splay, and an automated test of motor activity. Weekly clinical observations, body weights, and food consumption were also evaluated, and ophthalmic examinations were conducted pre- and post-exposure. At the end of the study, five rats/sex/dose were perfused for histopathologic evaluation of the central and peripheral nervous system, which was conducted on the control and high-dose groups. The other five rats/sex/dose were grossly examined at necropsy and liver weights were measured.

Treatment with test material did not affect FOB observations, grip performance, rectal temperature, ophthalmic examinations, or clinical observations in males or females at any dose level tested. At the end of the study, males of the 120 mg/kg/day group had mean in-life body weight and body weight gain that was 9.5 and 18.0 % less than controls, respectively. Males of the 120 mg/kg/day group also had a slight decrease in feed consumption during the course of the study. There were no treatment-related effects on body weight or feed consumption in low or mid-dose males or in females from any dose group. There was a treatment-related increase in landing foot splay in the 120 mg/kg/day dose group at week 13 in males and at weeks 8 and 13 in females. There also was a treatment-related increase in total motor activity in the 120 mg/kg/day dose group at weeks 8 and 13 in males and at week 13 in females. Absolute and relative liver weights for animals given 120 mg/kg/day were increased 88.0 and 105 % for males and 75.1 and 75.4 % for females, respectively.

There were no treatment-related gross or histopathologic observations in the central or peripheral nervous systems of rats administered test material.

The treatment-related effects on landing foot splay and motor activity could be secondary to the observed liver toxicity (weight increases of 75 - 88 %) in rats administered 120 mg test material/kg/day, based on the apical nature of these end points, the lack of effects on other associated FOB parameters, and the lack of neuropathology. However, while there were no treatment-related findings that indicate a specific (direct) effect on the nervous system, the subchronic dietary no observed effect level (NOEL) for test material neurotoxicity in male and female F344/DuCrl rats was judged to be 40 mg/kg/day due to these neurobehavioral changes (increased landing foot splay and motor activity). The NOEL for neuropathology was 120 mg/kg/day, the highest dose level tested.

Justification for selection of effect on neurotoxicity via oral route endpoint:

Only one study is available.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008, the substance does not require classification with respect to neurotoxicity.

In accordance with the criteria for classification as defined in Annex VI, Directive 67/548/EEC (DSD), the substance does not require classification with respect to neurotoxicity.