N-nitro-N-(3-methyl-3,6-dihydro-2H-1,3,5-oxadiazin-4-yl)amine

Endpoint summary

Description of key information

A GLP guideline 28-day feeding study (OECD 407; Novartis, 1997) was conducted with dose levels of 0, 50, 200, 1000, 5000 ppm. At 1000 ppm, slight hepatotropic effects were noted in both sexes. A NOAEL of 200 ppm (15.7 mg/kg bw/d in females) was concluded. Several additional GLP non-guideline studies were conducted at higher doses (CTL, 2005, 28-day, 0-6000 ppm; Syngenta, 2006, 14-days, 0-400 mg/kg bw/d; Syngenta, 2006, 28-days, 0-400 mg/kg bw/d; RCC, 2007, 0-500 mg/kg bw/d. In addition a 90 day GLP guideline inhalation study (OECD 413, CTL, 2003) was conducted with aerosol concentrations from 0 to 0.25 mg/l. A NOAEC of 0.05 mg/l was established.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

15.7 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

50 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

Oral:

A GLP guideline 28-day feeding study (OECD 407; Novartis, 1997) was conducted with dose levels of 0, 50, 200, 1000, 5000 ppm. At 1000 ppm, slight hepatotropic effects were noted in both sexes. A NOAEL of 200 ppm (15.7 mg/kg bw/d in females) was concluded. The LOAEL is 1000 ppm (87.2 mg/kg bw/d (males)).

In addition, several GLP non-guideline studies were conducted at higher doses:

- 28 day feeding study (CTL, 2005; 0, 2000, 4000, 6000 ppm; corresponding to 0, 230, 470, and 680 mg/ kg bw/d in males and 0, 210, 440, and 590 mg/kg bw/d in females). At 6000 ppm, animals were sacrificed halfway through the test since they were deemed moribund. A LOAEL of 2000 ppm was determined based on reduced body weight and changes in haematological parameters.

- 14 day oral gavage study (Syngenta, 2006; 0, 100, 200, 400 mg/kg bw/d): Examinations were restricted to behavior, food consumption and body weight as well as gross pathology at the end of the study. Minimal effects were seen at the lowest dose. This study was intended as a range-finder for longer-term studies.

- 28 day oral gavage study (Syngenta, 2006; 0, 100, 200, 400 mg/kg bw/d): clear effect of 100, 200 and 400 mg/kg bw/d following a single dose; clinical signs (including decreased activity, piloerection, tip toe gait, cold) and weight loss in females and reduced food consumption in males and females. A dose-related effect of treatment on the body weights of the males was seen subsequently. For the males given 400 mg/kg/day, lower body weights persisted throughout day 29. The maximum effect was 19 % when compared with the controls. Lower body weights in females were not sustained after approximately one week of treatment. Lower food consumption was not sustained in males or females after one week of treatment. LOAEL is 100 mg/kg bw/d.

- 28 day oral gavage study (RCC, 2007; 0, 300, 400, 500 mg/kg/d): signs of toxicity at all dose levels.

Inhalation:

Nose-only exposure for 6 hours per day, 5 days per week over a period of 90 days at concentrations of 0.01, 0.05 or 0.25 mg/l resulted in lower body weight and food consumption and histopathological changes in the olfactory epithelium in both sexes exposed to 0.25 mg/l. There were no adverse effects of treatment in animals exposed to 0.05 mg/l (NOAEC).

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

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: nose

Justification for classification or non-classification

Guidance values for classification according to EC 1272/2008 are 10 < C <= 100 mg/kg/d (STOT RE, Category 2, oral) and 0.02 < C < 0.2 mg/l/6h/d (STOT RE, Category 2, inhalation, aerosol).

The oral LOAEL is at 87.2 mg/kg/d. The value is derived from a 28-day study. The CLP reference values are based on sub-chronic studies. Thus, this LOAEL would need to be extrapolated using a default factor of 3 (as recommended in the CLP regulation), resulting in an effect level of ca. 30 mg/kg/d. Both values are within the range of the guidance values for STOT RE, Category 2. However, there are only slight, mainly reversible, hepatotropic effects without corresponding histopathological findings. This is not considered sufficient to warrant a classification.

The inhalatory LOAEL of 0.25 mg/l is based on reduced body weight, reduced food consumption and histopathological changes in the olfactory epithelium. The NOAEL is at 0.05 mg/l. Hence there may be an effect at concentrations within the range of the guidance value (0.02 < C < 0.2 mg/l). However, the effects at 0.25 mg/l are not considered severe enough to warrant a classification.