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Description of key information

An oral diet repeated dose toxicity study (combined with a reproduction/developmental toxicity screening test) was conducted with nopyl acetate according to OECD Guideline No 422 and in compliance with GLP.
The NOAEL (No Observed Adverse Effect Level) for systemic toxicity was determined to be 3000 ppm (equivalent to 180.2 mg/kg bw/day) based on reduced bodyweight gain in both males and females.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
180.2 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Recent GLP study conducted according to OECD Guideline No 422 without any deviation (Klimisch score = 1).

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a combined repeated dose toxicity study with a reproduction / developmental toxicity screening test conducted according to OECD 422 Guideline and in compliance with GLP, nopyl acetate was administered by dietary admixture (initially mixed with 2 % corn oil to avoid evaporation) to three groups of Sprague-Dawley rats, for 42 consecutive days, at dietary concentrations of 0,1000, 3000 and 9000 ppm (equivalent to a mean achieved dosage of 0, 56.5, 180.2 and 478.5 mg/kg bw/day, respectively). Animals allocated to the recovery phase assay were treated for 42 days and then given untreated diet (with 2% corn oil) for a further 14 days.

No unscheduled deaths or treatment-related clinical signs were noted. No treatment-related effects were noted on behavioural, sensory reactivity and functional performance parameters.

Reduced overall body weight gain was evident in animals of either sex treated with 9000 ppm (-14% in males, -48% in females). Statistically significant reductions in body weight gain were achieved for males during week 1 and in females during weeks 2 and 3.

At 9000 ppm, mean food consumption for females was lower than control during the first week of the study (-23%) and was considered to reflect an initial reluctance to eat the diet admixture due to its low palatability. Food efficiency was intermittently adversely affected in animals of either sex treated with 9000 ppm.

Increased water consumption was observed in several animals but it would not be considered as an adverse effect to treatment.

Females and males (including recovery phase males) treated with 9000 ppm showed an increase in liver weight both absolute and relative to terminal body weight. All males treated with 9000 ppm showed also an increase in kidney weight both absolute and relative to terminal body weight.

Histopathology revealed fully reversible microscopic abnormalities in liver (minimal to slight diffuse hepatocellular hypertrophy in males and females) and thyroid (minimal diffuse follicular cell hypertrophy in females) at 9000 ppm. At 3000 and 9000 ppm, partly reversible changes in kidney (tubular degeneration/regeneration, hyaline droplets and granular casts) were observed in main phase and recovery males. These kidney effects were considered to be related to alpha 2u-globulin nephropathy and of no relevance to humans.

No treatment-related significant changes were detected after haematology and blood chemistry investigations.

No toxicologically significant macroscopic abnormalities were detected in animals of either sex treated with 9000, 3000 or 1000 ppm.

Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of nopyl acetate for systemic toxicity was considered to be 3000 ppm (180.2 mg/kg bw/day) for females and for males (when excluding the sex and species, specific kidney effects in male rats are not relevant for human risk assessment).

As no specific target organ toxicity relevant to humans was identified, it is not deemed necessary to perform a 90-day toxicity study.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study available

Justification for classification or non-classification

No toxic effects were observed in the repeated dose toxicity study below 478.5 mg/kg bw/day (dose level >300 mg/kg bw/day). The major toxic effect observed at this dose level was a reduction in bodyweight gain, no target organ was identified. Therefore nopyl acetate is not classified for repeated dose toxicity according to Directive 67/548/EEC and CLP Regulation (EC) No 1272 /2008.