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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
478.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Recent GLP study conducted according to OECD Guideline 422 without any deviation (Klimisch score = 1).
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
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 Guideline No 422 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 up to 64 consecutive days (including a three week maturation phase, pairing, gestation and early lactation for females), 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).

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

Statistically significant reductions in body weight gain were achieved for males treated with 9000 ppm during week 1 and in females treated with 9000 ppm during weeks 2 and 3.

Reduced overall body weight gain in animals of either sex treated with 9000 ppm: -14% in males, -48% in females.

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.

Main phase males (used in the reprotox screening) treated with 9000 ppm showed an increase in kidney and liver weight both absolute and relative to terminal body weight. Main phase females treated with 9000 ppm also showed an increase in liver weight both absolute and relative to terminal body weight.

Histopathology in males (and in females used for repeated dose toxicity study) revealed fully reversible microscopic abnormalities in liver (minimal to slight diffuse hepatocellular hypertrophy) at 9000 ppm. Fully reversible microscopic abnormalities were also observed in thyroid of "toxicity phase" females (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 males. These kidney effects were considered to be related to alpha 2u-globulin nephropathy and of no relevance to humans.

No treatment-related effects were detected in mating performance, fertility and gestation lengths:

- all animals mated (excluding one female treated with 9000 ppm and one female treated with 3000 ppm) within four days of pairing;

- there were no differences in conception rates for treated animals;

- the distribution of gestation lenghts for treated females was comparable to controls. The majority of females showed a gestation lenghts between 22 and 23 days.

No treatment-related significant effects were noted on offspring litter size, sex ratio, viability, growth and development.

Under the test condition, the 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).

The NOAEL for reproductive toxicity and developmental toxicity was considered to be 9000 ppm (478.5 mg/kg bw/day).

No signs of toxicity to reproduction were identified in this study. Therefore, no further testing is deemed necessary.


Short description of key information:
A combined repeated dose toxicity study 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.
The NOAEL for reproductive toxicity was determined to be 9000 ppm (equivalent to 478.5 mg/kg bw/day, highest dose tested).

Justification for selection of Effect on fertility via oral route:
Only one study is available for this endpoint.

Effects on developmental toxicity

Description of key information
A developmental toxicity screening test combined with a repeated dose toxicity study 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.
The NOAEL for developmental toxicity was determined to be 9000 ppm (equivalent to 478.5 mg/kg bw/day, highest dose tested).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
478.5 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).
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
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 Guideline No 422 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 up to 64 consecutive days (including a three week maturation phase, pairing, gestation and early lactation for females), 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).

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

Statistically significant reductions in body weight gain were achieved for males treated with 9000 ppm during week 1 and in females treated with 9000 ppm during weeks 2 and 3.

Reduced overall body weight gain in animals of either sex treated with 9000 ppm: -14% in males, -48% in females.

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.

Main phase males (used in the reprotox screening) treated with 9000 ppm showed an increase in kidney and liver weight both absolute and relative to terminal body weight. Main phase females treated with 9000 ppm also showed an increase in liver weight both absolute and relative to terminal body weight.

Histopathology in males (and in females used for repeated dose toxicity study) revealed fully reversible microscopic abnormalities in liver (minimal to slight diffuse hepatocellular hypertrophy) at 9000 ppm. Fully reversible microscopic abnormalities were also observed in thyroid of "toxicity phase" females (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 males. These kidney effects were considered to be related to alpha 2u-globulin nephropathy and of no relevance to humans.

No treatment-related effects were detected in mating performance, fertility and gestation lengths.

No treatment-related significant effects were noted on offspring litter size, sex ratio, viability, growth and development:

- no significant differences were detected for implantation losses or litter size for treated animals when compared to controls;

- no adverse effects were detected in offspring weights or subsequent litter viability;

- there were no intergroup differences in sex ratio (percentage male offspring) for litters from treated groups compared to controls;

- no toxicologically significant effects were detected in offspring body weight gain or litter weights at birth and subsequently on Days 1, 4 and 7 post partum;

- no obvious clinical signs of toxicity were detected for offspring from treated females when compared to controls.

Under the test conditions, the 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). The NOAEL for reproductive toxicity and developmental toxicity was considered to be 9000 ppm (478.5 mg/kg bw/day).

No signs of toxicity to development were identified in this study, therefore no further testing is deemed necessary.


Justification for selection of Effect on developmental toxicity: via oral route:
One reproduction / developmental screening study showing no adverse effect on development is available (Iuclid section §7.8.1). A waiver is therefore submitted for this endpoint.

Justification for classification or non-classification

In a recent GLP combined repeated dose toxicity with reproduction / developmental toxicity screening test conducted with nopyl acetate according to OECD 422 Guideline, no signs of toxicity to reproduction that could be attributable to the test item were identified in male and female rats. No effects were identified on offspring of female rats exposed by diet from 2 weeks before mating until Day 7 of lactation.

Therefore, nopyl acetate is not classified for reproduction and developmental toxicity according to Directive 67/548/EEC and CLP Regulation (EC) No 1272 /2008.