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EC number: 800-940-9
CAS number: 35836-72-7
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 Crl:
CD® BR strain rats, for up to 63 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). Each dose group was subdivided into two phases:
main phase (at 1000 and 3000 ppm: 10 rats/sex/dose; at 0 and 9000 ppm: 5
males and 10 females/dose) and toxicity phase (5 female/dose). A control
group was treated with basal laboratory diet (with 2% corn oil). During
the study, data was recorded on mortality, clinical signs, behavioural
assessments, body weight change, food and water consumption,
haematology, blood chemistry, mating performance, fertility and
gestation length. All animals were subjected to a gross necropsy
examination, selected organs were weighed and histopathological
evaluation of selected tissues was performed. The clinical condition of
offspring, litter size and survival, sex ratio and offspring bodyweight
were assessed and macroscopic pathology investigations were undertaken.
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. No treatment-related significant changes were detected after
haematology and blood chemistry investigations. No treatment-related
effects were detected in mating performance, fertility and gestation
lengths. Main phase males 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. Post
mortem examinations did not reveal any treatment-related macroscopic
findings for interim death or terminal kill offspring. Histopathology
revealed fully reversible microscopic abnormalities in liver (minimal to
slight diffuse hepatocellular hypertrophy in males and 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 males. These kidney effects were considered to be
related to alpha 2u-globulin nephropathy and of no relevance to humans.
No treatment-related significant effects were noted on offspring litter
size, sex ratio, viability, growth and development.
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.
Therefore, 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). The NOAEL of nopyl acetate for
reproductive toxicity and developmental toxicity was considered to be
9000 ppm (478.5 mg/kg bw/day).
Therefore, nopyl acetate is not classified
for reproduction according to Directive 67/548/EEC and CLP Regulation
(EC) No 1272 /2008.
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