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EC number: 211-989-5
CAS number: 732-26-3
1: Reproduction Data Summary
Group 23 mg/kg
Group 310 mg/kg
Group 430 mg/kg
Females with living pups on Day 1
Mating index (%)(Females mated / Females paired) * 100
Fertility index (%)(Pregnant females / Females paired) * 100
Conception index (%)(Pregnant females / Females mated) * 100
Gestation index (%)(Females with living pups on Day 1 / Pregnant females) * 100
Table 2: Corpora Lutea and Implantation Sites Summary
Table 3: Mean Body Weights of
*/** Dunnett-test based on pooled
variance significant at 5 % (*) or 1 % (**) level
Table 4: Summary of Developmental Data
Number of litters
Duration of gestation
Dead pups at first litter check
Living pups at first litter check
% of males / females
% of living pups
## Fisher’s Exact test significant at 1 % Level
The developmental toxicity of the test material was investigated in a
combined repeated dose toxicity study with the reproduction /
developmental toxicity screening test conducted in accordance with the
standardised guidelines OECD 422 and US EPA OPPTS 870.3650 under GLP
Based on the results of a 10-day dose range finding study, the dose
levels for this study were selected to be 3, 10 and 30 mg/kg.
The test material, formulated in corn oil, was administered daily by
oral gavage to SPF-bred Wistar Han rats. One control group and three
treated groups were tested, each consisting of 10 males and 10 females.
Males were exposed for 29 days, i.e. 2 weeks prior to mating, during
mating, and up to termination. Females were exposed for 41 to 56 days,
i.e. during 2 weeks prior to mating, during mating, during post-coitum,
and during at least 4 days of lactation.
The following observations and examinations were evaluated: mortality /
viability, clinical signs (daily), functional observations and locomotor
activity (end of treatment), body weight and food consumption (at least
at weekly intervals), clinical pathology (end of treatment), macroscopy
at termination, organ weights and histopathology on a selection of
tissues. Reproduction/developmental parameters were also evaluated.
Formulations were analysed once during the study to assess accuracy,
homogeneity and stability. Analysis showed that the formulations were
prepared accurately and homogenously, and were stable for at least 6
hours at room temperature.
Histopathological examination showed hepatocellular hypertrophy up to
moderate degree at 10 and 30 mg/kg. This was supported at necropsy by
enlargement and/or accentuated lobular pattern of the liver for some
animals at 30 mg/kg. At 30 mg/kg, hepatocellular necrosis was present in
a single female at minimal degree. Additionally, higher liver weights
(absolute and/or relative to body weights) were recorded at 10 and 30
mg/kg; relative liver weights were increased 63 % in females at 30
mg/kg, and 21 % in females at 10 mg/kg. The higher liver weights in
females at 10 and 30 mg/kg along with the combined occurrence of
hepatocellular hypertrophy with necrosis at 30 mg/kg were considered to
be adverse in nature.
At 30 mg/kg, changes in blood of females that were considered to be
related to treatment consisted of lower relative neutrophil counts,
higher relative lymphocyte counts, lower mean corpuscular volume and
mean corpuscular haemoglobin, higher total protein, albumin, calcium,
cholesterol, potassium and glucose and lower urea and total bilirubin.
Females at 10 and 30 mg/kg showed lower food consumption during the
lactation period, as well as notable weight loss during lactation
ranging from 4 to 9 % of Day 1 lactation values. The lower maternal food
intake and body weight gain and mean pup body weight gain appeared
unrelated on an individual animal basis. Also, these changes were not
accompanied by supportive clinical signs or inadequate maternal care. As
such, these changes in food intake and body weight gain during lactation
were considered not adverse in nature.
No toxicologically relevant clinical signs or changes in functional
observation parameters were noted.
No toxicologically relevant changes in reproduction parameters were
observed up to the highest dose level tested (30 mg/kg). These
parameters included mating, fertility and conception indices, pre-coital
time, and numbers of corpora lutea and implantation sites and
histopathological examination of reproductive organs.
At 30 mg/kg, the mean number of living pups at first litter check
appeared slightly lower than controls. Also, an increased postnatal loss
and lower viability index was noted at 10 and 30 mg/kg. At 10 mg/kg, a
total of 3 dams showed postnatal loss (1 dead or missing pup for two
litters, and 6 missing pups for another litter). At 30 mg/kg, a total of
5 dams showed postnatal loss (1 missing pup for 3 litters, and 4 or 5
missing pups for two litters). The
significance of these findings is not clear at this stage and are
proposed to be further investigated. The
registrant therefore proposes to conduct a full prenatal developmental
toxicity study in rats in accordance to the OECD Guideline 414.
Mean pup body weights for both sexes combined on Day 4 of lactation were
approximately 16 and 20 % lower than the control mean at 10 and 30
mg/kg, respectively. Although there were no other developmental changes
noted for these pups (macroscopy and clinical signs), the magnitude of
changes in pup body weight was considered to represent an adverse effect
on pup development. No apparent relationship could be found between
maternal food intake and mean pup body weight gain on an individual
Mean male pup body weight was also lower at 3 mg/kg on Day 4 lactation
(approximately 8 % lower than the control mean). Since this change in
body weight was slight this was considered not to represent an adverse
effect on pup development.
No treatment-related changes were noted in any of the remaining
developmental parameters investigated in this study (i.e. gestation
index and duration, parturition, maternal care and early postnatal pup
development consisting of clinical signs and macroscopy).
Under the conditions of the study, the repeated dose NOAEL was
determined to be 3 mg/kg (based on higher liver weights at 10 and 30
mg/kg, with hepatocellular hypertrophy and necrosis at 30 mg/kg). The
developmental NOAEL was determined to be 3 mg/kg (based on lower pup
body weight and increased postnatal loss at 10 and 30 mg/kg, and lower
mean number of living pups at first litter check at 30 mg/kg).
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