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EC number: 225-184-1
CAS number: 4702-90-3
In a GLP-compliant OECD 422 study the gestation index (reduced to
66.7%) as well as the live birth index (58.1% due to the reduced number
of females with live pups on the day of birth) were clearly affected at
1000 mg/kg body weight. The number of dams with stillborn pups was
significantly increased at 1000 mg/kg and in 2 litters all pups were
stillborn. The mean value of perinatal loss was significantly increased
(47.2%) as well. The reason for the increased perinatal deaths as well
as for dystocia were unknown but one effect might also cause the other.
Therefore, at a critical internal dose level, the test substance (or a
metabolite) affects either fetal life or the process of birthing or
both. The NOAEL for reproductive performance and fertility was set to
1000 mg/kg bw/d for male and 300 mg/kg bw/d for female Wistar rats
because of the increased perinatal loss of pups. Thus, the NOAEL for
developmental toxicity was 300 mg/kg bw/d.
The test article was given daily as a suspension to groups of 10
male and 10 female Wistar rats (F0 animals) by gavage at dose levels of
0 mg/kg body weight/day (mg/kg bw/d; test group 0), 100 mg/kg bw/d (test
group 1), 300 mg/kg bw/d (test group 2) and 1000 mg/kg bw/d (test group
3). Corn oil served as vehicle, control animals were dosed daily with
the vehicle only. The duration of treatment covered a 2-week premating
period and mating in both sexes (mating pairs were from the same test
group) as well as entire gestation and lactation period in females up to
one day prior to the day of schedule sacrifice of the animals. During
clinical examinations signs of general systemic toxicity were not
observed in male animals of test groups 1-3 (100, 300 and 1000 mg/kg
bw/d) during the entire study period. The same was true for female
animals of test groups 1 and 2. However, two female animals of test
group 3 (1000 mg/kg bw/d) showed piloerection and pale skin during end
of gestation and early lactation, each one additional individual showed
either one finding, only. The observed effects were most likely a
consequence of dystocia, the labored birthing process.
Fertility indices for male and female animals were not impaired by
test-substance administration even at a dose level of 1000 mg/kg bw/d.
However, the gestation index (reduced to 66.7%) as well as the live
birth index (58.1% due to the reduced number of females with live pups
on the day of birth) were clearly affected in test group 3. In test
group 3, the mean duration of gestation was 23.3 days and significantly
increased when compared to the controls. The postimplantation loss in
test group 3 was clearly outside the historical range. The number of
dams with stillborn pups was significantly increased in test group 3 and
in 2 litters all pups were stillborn. The mean number of stillborn
pups/litter was also significantly increased. Mean value of perinatal
loss was significantly increased (47.2%) in test group 3. All findings
with regard to reproductive performance and developmental toxicology
were assessed to be related to treatment since they occurred in a
dose-dependent manner. The reason for the increased perinatal deaths as
well as for dystocia were unknown but one effect might also cause the
other. Concerning clinical pathology, no treatment-related, adverse
effects were observed up to a dose of the compound of 1000 mg/kg bw/d.
Regarding pathology, there were no treatment-related organ weighs
changes. Macroscopically, a dose-dependent yellow discoloration of the
adipose tissue was noted in males of test groups 2 and 3 (300 and 1000
mg/kg bw/d) and in females of all test groups. This finding was
consistent with the color of the test-substance but had no
histopathological correlate. Therefore, it was judged as
treatment-related but not adverse per se since only bioavailability was
demonstrated. All other histopathological findings occurred either
individually or were biologically equally distributed over control and
treatment groups. They were considered incidental or spontaneous in
origin and without any relation to treatment. Taken together, the
discoloration of adipose tissue obviously corresponds with duration of
treatment and dose level since low-dose male animals did not show the
discoloration (treated for 4 weeks), but females did (treated for about
8 weeks). These observations support the hypothesis of systemic
bioavailability and lead to the conclusion that the test substance
accumulates by time and dose. At a critical internal dose level, the
test substance (or a metabolite) affects either fetal life or the
process of birthing or both.
Under the conditions of this Combined Repeated Dose Toxicity Study
with the Reproduction/Developmental Toxicity Screening Test, the oral
administration by gavage of the test item to Wistar rats revealed
adverse signs of toxicity in female animals at a dose level of 1000
mg/kg bw/d. No effects were observed in male animals at any dose level.
Thus, the no observed adverse effect level (NOAEL) for general systemic
toxicity was 1000 mg/kg bw/d for male and 300 mg/kg bw/d for female
In a GLP-compliant OECD 422 study the NOAEL for developmental
toxicity was 300 mg/kg bw/d (see above).
Classification, Labeling, and Packaging Regulation (EC) No.
The available experimental test data are reliable and suitable for the
purpose of classification under Regulation (EC) No.1272/2008. In the
available screening study adverse effects regarding reproductive
performance and development were observed at the high dose level only.
While some animals were free of findings even at the high dose levels,
other high dose females suffered from prolonged gestation duration and
an increased number of stillborns. No findings were reported at the mid
and low dose level. Based on these data, the test substance is suspected
of causing developmental and reproductive toxicity effects at very high
doses and classification with H361fd is warranted.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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