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EC number: 213-590-1
CAS number: 991-84-4
In accordance with Annex IX, 8.7.3 of the REACH legislation, this study
at the 100-1000 tpa level is only required if the 28- or 90-day study
indicate adverse effects on reproductive organs or tissues. No such
effects on reproductive organs were observed in two subchronic studies
(see Chapter 7.5).
Developmental and teratogenic effects were not detected in the rat and
at doses that were not significantly toxic to the parent animals. NOAEL
(parental) = 3000 mg/kg bw/day and NOAEL (developmental) = 3000 mg/kg bw
The test article was administered at dosages of 0 (Control), 300, 1000
and 3000 mg/kg/day by intra gastric intubation during Days 6 to 15
inclusive of gestation. The animals were killed on Day 20 of gestation,
litter values determined and the foetuses examined for
structural malformations and anomalies. Prior to the main study, the
feasibility of administering 3000 mg/kg/day - the highest intended
dosage - was investigated in non-pregnant females which were treated for
ten consecutive days. No clinical signs of reaction to treatment were
observed in the feasibility study and there were no deaths; other
parameters, such as overall food intake and mean bodyweight gain, also
appeared to be unaffected and no macroscopic changes attributable to
treatment were recorded at terminal autopsy. In the main study, pale
coloured faeces were observed amongst rats treated at 3000 mg/kg/day,
the incidence - occurring between Days 8 and 16 of gestation - basically
coinciding with the dosing period. No signs of reaction were recorded at
either 300 or
1000 mg/kg/day. Two deaths occurred, one at 1000 mg/kg/day and another
at 3000 mg/kg/day, but both were consistent with intubation error. Mean
bodyweight gain of dams treated at 3000 mg/kg/day was slightly retarded
during the dosing period and parity with that of the control group had
not been regained by Day 20. Mean weight gain at 300 and 1000 mg/kg/day
remained essentially similar to that of the control group throughout. No
macroscopic changes were observed at terminal autopsy of treated animals
which were considered to be attributable to the test article. There were
no instances of total litter loss (total resorption) at any dosage, nor
any significant effects on litter parameters, as assessed by mean values
for pre- and post implantation loss, litter size, sex ratio, litter
weight and foetal weight. Embryonic and foetal development, as assessed
by the overall incidence of malformations, anomalies and skeletal
variants did not appear to have been adversely affected by treatment of
the dam at any of the dosages used in this study. It was concluded that
under the conditions of this study, the test item showed no evidence of
teratogenicity or of significant effects on embryo-foetal development.
In a developmental toxicity study the test substance (purity of > 99%)
was administered to 25 pregnant rats ((CrL: COBS CD (SD) BR strain) SPF)
per dose by gavage at dose levels of 300, 1000, 3000 mg/kg bw/day in
aqueous methylcellulose (1%). Treatment was performed once daily from
days 6 through 15 of gestation. Control animals were treated with the
vehicle only. Animals were sacrificed on day 20 of gestation. Two deaths
occurred, one at 1000 mg/kg day and another at 3000 mg/kg bw/day, but
both were consistent with intubation error. Pale coloured faeces were
observed amongst rats treated at 3000 mg/kg bw/day, the incidence -
occurring between Days 8 and 16 of gestation - basically coinciding with
the dosing period. No signs of reaction were recorded at either 300 or
1000 mg/kg bw/day. No other effects in the dams were observed. The
maternal NOAEL is 3000 mg/kg bw/day. There were no instances of total
litter loss (total resorption) in any group. Mean post implantation loss
of all treated groups was lower than that of the control group. Slightly
lower mean values recorded for litter size in all test groups were not
significantly different from the control value (P > 0.05) and appeared
to be largely a perpetuation of differences in ovulation rate which
would have pre-dated commencement of treatment. There was no appreciable
intergroup difference in mean sex ratio. Mean foetal weight of all test
groups was similar, or superior, to the control mean. Intergroup
variation in mean values for litter weight reflected differences in mean
litter size; there was no indication of any adverse effect of treatment.
Of the nine foetuses which were recorded as showing malformations, none
occurred at 3000 mg/kg bw/day: three were recorded in the control group,
five at 300 mg/kg bw/day and one at 1000 mg/kg bw/day. Neither the types
of defect seen nor their distribution indicated any association with
treatment. The overall incidence of visceral and skeletal anomalies did
not indicate any adverse treatment-related pattern. There were no
foetuses with extra (14) ribs amongst treated groups and mean values for
variant sternebrae did not indicate any adverse treatment-related
effects. Based on these findings, no substance-related effect on
embryonic or foetal development is assumed. The NOAEL for developmental
toxicity is 3000 mg/kg bw/day (Ciba Geigy, 1983).
The developmental toxicity study in the rat is classified acceptable for
assessment purposes of developmental toxicity as it satisfies the
guideline requirement for a developmental toxicity study (OECD 414) in
rodents in all but one aspect: treatment of dams was limited to
gestation periods Day 6-15 of gestation as opposed to treatment up to a
day before scheduled kill.
The findings of the above described study are supported by the findings
observed in a combined 2 -Generation toxicity/Carcinogenicity study,
performed by Mosinger (1976), where Wistar rats were treated with 200
mg/kg bw /day (nominal concentration) of the unchanged substance in diet
for 2 years. The animals were treated as follows: 3 months treatment
before mating for the P1 generation, 6 months treatment before mating
for the F1 generation and 8 months treatment for the F2 generation. The
first treatment was conducted on January 20, 1974 and the last one on
January 20, 1976. Each 1 male and 5 females of the P1 and F1 generations
were mated, each 5 animals per sex of the F1 generation were further
treated until mating. Each 5 animals per sex of the F2 generation were
further treated until the end of the study (growth). The following
parameters were examined in F1 / F2 offspring: number and sex of pups,
live births, postnatal mortality, presence of gross anomalies, weight
gain. The pups were examined for external and internal abnormalities,
including the cervical, thoracic, and abdominal viscera (not further
specified). Liver, kidneys and lungs were prepared for microscopic
examination in 2 animals. In the dams, no toxic effects were observed.
In the F1 and F2 generations, no congenital malfomations, teratogenic
effects or growth retardations were observed at this unique dose level.
Therefore, a NOAEL was set at 200 mg/kg bw/day for maternal toxicity as
well as for developmental toxicity.
Classification, Labeling, and Packaging Regulation (EC) No.
The available experimental test data is reliable and suitable for the
purpose of classification under Regulation (EC) No.1272/2008. Based on
the data, classification for toxicity to reproduction is not warranted
under Regulation (EC) No.1272/2008.
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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