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Diss Factsheets

Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test guideline (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 2008 - Sept 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Good quality GLP study conforming to applicable guidelines.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report date:
2009

Materials and methods

Test guidelineopen allclose all
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.34 (One-Generation Reproduction Toxicity Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
CD-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: males 8-9 weeks, females 9-10 weeks
- Weight at study initiation: males 283.2-351.5 g, females205.5-258.4 g
- Fasting period before study: overnight
- Housing: The pre-mating animals and the pregnant females were kept singly, the rearing females together with their pups and the mating animals were kept as pairs
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12/12
In-life dates:
Males 1st Administration: July 28th 2008
Females 1st Administration: Sept 22nd 2008
Satellite Females 1st Administration: August 4th 2008
Termination of in-life phase: December 5th 2008

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Oral, by gavage

Groups and Dose levels

Group 1 vehicle control
Group 2 31.6 mg/kg b.w./day
Group 3 100 mg/kg b.w./day
Group 4 316 mg/kg b.w./day
Details on mating procedure:
Main Study Animals:
Sexually mature male and female rats (F0 generation) were randomly paired for mating.
Mating was monogamous: 1 male and 1 female animal were placed in one cage during the dark period. The female was placed with the same male until pregnancy occurred or three weeks had elapsed.
Each morning the females were examined for the presence of sperm or a vaginal plug. If findings were negative, mating was repeated. The day on which sperm or a vaginal plug was found was considered as the day of conception and was defined as day 0 of pregnancy. In case pairing was unsuccessful, re-mating of females with proven males of the same group were considered. This procedure was repeated until at least 20 pregnant dams were available for each main study group.

Satellite animals:
Four groups of pregnant satellite rats (8 animals per group) were formed from monogamous matings with non-study sires of the same strain which were carried out on a daily basis. The satellite females were assigned to their respective groups according to their mating day i.e. in a cyclic way following the listing of positive findings during vaginal lavages (taken each morning and the stages of oestrus cycle were recorded).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test item-vehicle solution samples were taken by LPT during the course of the study. The samples were stored at -20 °C and were analysed by LPT.
Duration of treatment / exposure:
5 mL/kg b.w./day administered once daily, 7 days per week
Frequency of treatment:
Once daily, 7 days per week
No. of animals per sex per dose:
192 F0 animals (96 male and 96 female animals)
i.e. 24 males and 24 females per group in order to obtain at least 20 pregnant females per group for evaluation of the F0 generation.

Teratogenic effects (Satellite animals)
10 female animals were allocated to groups 1 to 4 for screening for teratogenic effects, a sufficient number to obtain at least 8 pregnant animals for each group.
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
Mortality: One high dosed female rat treated with 316 mg prematurely during parturition on test day 99.

Clinical signs
Treatment with 100 or 316 mg/kg b.w./day led to haemorrhagic urine in 4 of 24 (group 3) or 13 of 24 (group 4) male rats during pre-mating and mating, starting on test days 68 or 16 during the pre-mating period, respectively.
Haemorrhagic urine was not noted in any of the dosed female rats.
Further, treatment with 316 mg/kg b.w./day led to salivation (slight or moderate) in a few male rats during pre-mating and mating on up to 11 test days as well as in 1 or 2 females during pre-mating, mating and gestation, starting on test day 26 (males) or on test day 66 (females) during the pre-mating period.

Body weight and body weight gain:

Males
The mean body weight of the males animals treated with 100 mg/kg b.w./day was slightly but significantly decreased by 7% from test week 2 onwards until the end of the mating period (by 9% in test week 13).
Treatment with 316 mg/kg b.w./day led to a markedly significantly decreased mean body weight from pre-mating week 1 onwards until the end of the mating period in test week 13 (by 11% in test week 1, by 20% in test week 13).
Body weight gain was reduced accordingly in both groups.

Females
The mean body weight of the females treated with 100 mg/kg b.w./day of test substance was slightly decreased during the pre-mating period (by 4%), during the mating period (by 6%) and slightly reduced during the entire gestation period (up to 6%).
Treatment with 316 mg/kg b.w./day led to a reduced mean body weight of the female animals from test week 1 onwards (by up to 18%) until the end of the lactation period (statistically significant at p ≤ 0.01 during pre-mating, mating and gestation, as well as on lactation days 4 and 7). Body weight gain was reduced accordingly in both groups.

Food consumption

Males
The male rats treated with 100 or 316 mg/kg b.w./day of the test susbtance revealed a significantly decreased food intake in test week 1 of the pre-mating period (by 11% and by 19%, respectively).

Females
The females treated with 100 or 316 mg/kg b.w./day revealed a significantly decreased food intake by 11% (group 3) and by 23% (group 4) in test week 1 of the pre-mating period.
Treatment with 316 mg/kg b.w./day revealed a significantly reduced mean relative food intake on lactation days 4 to 21 (up to 37% on lactation day 14).

Drinking water consumption:
No test item-related influence was noted.
Oestrous cyclicity (parental animals):
No test item-related influence was noted on the total number, length or number of abnormal cycles of the oestrous cycles.
A slightly reduced female fertility index was noted in the high dose group after treatment with 316 mg/kg b.w./day.
Sperm parameters (parental animals):
Treatment with 316 mg/kg b.w./day led to a slightly reduced mean percentage of motile spermatozoa in the male rats (by 61.40%, statistically not significant, control: 69.61%).
Further, the mean percentage of morphologically normal spermatids was slightly reduced in the high dosed male rats at 316 mg/kg b.w./day (statistically not significant).
No test item-related influence was noted on the male fertility at any of the tested dose levels.
Litter observations:
Treatment with 316 mg/kg b.w./day led to a slightly reduced mean body weight of male and female pups from lactation day 1 onwards until lactation day 7 (by 15% in males, by 15% or 16% in females).

No test item-related influence was noted on the physical development of the F1 pups at any of the tested dose levels.

Postmortem examinations (parental animals):
Macroscopic:
Treatment with 316 mg/kg b.w./day led to macroscopic changes in form of an enlarged spleen in all 20 high dosed male rats and in four female animals. The spleen of one further female animal was partly adhered to fatty tissue.

Microscopic:
The histomorphological examination revealed morphological lesions in the spleen of group 4 animals which are considered to be related to the test item. Microscopic changes of the spleen in form of congestion, brownish pigments and haematopoiesis were noted in 15 male and 4 female high-dosed animals. Spermatic granuloma were noted in the epididymis of 3 of 20 male test item-treated males of the high dose.
Postmortem examinations (offspring):
Macroscopic inspection at necropsy did not reveal any test item-related changes in the organs or tissues of the F1 pups.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
-Haemorrhagic urine in 4 of 24 (group 3) or 13 of 24 (group 4) male rats during pre-mating and mating.Haemorrhagic urine was not noted in any of the dosed female rats. -Salivation (slight or moderate) noticed in some animals.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slight decrease m/f
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Slight decrease m/f
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Spleen lesions in all highest dose anmials. Spermatic granuloma in 3 of 20 males in highest-dose group.
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
At highest dose, slightly reduced mean percentage of motile spermatozoa in the male rats.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
The mean number of viable male and female pups at birth was statistical significantly decreased in the high dose group (316 mg/kg bw/day.

Details on results (P0)

In general, macroscopic and histopatholical effects were only observed in animals receiving the highest doses (316 mg/kg bw/day)

Effect levels (P0)

open allclose all
Dose descriptor:
NOEL
Effect level:
> 31.6 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effects on the parental F0 Generation
Dose descriptor:
NOEL
Effect level:
> 31.6 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Screening for Teratogenic Effects (Satellite Animals): Effects on the dams

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
High-dose group (316 mg/kg bw/day): Slightly reduced mean body weight of male and female pups from lactation day 1 onwards until lactation day 7.
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Effect levels (F1)

open allclose all
Dose descriptor:
NOEL
Generation:
F1
Effect level:
> 31.6 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effects on the development of the conceptus and the offspring (F1 generation) through sexual maturity
Dose descriptor:
NOEL
Generation:
F1
Effect level:
> 100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Screening for Teratogenic Effects (Satellite Animals): Effects on the Fetuses.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
One-generation Reproductive Toxicity Study:
Under the test conditions the following NOELs were noted after administration by oral gavage during pre-mating and mating periods (parental males) and during the pre-mating, mating, gestation and lactation periods (parental females):

Effects on the parental F0 Generation:
NOEL 31.6 mg/kg bw/day

Effects on the development of the conceptus and the offspring (F1 generation) through sexual maturity:
NOEL 31.6 mg/kg bw/day

Screening for Teratogenic Effects (Satellite Animals)
Under the test conditions the following NOELs were noted following adminstration by oral gavage from the 6th to 19th days of pregnancy:

Effects on the dams:
NOEL 31.6 mg/kg bw/day

Effects on the Fetuses:
NOEL 100 mg/kg bw/day

No teratogenic properties were noted even at materno-toxic dose levels up to 316mg/kg/day