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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2012-11-06 to 2013-10-31
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study, non GLP, but in compliance with China National Metrology Accreditation, in which the test parameters documented are based on testing guideline.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
no
Remarks:
non GLP, but in compliance with China National Metrology Accreditation
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
445-090-6
EC Name:
-
Cas Number:
5614-37-9
Molecular formula:
C6 H12 O
IUPAC Name:
Cyclopentyl methyl ether
Test material form:
liquid
Specific details on test material used for the study:
Batch No.: 2820246
Purity: 99.9%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Zhejiang center of laboratory animals
- Age at study initiation: 3 months old
- Weight at study initiation: 200-240 g for female and 350-450 g for male
- Fasting period before study:
- Housing: Suspended, wire bottom, stainless steel cage, no more than 5 rats per cage
- Diet (e.g. ad libitum): Conventional laboratory diet
- Water (e.g. ad libitum): Tap water by aseptic filtration, ad libitum
- Acclimation period: more than 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 30-70%
- Air changes (per hr): 12 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The weighed sample is added to tween-80 and distilled water to form emulsion, add distilled water to the nominal dose.
Exposure pathway is gavage exposure and gavage volume is 5 mL/kg.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Female and male rats should be mated in a cage on the ration of 1:1 at 4:00 pm daily, check the vaginal plug or vaginal smear the next morning.
Day 0 of pregnancy is defined as the day a vaginal plug or sperm are found.
Duration of treatment / exposure:
6-15 days after conception
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
800 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
140 SD rats with 40 male and 100 female were applied. Four groups were assigned.
The number of pregnant rats in control group, low dose level group, intermediate dose level group and high dose level group was 22, 24, 25 and 21 respectively.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on acute LD50 value 3160 mg/kg in female rats
- Rationale for animal assignment (if not random): randomly
- Other:

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: weigh female rats once every 3 days from conception

POST-MORTEM EXAMINATIONS: Yes
Females showing signs of abortion or premature delivery prior to scheduled termination should be killed and subjected to a thorough macroscopic examination.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes, each fetus is examined for external anomalies during caesarean section.
- Soft tissue examinations: Yes, one third of each litter was immersed in Bouin's solution and examined for viscera anomalies.
- Skeletal examinations: Yes, the remainder was immersed in 90% ethanol and examined for skeletal alterations.
Statistics:
Method
Each group of pregnant rats’ body weight, body length, tail length and body weight was compared with the control group applying Dennett’s t test. The rate of fetal resorptions, mortality and teratogenic rate deal with the chi-square test. Significance level α=0.05, chi-square test corrected significance level a=0.0170 (low, intermediate and high dose group compared with the control group, respectively).
Analysis of indicators
The number of experimental animal, average weight, number of pregnant animals, the number of corpus luteum, implantation, absorption fetus, number of live births, the number and percentage of stillbirth, fetal situation (sex, weight, placental weight, body length, tail length), teratogenic types (including appearance, bones and internal organs), the number and percentage.
Teratogenic rate:
Total teratogenic rate of each treatment group (%) = (total live fetuses of teratogenic / total live fetuses) *100%
(It was treated as a terata when live fetuses had more than one malformation)
It should be calculated for the single teratogenic rate when terata based on one or a few defects.
Single teratogenic rate of each treatment group (%) = (total terata / total live fetuses) *100%
Teratogenic index:
If total teratogenic rate or single teratogenic rate of group was significantly higher than the control group. It indicates that the dose had teratogenic effect.
Teratogenic index = LD50 of female animal/minimum teratogenic dose.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight of high dose group from day 9 were lower than the control group, body weight gain during pregnancy and absolute gain of high dose group were lower than the control group, the differences were statistically significant.
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed

Maternal developmental toxicity

Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Formation of rat embryos and fetal growth and development status:
In high dose group the weight of uterus (with fetal), the average fetal body weight, body length and tail length were lower than the control group, the differences were statistically significant.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
maternal abnormalities

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
In high dose group the weight of uterus (with fetal), the average fetal body weight, body length and tail length were lower than the control group, the differences were statistically significant.
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
In high-dose group a fetal was found gastroschisis with no tail and left hind foot valgus. But litters or fetuses as statistical unit compared with the control group, the difference was not statistically significant.
In high dose group two fetal malformations were found (different nest), a fetal with gastroschisis, no tail and left hind foot valgus, other one with rib deletion. But litters or fetuses as statistical unit compared with the control group, the difference was not statistically significant.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Some fetuses appears with hypoplastic supraoccipitals, hypoplastic interparietals and agenesis of other skull bone in high, intermediate and low dose level group. But litters or fetuses as statistical unit compared with the control group, the differences were not statistically significant.
A fetal with the right rib 13 deletion was found in high-dose group. But litters or fetuses as statistical unit compared with the control group, the differences were not statistically significant.
Visceral malformations:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Total teratogenic rate of high dose group was 0.8%, the difference was not statistically significant compared with the control group.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Abnormalities:
effects observed, non-treatment-related

Overall developmental toxicity

Developmental effects observed:
no
Lowest effective dose / conc.:
800 mg/kg bw/day (actual dose received)
Treatment related:
no

Applicant's summary and conclusion

Conclusions:
The results of teratogenicity study for this substance to pregnant rats repeated exposed by oral in 6 to 15 days of pregnancy showed that no obvious symptoms of poisoning was observed in all dose group (including period of exposure and the observation period). Compared with the control group, in the high dose level group, body weight gain of pregnant rats in later pregnancy was slower, the weight of uterus (with fetal), the average fetal body weight, body length and tail length were lower, the differences were significant. In high dose group two fetal malformations were found (different nest), a fetal with gastroschisis, no tail and left hind foot valgus, other one with rib deletion. But litters or fetuses as statistical unit compared with the control group, the difference was not statistically significant. The low-dose group and intermediate dose level group showed no abnormal compared with the control group. The results show that under the experimental conditions, the tested sample to the SD rats had no significant teratogenic effects. The NOAEL for maternal toxicity and the NOAEL for offspring developmental toxicity were both 200mg/(kg.d).