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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
7 April 2016 to 21 July 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
1996
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: OECD 421, Reproduction/Developmental Toxicity Screening Test
Version / remarks:
1995
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: OPPTS 870.3550, Reproduction/Developmental Toxicity Screening Test
Version / remarks:
2000
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents
Version / remarks:
2000
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane
EC Number:
241-881-3
EC Name:
1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane
Cas Number:
17955-88-3
Molecular formula:
C15H38O2Si3
IUPAC Name:
2,2,4,6,6-pentamethyl-4-octyl-3,5-dioxa-2,4,6-trisilaheptane
Test material form:
liquid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Expiration date of the lot/batch: 04 June 2017
- Purity test date: no data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: In refrigerator (2-8°C)
- Stability under test conditions: stable
- Solubility and stability of the test substance in the solvent/vehicle: Predicted solubility = 2.8E-05 mg/L at 20°C

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and the test substance.
- Preliminary purification step (if any): No correction was made for the purity/ composition of the test item.

FORM AS APPLIED IN THE TEST (if different from that of starting material): diluted in corn oil

Test animals

Species:
rat
Strain:
other: Crl:WI(Han)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, germany
- Age at study initiation: 10 weeks males and 11 weeks females
- Weight at study initiation: all animals were within ± 20% of the sex mean
- Fasting period before study: none
- Housing: During pre-mating the animals were housed in groups of 5 animals/ sex/ cage in Macrolon plastic cages. During mating main group females were caged together with main group males on a one to one basis in Macrolon plastic cages. During post-mating period main group males were housed in their home cage with a maximum of 5 animals/ cage; main group females were individually housed in Macrolon plastic cages.
- Diet: pelleted rodent diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24°C
- Humidity (%): 40 - 70%
- Air changes (per hr): 10/ hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
Using a plastic feeding tube. formulations were placed on a magnetic stirrer during dosing.
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and test substance. No correction was made for the purity/ composition of the test item.

VEHICLE
- Justification for use and choice of vehicle (if other than water): dried and deacidified corn oil
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Lot/batch no. (if required): no data
- Purity: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses were conducted during the treatment phase in week 1 and week 6, according to a validated method. The highest and the lowest concentrations were analyzed for homogeneity. All the concentrations were analysed for accuracy of preparation. The accuracy of preparation was considered acceptable if the mean measured concentrations were 90 - 110 % of the target concentration. Homogeneity was demonstrated if the coefficient of variation was =< 10%.
Details on mating procedure:
- Impregnation procedure: Following a minimum of 14 days pf expposure the animals were cohabitated.
- If cohoused: yes
- M/F ratio per cage: One main male and one main female of the same treatment group. Sibling mating was avoided.
- Length of cohabitation: Maximum of 14 days
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: Not applicable
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: no data
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: none
Duration of treatment / exposure:
Main and recovery males: 29 days
Main females: 41 to 47 days
Recovery females: 43 days (14 days recovery)
Frequency of treatment:
Daily, 7 days a week
Duration of test:
Up to 47 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
Main males and females: 10 males and 10 females
Control and recovery animals: 5 males and 5 females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on toxicity results of a 14-day dose range finding study.
- Rationale for animal assignment (if not random): The animals were assigned randomly.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily for clinical signs and twice daily for mortality and viability.
- Cage side observations checked included: clinical signs of toxicity, mortality and viability

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once prior to start of treatment and at weekly intervals during the treatment period. This was also performed outside the home cage in a standard arena.

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of exposure (prior to first exposure) and weekly thereafter. Mated main females were weighed on days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on days 1 and 4.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on Lactation days 5-7.
- Organs examined: See table No. 1.

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: No
- Number of late resorptions: No
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
• If the variables could be assumed to follow a normal distribution, the Dunnett-test based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
• The Steel-test was applied if the data could not be assumed to follow a normal distribution.
• The Fisher Exact-test was applied to frequency data.
• The Kruskal-Wallis nonparametric ANOVA test was applied to motor activitydata to determine intergroup differences.
Indices:
Reproductive indices: mating index; fertility index; conception index; gestation index; duration of gestation
Fetal indices: percentage live males at first litter check; percentage live females at first litter check; percentage of postnatal loss; viability index

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs or abnormalities were noted during the observation period that were considered to be related to treatment.
Any clinical signs noted during the treatment period occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No toxicologically relevant changes in body weight were noted.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
At 1000 mg/kg bw/day, an elongated mean activated partial thromboplastin time (APTT) was recorded for males at the end of treatment. The mean remained within the range considered normal for rats of this age and strain and at the end of the recovery period, mean activated partial thromboplastin time was similar to controls. The statistically significant lower red blood cell counts and haematocrit of females at 300 mg/kg at the end of treatment occurred in the absence of a dose-related trend. As such this was considered to be unrelated to treatment.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No toxicologically relevant changes occurred in clinical biochemistry parameters of treated rats.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No toxicologically relevant effects on hearing ability, pupillary reflex, static righting reflex and grip strength were observed in selected animals. Motor activity was similar between treated and control groups. All groups showed a similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period. One male at 100 mg/kg (no. 18) had an absent pupillary reflex of the right eye and had a white stain on the eye. Given the incidental nature of this finding, this was considered unrelated to treatment with the test item.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No toxicologically relevant changes in organ weights were recorded. There was a minimal statistically significant increase in liver weights (absolute only) in main group females treated at 300 and 1000 mg/kg/day without any correlating findings at necropsy or after microscopic evaluation. Also, the liver weights were all within the range expected for female rats of this age and strain treated in this type of study and therefore not considered to be toxicologically relevant.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test item-related gross observations. All of the recorded macroscopic findings were within the range of background gross observations encountered in rats of this age and strain.
Neuropathological findings:
not examined
Description (incidence and severity):
There were no test item-related microscopic observations. Slight vacuolation in the zona fasiculata of the adrenal glands was recorded in 1 male of the 100 mg/kg/day main group and 1 male of the 1000 mg/kg/day main group and in 2 males of the 1000 mg/kg/day recovery group. Based on the absence of a clear dose-relationship and the fact that slight vacuolation in the zona fasciculata can be observed as a background finding in control rats (although this was not the case in the present study), the adrenal gland finding is not considered to be test item related.
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not examined
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
No changes in body weight occurred among pups.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In the combined 28-day repeated dose toxicity study with the reproduction/ developmental toxicity screening test, the reported NOAEL for maternal toxicity and developmental/ teratogenic effects was greater than 1000 mg/kg bw. No treatment-related changes were observed in any of the test animals.