Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In an oral combined repeated dose toxicity study with the reproduction / developmental toxicity screening test conducted to OECD 422 and to GLP (Harlan Laboratories Ltd., 2010) the NOAEL for general toxicity was 200 mg/kg bw/day in rats, based on the histopathology findings of hepatic brown pigment accumulation noted at 800 mg/kg bw/day in males and on the dose dependent and statistically significant increase of liver weight in females at 200 and 800 mg/kg bw/day. There were no adverse effects on any of the reproductive parameters measured. Therefore, the NOAEL for reproductive effects was at least 800 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 December to 22 March 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Qualifier:
according to
Guideline:
other: "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test” Health Effects Test Guideline OPPTS 870.3650
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories Ltd.
- Age at study initiation: 11 weeks
- Weight at study initiation: Males: 287-335 g: Females: 179-211 g.
- Fasting period before study: no data
- Housing: individually in Makrolon type-3 cages (except in pairing period)
- Diet (e.g. ad libitum): standard diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: seven days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17 December 2008 To: 7 February 2009
Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
dried and deacidified
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The dose formulations were prepared weekly. The test substance was weighed into a glass beaker on a tared precision balance and approximately 100% of the vehicle was added (w/v). Using an appropriate homogenizer, a homogeneous suspension was prepared. Separate formulations were prepared for each concentration. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: nightly until evidence of copulation was observed
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no data
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
On the first treatment day samples from the control group as well as three samples (top, middle and bottom) of about 2 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. Samples of about 2 g of each concentration were taken from the middle only to confirm stability (7 days). During the last week of the treatment, samples were taken from the middle only to confirm concentration. The samples were analysed by GC coupled to an FI detector following an analytical procedure developed at Harlan Laboratories.
Duration of treatment / exposure:
Males: at least 28 days
Females: approximately 49 days
Frequency of treatment:
Daily
Details on study schedule:
Animals were treated for two weeks, then moved to mating cages for up to two weeks, until evidence of mating was observed. Males were treated for a total of 28 days (including 14 days prior to pairing), and females for approximately 49 days (14 days prior to pairing, through the pairing and gestation periods, up until day 4 postpartum)
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:
Ten
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose range-finding study
Positive control:
Not applicable
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily cage-side clinical observations (once daily, during acclimatization and up to day of necropsy). Additionally, females were observed for signs of difficult or prolonged parturition, and behavioural abnormalities in nesting and nursing.

DETAILED CLINICAL OBSERVATIONS: Yes, once prior to the first administration of the test item and weekly thereafter, detailed clinical observations were performed outside the home cage. Animals were observed for the following: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies or bizarre behaviour were also reported, if present.

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded daily from treatment start to day of necropsy.

FOOD CONSUMPTION: Males: Weekly during pre-pairing and after pairing periods; Females: Pre-pairing period days 1-8 and 8-14; gestation days 0-7, 7-14 and 14-21 post coitum, and days 1-4 post partum. No food consumption was recorded during the pairing period.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were obtained on the day before or on the day of the scheduled necropsy from 5 males from each group. Blood samples from 5 lactating females from each group were obtained on day 5 postpartum.
- Anaesthetic used for blood collection: Yes, isoflurane
- Animals fasted: Yes, 18 hours
- Parameters checked in table 1 (Section 7.5.1) were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Time schedule for collection of blood: Blood samples were obtained on the day before or on the day of the scheduled necropsy from 5 males from each group. Blood samples from 5 lactating females from each group were obtained on day 5 postpartum.
- Animals fasted: Yes, 18 hours
- Parameters checked in table 1 (Section 7.5.1) were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: functional observation battery (FOB) and locomotor activity
Oestrous cyclicity (parental animals):
Not applicable
Sperm parameters (parental animals):
Parameters examined in P males: testis weight, epididymis weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: all surviving animals when no longer needed for the assessment of reproductive effects
- Maternal animals: all surviving animals on day 5 postpartum

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera
- Number of implantation sites and corpora lutea recorded for all dams with litters. Uteri visualised for possible haemorrhagic areas of implantation sites (with ammonium sulphide solution)

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 2 (Section 7.5.1) were prepared for microscopic examination and weighed
Postmortem examinations (offspring):
SACRIFICE
- Pups were sacrificed on day 4 postpartum

GROSS NECROPSY
- Gross necropsy consisted of macroscopic examination [no further details on exact parameters checked]

HISTOPATHOLOGY / ORGAN WEIGHTS
- Not performed on pups
Statistics:
The following statistical methods were used to analyse food consumption, body weights, functional observational battery, locomotor activity and reproduction data:
• Means and standard deviations of various data were calculated.
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the Dunnett test when the data could not be assumed to follow a normal distribution.
• Fisher’s exact-test was applied if the variables could not be dichotomized without loss of information.
Reproductive indices:
Fertility and gestation indices, mean precoital time, conception rate, duration of gestation, corpora lutea, implantation rate, post-implantation loss and pup sex ratio.
Offspring viability indices:
Viability index, birth index, mean litter size and post-natal loss
Clinical signs:
no effects observed
Description (incidence and severity):
See Section 7.5.1 for details on systemic effects.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
(Data for control, low-, mid- and high-dose groups, respectively)
Fertility index: 100% in all groups
Gestation index: 100% in all groups
Mean precoital time (mean): 2.3, 2.5, 2.9, 2.8
Conception rate: 100% in all groups
Duration of gestation (days): 21.2, 21.5, 21.6, 21.6
Corpora lutea count (mean per dam): 14.7, 15.2, 15.3, 16.1
Implantation rate (mean number of implantations per litter): 13.8, 13.8, 14.8, 14.2
Post-implantation loss (per dam): 1.0, 1.2, 0.4, 2.0
Although post-implantation loss in group 4 was significantly higher than in the control group, the loss as a percentage of total implantations and mean post-implantation loss was within the range of historical control data. A statistically significantly reduced birth index in group 4 was not considered to be an adverse effect of treatment as mean litter size was similar to the control group.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 800 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse reproductive effects observed at any tested concentration
Critical effects observed:
no
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At first litter check, in group 4 no milk in the stomach was observed in 13 pups in three litters. This was considered to be treatment-related. One pup was noted to have the right hind leg cannibalized and autolysis was observed in two pups which were found dead. One pup in group 3 had abdomen blue swollen and one pup in group 2 had tail thread-like. These findings were considered to be incidental.

During lactation, in group 4 twelve pups in one litter and six pups in another were noted to have cold skin at touch on day 2 postpartum or at last litter check. This was considered to be related to the treatment with the test substance. Autolysis was observed in all pups in one litter (same dam lost its whole litter on day 3 postpartum). The other observations noted were no milk in the stomach in one pup and in six pups in another litter, right hind leg cannibalized in one pup were considered to be incidental.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
There was increased post-natal pup loss in the highest dose group (see Table in Section 7.8.2)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean pup weights on day 1 postpartum were unaffected by treatment with the test item. During the lactation period (to day 4 postpartum), in group 4 body weight development was reduced although not statistically significant (+22.0% versus 37.3% in the control).
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At macroscopic examination: In group 4, no milk in the stomach was noted in seven pups in one litter and in six pups in another litter and in all pups in a further litter which were found dead between days 2 and 3 postpartum. Autolysis was observed in two pups in one litter. No macroscopical findings were noted in groups 1, 2 and 3.
Histopathological findings:
not examined
Other effects:
not specified
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on post-natal pup loss and reduced body weight gain.
Critical effects observed:
not specified
Reproductive effects observed:
no
Conclusions:
In an oral reproductive toxicity screening study, performed to GLP and conducted according to OECD Guideline 422, the no-observed-adverse-effect level (NOAEL) for toxicity to reproduction with 1,1,1,3,5,5,5-heptamethyltrisiloxane in rats was at least 800 mg/kg bw/day, the highest dose tested.
Executive summary:

In an oral reproductive toxicity screening study (combined with a repeated dose toxicity study and developmental toxicity screening test),

performed to GLP and conducted according to OECD Guideline 422, 1,1,1,3,5,5,5-heptamethyltrisiloxane was assessed for its ability to induce reproductive toxicity in Wistar rats.

Four groups of ten male and ten female rats were treated by oral gavage with the test substance (in corn oil) at 0, 50, 200 or 800 mg/kg bw/day. Following two weeks of treatment, animals were allowed to mate for up to two weeks. In total, males were treated for at least 28 days (including the pre-mating period of 14 days), while females were treated for approximately 49 days (a pre-mating period of 14 days, a mating period of up to 14 days, throughout gestation and up until 4 days post-partum). Animals were observed throughout the study for any overt signs of toxicity or morbidity, until sacrifice and gross necropsy. A number of reproductive parameters were measured, including fertility and gestation indices, mean precoital time, conception rate, duration of gestation, corpora lutea, implantation rate, post-implantation loss and pup sex ratio.

 

All animals survived until scheduled necropsy. Fertility index, gestation index and conception rate were 100% in all groups and mean precoital time and duration of gestation were unaffected by treatment. There were no adverse effects of treatment with 1,1,1,3,5,5,5-heptamethyltrisiloxane on fertility, and a no-observed-adverse-effect-level (NOAEL) of at least 800 mg/kg bw/day (the highest dose tested) was determined for toxicity to reproduction on the basis of this screening test.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
800 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There is a reliable OECD 422 screening study available for 1,1,1,3,5,5,5 -heptamethyltrisiloxane.

There were no adverse effects on any of the reproductive parameters measured up to the maximum dose level of 800 mg/kg bw/day. Therefore, the NOAEL for reproductive effects was at least 800 mg/kg bw/day.




Effects on developmental toxicity

Description of key information

In line with the read-across approach accepted in ECHA final decision TPE-D-2114424726 -47 -01/F, the key study for developmental toxicity was read-across from the structural analogue octamethyltrisiloxane.

In the developmental toxicity study (Dow Corning Corporation, 2017b) conducted according to OECD Test Guideline 414 and in compliance with GLP, via oral (gavage) route, there was no indication of embryo/fetal toxicity or teratogenicity at any dose level tested. The NOAEL for developmental toxicity was determined to be 750 mg/kg/day, the highest dose level tested.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 March 2017 to 21 September 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF, the Japanese Ministry of Agriculture, Forestry and Fisheries, Notification of 12 NohSan-8147, Guideline 2-1-18, Teratogenicity study, 24 November 2000.
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Details on test animals and environmental conditions:
Species and Sex: Rats, time-mated females
Strain and Justification: Crl:CD(SD) rats were selected because of their general acceptance and suitability for toxicity testing, the availability of historical background data, and the reliability of the commercial supplier.
Supplier and Location: Charles River Laboratories (CRL) (Raleigh, North Carolina, USA)
Age and Weight at Study Start: Sexually mature adult, weighing approximately 200-250 g

Health Status and Acclimation: Upon arrival all animals were acclimated to the laboratory for at least four days prior to the start of test material administration. During the acclimation period, each animal was evaluated by a veterinarian trained in the field of Laboratory Animal Medicine, or a trained animal/toxicology technician, to determine the general health status and acceptability for study purposes. The Toxicology and Environmental Research and Consulting Laboratory is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).

Housing: Upon arrival animals were housed one per cage in stainless steel cages.

Environmental conditions:
Temperature: 22°C with a range of 20°C-26°C
Humidity: 50% with a range of 30-70%
Air Changes: 10-15 times/hour (average)
Photoperiod: 12-hour light/dark (on at 6:00 a.m. and off at 6:00 p.m.)
Enrichment: From the day of arrival until necropsy. Enrichment included paper nesting material and open areas on the cage sides for visualization of other rats.
Randomization and Identification: Animals were stratified by GD 0 body weight and then randomly assigned to treatment groups using a computer program designed to increase the probability of uniform mean group weights and standard deviations at the start of the study.
Animals that were placed on study were uniquely identified via subcutaneously implanted transponders (BioMedic Data Systems, Seaford, Delaware) that were correlated to unique alphanumeric identification numbers.

Feed and water: LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in meal form. Feed and municipal water were provided ad libitum.
Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
(dried and deacidified corn oil)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

- Octamethyltrisiloxane was prepared in dried and deacidified corn oil at dose levels of 0, 75, 250, or 750 mg/kg/day.

VEHICLE
- dried and deacidified corn oil

The rats were ordered and mated in six different replicates from the supplier to stagger cesarean sections over a period of two weeks.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration Verification and Homogeneity:
Dose solutions were prepared for analysis. Dosing solutions were shipped and stored at room temperature. Dose confirmation analyses of all dose levels, plus control, were determined from the first mix prior to exposure. The homogeneity of the low-dose and the high-dose test solutions was determined concurrent with dose confirmation. Additional samples of the low-dose and mid-dose concentrations were sent to the Lab to be analysed for dose confirmation and homogeneity following the start of dosing.
The initial analytical dose check for the low-dose and mid-dose solutions were below the acceptable range of targeted concentration from the first mix; therefore, no solutions from this mix were used to dose the animals and samples from the low-dose and mid-dose of the second mix were analysed. The method used for analysing the test material in dried and deacidified corn oil was gas chromatography with flame ionization detector (GC/FID) (Vogel, 2016) and followed the Lab's Standard Operating Procedures.
Octamethyltrisiloxane in dried and deacidified corn oil has been shown to be stable for up to 14 days at concentrations ranging from 12.5 - 250 mg/mL (Vogel, 2016). Dose solutions were prepared and used within these ranges; therefore, additional stability analyses were not conducted.
Retainer Samples. A sample of each lot number of the bulk test material was retained. No samples of dose solutions were retained.
Details on mating procedure:
The rats were ordered and mated in six different replicates from the supplier to stagger caesarean sections over a period of two weeks.
Duration of treatment / exposure:
GD 6-20
Frequency of treatment:
Daily
Duration of test:
Test material administration began on March 20, 2017 and the last group of rats were necropsied on April 19, 2017.
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
75 mg/kg bw/day
Dose / conc.:
250 mg/kg bw/day
Dose / conc.:
750 mg/kg bw/day
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
Groups of 24 Crl:CD(SD) rats were administered octamethyltrisiloxane in dried and deacidified corn oil by gavage at dose levels of 0, 75, 250, or 750 mg/kg/day on GD 6-20. The rats were ordered and mated in six different replicates from the supplier to stagger cesarean sections over a period of two weeks.

Route, Method of Administration, Frequency, Duration, and Justification: Test material was administered daily by oral gavage from GD 6-20. Oral administration is the preferred route of exposure specified in the relevant test guideline.
Dose Levels and Justification: Dose levels for this study were selected based on the 28-day and KMD studies discussed in the Previous Toxicity Information section above. The high-dose of 750 mg/kg/day was expected to induce overt signs of maternal toxicity (i.e., increased liver weights and histopathology). The lower dose levels were selected to provide dose response data for any toxicity observed among the high-dose group rats.
Maternal examinations:
Daily Observations: A cage-side examination (including morbidity, mortality, and the availability of feed and water) at least twice daily, at approximately the same time each day.
Clinical Observations: At least once daily.
Body weights: On GD 0 by the supplier and daily from GD 6-21.
Feed Consumption: Recorded and statistically analysed for all animals every 3 days from GD 3-21 by weighing feed containers at the start and end of a measurement cycle.
Necropsy: On GD 21
Histopathology: Histopathological evaluation of the liver on all pregnant animals that survived to the scheduled necropsy.
Ovaries and uterine content:
Gravid uterine weights were recorded, along with the number of corpora lutea, uterine implantations, resorptions, and live/dead foetuses. All foetuses were weighed, sexed, and examined for external alterations. Approximately one half of the foetuses were examined for visceral and craniofacial alterations while skeletal examinations were conducted on the remaining foetuses.
Fetal examinations:
The individual body weight of all viable/dead foetuses and sex of all foetuses was recorded.
Total litter weight was calculated by addition of individual foetal body weights in a litter.
All foetuses were given an external examination that included observations on body proportions, the head and face (including closure of the palate), abdomen, spine, extremities, genitalia, rectum, and tail.
All viable foetuses were euthanized by sublingual oral administration of sodium pentobarbital solution. At least one half of all the foetuses in each litter were chosen randomly via computer for visceral examination conducted by dissection under a low power stereomicroscope for evidence of visceral alterations (Staples, 1974; Stuckhardt and Poppe, 1984).
The visceral examination included observation of the thymus, trachea, esophagus, lungs, great vessels, heart (external and internal), liver, gastrointestinal tract, pancreas, spleen, kidney (sectioned), adrenal glands, ureters, bladder, and reproductive organs.
The heads of these foetuses were removed, placed in Bouin’s fixative and serially sectioned to allow for inspection of the eyes, brain, nasal passages, and tongue (Wilson, 1965). The foetal body was preserved in neutral, phosphate-buffered 10% formalin (to be discarded approximately six months after completion of the final report).
The remaining foetuses not selected for visceral examination were then skinned, eviscerated, preserved in alcohol, and double stained with Alcian Blue and Alizarin Red S for cartilage and bone according to methods based on Trueman et al. (1999) and Zablotny (2002) and a thorough evaluation of the foetal skeleton was conducted (foetal skeletal bodies were archived following completion of the final report). However, a foetus may have been intentionally changed from one selected for visceral examination to one processed for skeletal examination (and vice versa) if it was deemed that such examination would provide more meaningful data about a suspected abnormality.
All foetal alterations were classified as a variation or malformation. A variation is defined as a divergence beyond the normal range of structural constitution that may not adversely affect survival or health. A malformation is defined as a permanent structural change that may adversely affect survival, development or function and/or which occurs at a relatively low incidence in the specific species/strain.
The maternal necropsy and foetal examinations were conducted such that investigators were blind to treatment group assignment
Statistics:
Maternal body weights, maternal body weight gains, organ weights (absolute and relative with the exception of only absolute weight for gravid uterus), total litter weights, foetal body weights, and feed consumption were evaluated by Bartlett’s test (alpha = 0.01; Winer, 1971) for homogeneity of variance. Based on the outcome of Bartlett's test, a parametric (Steel and Torrie, 1960) or nonparametric (Hollander and Wolfe, 1973) analysis of variance (ANOVA) was performed. If the ANOVA was significant at alpha = 0.05, analysis by Dunnett's test (alpha = 0.05; Winer, 1971) or the Wilcoxon Rank-Sum test (alpha = 0.05; Hollander and Wolfe, 1973) with Bonferroni's correction (Miller, 1966) was performed, respectively.
Frequency of pre- and post-implantation loss (calculated), and foetal alterations (if any) were analysed using a censored Wilcoxon test (Haseman and Hoel, 1974) with Bonferroni’s correction applied when the incidence was greater than 5%. The number of corpora lutea, implantations, and litter size were evaluated using a nonparametric ANOVA (alpha = 0.05) followed by the Wilcoxon Rank-Sum test (alpha = 0.05) with Bonferroni's correction.
Pregnancy rates were analysed using the Fisher exact probability test (alpha = 0.05; Siegel, 1956) with Bonferroni’s correction. Foetal sex ratios were analysed using a binomial distribution test. Non-pregnant females, females with resorptions only, or females found to be pregnant after staining of their uteri were excluded from the appropriate analyses. Statistical outliers (alpha = 0.02) were identified by the sequential method of Grubbs (1969) and were routinely excluded from feed consumption only. Other outliers, if excluded, were excluded from analysis for documented, scientifically sound reasons. Both Dunnett’s test and Bonferroni’s correction corrected for multiple comparisons to the control and were reported at the corrected alpha level.
Clinical signs:
no effects observed
Description (incidence and severity):
Examinations performed on all animals revealed no treatment-related findings throughout the duration of the study.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a treatment-related 19.8% decrease in body weight gain of animals in the 750 mg/kg/day group from GD 6-9 (Table 1). This decrease recovered and was similar to control for the remainder of the study.

Body weight gains of animals in the 250 and 750 mg/kg/day groups were higher than control and statistically identified from GD 15-21 with concomitant increases in feed consumption.

Body weight gains of animals in the 250 mg/kg/day group were higher than control and statistically significant over the GD 6-21 and GD 0-21 measured intervals. These higher body weight gains were considered unrelated to treatment with Octamethyltrisiloxane as the differences were minimal, there was no effect in body weight at any dose level, and corrected body weights on GD 21 were similar to control. Body weights of animals in all dose groups and body weight gains of animals in the 75 mg/kg/day dose group were similar to control throughout the duration of the study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no treatment-related differences in the amount of feed consumed by any treated groups when compared to controls. Feed consumption of animals in the 250 and 750 mg/kg/day groups were higher and statistically significant from GD 15-21 with concomitant increases in body weight gains (Table 2). These higher feed consumption values were considered unrelated to treatment with octamethyltrisiloxane. Feed consumption was similar to controls for animals in the 75 mg/kg/day group throughout the duration of the study.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
There were treatment-related, statistically significant increases in mean absolute and relative liver weights at all dose levels tested (Table 3) with correlating histopathological observations. The mean relative liver weights of females given 75, 250, or 750 mg/kg/day were 9.3%, 13.5%, or 29.5% higher than controls, respectively.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related gross pathologic observations.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related very slight hypertrophy of centrilobular/midzonal hepatocytes was present in 12/24 females given 75 mg/kg/day and in 17/24 females given 250 mg/kg/day (Table 4). Treatment-related slight hypertrophy of centrilobular/midzonal hepatocytes was present in 7/24 females given 250 mg/kg/day and in 24/24 females given 750 mg/kg/day. The hepatocellular hypertrophy corresponded to the dose related increases in liver weights of females given 75, 250 or 750 mg/kg/day. Two females given 750 mg/kg/day had treatment-related very slight multifocal chronic inflammation in periportal regions of the liver, and one of the females with chronic inflammation also had treatment-related very slight increased number of mitotic figures in hepatocytes. Treatment-related pigment deposits were present in the intrahepatic bile ducts, hepatocytes and/or Kupffer cells of six females given 750 mg/kg/day. The pigment deposits were brown when examined with a light microscope and birefringent with some deposits featuring Maltese cross formations when examined with polarized light. All of the treatment-related liver effects were consistent with a previously conducted 28-day oral gavage toxicity study with octamethyltrisiloxane (Braun, 2010). The pigment deposits in animals 471, 475, 478, and 482 were negative for the presence of bile when processed with Fouchet’s bile stain.
Histopathological findings: neoplastic:
no effects observed
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:
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:
not specified
Details on maternal toxic effects:
No effects noted.
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: Based on the decreased body weight gain and liver weight increases combined with the chronic inflammation of the liver noted in animals in the 750 mg/kg/day group
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Foetal body weights of males in the 750 mg/kg/day group, females in the 250 and 750 mg/kg/day groups, and sexes combined in the 250 and 750 mg/kg/day groups were higher than control and statistically identified. These higher body weights were considered unrelated to treatment with octamethyltrisiloxane as they were within recent historical control values.
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
Details on embryotoxic / teratogenic effects:
No effects noted.
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: There was no indication of embryo/fetal toxicity or teratogenicity at any dose level tested.
Abnormalities:
no effects observed
Developmental effects observed:
no

Table 1. Body Weight Gains (g) – Selected Intervals

Dose

(mg/kg/day)

Day of Gestation

   6 -9  9 -12  15 -18  18 -21  6 -21  0 -21
0  12.1 19.0   37.0 50.4  139.9  171.2 
 75  14.0 21.4  40.7  55.8  153.7  184.9 
 250  13.2 21.6  43.2*  59.1*  159.3*  190.8* 
 750  9.7 20.6  42.5*  59.2*  152.8  184.9 

Bold type indicates the effect was interpreted to be treatment related.

* Statistically different from control mean by Dunnett’s Test, Alpha = 0.05.

Table 2. Feed Consumption (g/day)

 Dose (mg/kg/day)

Day of Gestation  

   6 -9  15 -18  18 -21
 0  17.4 21.0  19.8 
 75  17.7 22.6  21.5 
 250  17.6 24.1*  22.3* 
 750  16.5 24.4*  23.6* 

* Statistically different from control mean by Dunnett’s Test, Alpha = 0.05.

Table 3. Liver Weights

 Dose (mg/kg/day) Final Body Weight (g)   Liver (g) Liver (g/100) 
 0  391.8 13.346  3.407 
 75  405.4 15.122*  3.725* 
 250  411.5 15.928*  3.867* 
 750  405.0 17.835*  4.411* 

* Statistically different from control mean by Dunnett’s Test, Alpha = 0.05.

Table 4. Histopathologic Liver Alterations

 Sex           Females
 Dose level (mg/kg/day)/Liver (number examined)  0/24 75/24 250/24 750/24

Hypertrophy, increased eosinophilia, hepatocyte, centrilobular/midzonal (-very slight/-slight)

 0/0

12/0 17/7 0/24 

Increased Number of Mitotic Figures, hepatocyte, -very slight

 0

Inflammation, chronic, periportal, multifocal -very slight

 0
Pigment, bile duct, focal -very slight  0 1 
Pigment, bile duct, multifocal -very slight  0
Pigment, hepatocyte, multifocal -very slight  0
Pigment, Kupffer cell, multifocal -very slight  0

Bold type indicates the effect was interpreted to be treatment related.

Conclusions:
In a developmental toxicity study (Dow Corning Corporation, 2017) carried out according to OECD Test Guideline 414, there was no indication of embryo/foetal toxicity or teratogenicity at any dose level tested. The NOAEL for developmental toxicity was determined to be 750 mg/kg/day, the highest dose level tested.
Executive summary:

The maternal and developmental toxicity of octamethyltrisiloxane in Crl:CD(SD) rats was studied following repeated gavage administration in this OECD 414 study. Groups of 24 time-mated female Crl:CD(SD) rats were administered octamethyltrisiloxane in dried and deacidified corn oil by gavage at dose levels of 0, 75, 250, or 750 mg/kg/day on gestation day (GD) 6 through 20. In-life maternal study parameters included clinical observations, body weight, body weight gain, and feed consumption. On GD 21, all dams were euthanized and examined for gross pathologic alterations. Liver, kidneys, and gravid uterine weights were recorded, along with the number of corpora lutea, uterine implantations, resorptions, and live/dead foetuses. All foetuses were weighed, sexed, and examined for external alterations. Approximately one half of the fetuses were examined for visceral and craniofacial alterations while skeletal examinations were conducted on the remaining fetuses.

Administration of octamethyltrisiloxane via oral gavage produced treatment-related maternal toxicity evidenced by decreased body weight gains from GD 6-9 in the 750 mg/kg/day group (20% compared to control), increased absolute and relative liver weights and liver histopathology at all dose levels. Treatment-related very slight hypertrophy of centrilobular/midzonal hepatocytes was present in 12/24 females given 75 mg/kg/day and in 17/24 females given 250 mg/kg/day. Treatment-related slight hypertrophy of centrilobular/midzonal hepatocytes was present in 7/24 females given 250 mg/kg/day and in 24/24 females given 750 mg/kg/day. The hepatocellular hypertrophy corresponded to dose-related increases in absolute and relative liver weights of females given 75, 250, or 750 mg/kg/day. Two females given 750 mg/kg/day had treatment-related very slight multifocal chronic inflammation in periportal regions of the liver, and one of these females also had treatment-related very slight increased number of mitotic figures in hepatocytes. Treatment-related pigment deposits were present in the intrahepatic bile ducts, hepatocytes, and/or Kupffer cells of six females given 750 mg/kg/day. There were no treatment-related clinical observations and no effects on body weight, feed consumption, or reproductive parameters at any dose level tested. There was no indication of embryo/foetal toxicity or teratogenicity at any dose level tested.

Based on the decreased body weight gain and liver weight increases combined with the chronic inflammation of the liver noted in animals in the 750 mg/kg/day group, the NOAEL for maternal toxicity was determined to be 250 mg/kg/day. For developmental toxicity, the NOAEL was 750 mg/kg/day, the highest dose level tested.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no prenatal developmental toxicity tests conducted to OECD 414, for the registration substance, heptamethyltrisiloxane (CAS 1873 -88 -7). Therefore, as accepted by ECHA in Decision number TPE-D-2114424726-47-01/F the prenatal developmental toxicity test on the structural analogue, octamethyltrisiloxane (CAS 107 -51 -7) is read across to heptamethyltrisiloxane.

The maternal and developmental toxicity of the structural analogue, octamethyltrisiloxane L3, in Crl:CD(SD) rats was studied following repeated gavage administration in this OECD 414 study. Groups of 24 time-mated female Crl:CD(SD) rats were administered octamethyltrisiloxane in dried and deacidified corn oil by gavage at dose levels of 0, 75, 250, or 750 mg/kg bw/day on gestation day (GD) 6 through 20. In-life maternal study parameters included clinical observations, body weight, body weight gain, and feed consumption. On GD 21, all dams were euthanized and examined for gross pathologic alterations. Liver, kidneys, and gravid uterine weights were recorded, along with the number of corpora lutea, uterine implantations, resorptions, and live/dead foetuses. All foetuses were weighed, sexed, and examined for external alterations. Approximately one half of the fetuses were examined for visceral and craniofacial alterations while skeletal examinations were conducted on the remaining fetuses.

Administration of octamethyltrisiloxane via oral gavage produced treatment-related maternal toxicity evidenced by decreased body weight gains from GD 6-9 in the 750 mg/kg bw/day group (20% compared to control), increased absolute and relative liver weights and liver histopathology at all dose levels. Treatment-related very slight hypertrophy of centrilobular/midzonal hepatocytes was present in 12/24 females given 75 mg/kg bw/day and in 17/24 females given 250 mg/kg bw/day. Treatment-related slight hypertrophy of centrilobular/midzonal hepatocytes was present in 7/24 females given 250 mg/kg bw/day and in 24/24 females given 750 mg/kg bw/day. The hepatocellular hypertrophy corresponded to dose-related increases in absolute and relative liver weights of females given 75, 250, or 750 mg/kg bw/day. Two females given 750 mg/kg bw/day had treatment-related very slight multifocal chronic inflammation in periportal regions of the liver, and one of these females also had treatment-related very slight increased number of mitotic figures in hepatocytes. Treatment-related pigment deposits were present in the intrahepatic bile ducts, hepatocytes, and/or Kupffer cells of six females given 750 mg/kg bw/day. There were no treatment-related clinical observations and no effects on body weight, feed consumption, or reproductive parameters at any dose level tested. There was no indication of embryo/foetal toxicity or teratogenicity at any dose level tested.

Based on the decreased body weight gain and liver weight increases combined with the chronic inflammation of the liver noted in animals in the 750 mg/kg bw/day group, the NOAEL for maternal toxicity was determined to be 250 mg/kg bw/day. For developmental toxicity, the NOAEL was 750 mg/kg bw/day, the highest dose level tested.

In an oral combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with H-L3, conducted according to OECD Test Guideline 422 and in compliance with GLP (Harlan Laboratories Ltd., 2010) the NOAEL for general toxicity was 200 mg/kg bw/day in rats, based on the histopathology findings of hepatic brown pigment accumulation noted at 800 mg/kg bw/day in males and on the dose dependent and statistically significant increase of liver weight in females at 200 and 800 mg/kg bw/day. Based on the higher total number of postnatal losses and on lower pup weight gain at 800 mg/kg bw/day, the NOAEL for developmental toxicity was considered to be 200 mg/kg bw/day. The effects seen in offspring were considered to be secondary non-specific effects due to maternal toxic effects. Reduced food consumption by maternal animals and no milk in stomach of pups suggest that the dams were weak and unable to feed the offspring.


Justification for classification or non-classification

Based on the available repeated dose (oral and inhalation), reproductive and developmental toxicity tests on the registered substance 1,1,1,3,5,5,5 -heptamethyltrisiloxane and structural analogue octamethyltrisiloxane (CAS 107 -51 -7), the registered substance is not classified for adverse effects on reproduction under Regulation EC (No) 1272/2008.