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Key value for chemical safety assessment

Effects on fertility

Description of key information

In the key combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted by the inhalation route using a protocol comparable to OECD 422 and to GLP (Dow Corning Corporation, 2007) the NOAEC for reproductive toxicity was at least 400 ppm (the only concentration tested). In 28-day oral and 90-day inhalation repeat dose studies there were no histopathological findings noted in the reproductive organs.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27.10.2006 to 21.12.2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Only one concentration tested.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: 9 weeks
- Weight at study initiation: (P) Males: 300.7-350 g; Females: 195.5-240 g
- Fasting period before study: No
- Housing: Individually housed in suspended wire-mesh cages. Except during mating, gestation and lactation periods. Mating: home cage of the male; Gestation: shoebox cages; Lactation: dams housed with litters.
- Diet (e.g. ad libitum): Ad libitum (except during inhalation exposure or FOB.
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.95-21.71
- Humidity (%): 31-69
- Air changes (per hr): 12.1
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 27.10.2006 To: 21.12.2007
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
clean air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 litre stainless steel and glass, TSE-system style, whole-body inhalation exposure chambers.
- Method of holding animals in test chamber: In cages
- Source and rate of air: Nash Air Compressor (rate not specified).
- Method of conditioning air: Series of filters to remove contaminants.
- Temperature, humidity, pressure in air chamber: Temp: 19-25oC (no other information, but it was stated that conditions were maintained according to the protocol).
- Air change rate: No data
- Treatment of exhaust air: No data

TEST ATMOSPHERE
- Brief description of analytical method used: No data
- Samples taken from breathing zone: yes
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Continuous until evidence of copulation observed.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged (how): Shoebox cages.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
None given (apparent Annex missing)
Duration of treatment / exposure:
Males: 30 days
Toxicity group females: 29 days
Reproductive group females: 15 days prior to mating, through the mating period and up to day 19 of gestation.
Frequency of treatment:
Daily (seven days per week)
Dose / conc.:
5.1 mg/L air
Remarks:
target concentration equivalent to 400 ppm
No. of animals per sex per dose:
Ten
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on previously conducted study.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily in their cages for mortality, morbidity and moribundity throughout the in-life phase of the study. General clinical observations were made at least once per day, beginning on the first day of treatment (except on days of detailed examinations). Clinical observations were also performed on all animals on the day of, but prior to, scheduled necropsy.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals, once before the first exposure and weekly thereafter. Examinations included but were not limited to changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity. Changes in gait, posture and response to handling as well as the presence of clonic or tonic movement, stereotypies, difficult or prolonged parturition or bizarre behaviour.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined beginning with randomisation into test groups, on the first day of exposure, at least weekly thereafter, and the day of necropsy. During gestation, the females were weighed (at a minimum) on gestation days 0, 7, 14 and 20 within 24 hours after parturition, and day 4 postpartum.

FOOD CONSUMPTION: Individual animal food consumption was recorded at least weekly on an individual animal basis for the periods listed: Male rats: two week pre-mating period only (feeder weights were taken on days 1, 8 and 15). Female rats: toxicity group on day 1 of exposure to necropsy (feeder weights were taken on day 1, 8, 15, 22 and the day prior to necropsy. Reproductive female rats: two week pre-mating period, gestation and postpartum (feeder weights were taken on days 1, 8, 15 and on gestation days 0, 7, 14, 20 and on day 0 and 4 postpartum).

WATER CONSUMPTION: No

OTHER: The duration of gestation was calculated from Day 0 gestation for each female. From Day 20 after evidence of mating, pregnant animals were checked at least three times daily for evidence of parturition.

Functional Observational Battery (FOB) performed on all adult males and all toxicity group females prior to the start of exposure and during the fourth week of exposure (prior to daily exposures).

Clinical pathology assessments on all adult male and toxicity group females - See section 7.5.2.
Oestrous cyclicity (parental animals):
No evidence that estrous cyclicity was investigated.
Sperm parameters (parental animals):
Parameters examined in male parental generations: testis weight and epididymis weight.
Litter observations:
STANDARDISATION OF LITTERS:
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 pups: each litter was examined as soon as possible after delivery to determine the number and sex of the pups, the number of live pups, number of pups dead, runts. Live pups were counted, sexed and the sex ratio calculated. Litter weights were taken within 24 hours of parturition and on day 4 post-partum.

GROSS EXAMINATION OF DEAD PUPS: yes, for external abnormalities. Possible cause of death was not determined for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after 30 days exposure.
- Maternal animals: Day 4 postpartum.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. For pregnant females, the number of corpora lutea and the number of implantation sites were recorded. For the three females with positive evidence of mating that failed to deliver a litter, the uterus was stained to enable counting of possible reabsorbed implant sites.

HISTOPATHOLOGY / ORGAN WEIGHTS: At necropsy, the following organs from males and toxicity group females were weighed: adrenal glands, brain, heart, lungs, kidneys, liver, spleen and thymus. Testes, epididymides, seminal vesicles and prostate weights were recorded for all male adult animals. Ovaries with oviducts and uterine weights were recorded for toxicity group females. Selected organs and tissues were examined histopathologically in the toxicity group males and females, not reproductive group females (see Section 7.5.2).
Postmortem examinations (offspring):
SACRIFICE: Day 4 post-partum.

GROSS NECROPSY: Dead and sacrificed pups examined for external gross abnormalities only.

HISTOPATHOLOGY / ORGAN WEIGHTS: Not conducted.
Statistics:
All data analyses was conducted using SAS version 9.1.3. Statistically significant probabilities were reported for p-values of <0.05, <0.02 and <0.01.
Reproductive indices:
Gestation length, mean number of implantation sites, mean number of corpora lutea, mean mating and fertility indices. Mean litter size, mean live litter size, mean litter weight, mean ratio live births/litter size.
Offspring viability indices:
Survival to postpartum day 4.
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No deaths and no significant treatment-related clinical signs of toxicity.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Significant increases in body weight gains were noted in the 400 ppm parental females during the third week of gestation, which were not considered to be treatment-related. There were no statistically significant differences in food consumption in females. The food consumption for treated males was significantly decreased during weeks 1 and 2 and for total food consumption. However, food consumption for weeks 1 and 2 was within the normal range of the laboratory's historical controls. The difference was not considered to be related to treatment.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): there was no effect on testes or epididymides weights. No other parameters were examined.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): Three female rats in the 400 ppm group with evidence of copulation failed to deliver a litter. One of these three females showed signs of parturition (blood discharge) on gestation day 25, but no pups were found. However, seven implant sites were present. The remaining females produced litters that were similar to the controls.

There were no treatment-related effects apparent for any of the reproductive endpoints. There were no changes observed in the litter size, male-to-female ratio, pup body weights or the pup survival.

ORGAN WEIGHTS (PARENTAL ANIMALS): There were no differences in absolute organ weights. The spleen to body weight ratio was slightly lower for toxicity group females, but not males, exposed to 400 ppm test substance. There was no histopathological correlate, nor any effect of exposure in other lymphoid tissues. This was considered to be random variation and not of toxicological significance.

GROSS PATHOLOGY (PARENTAL ANIMALS): There were no gross lesions attributed to the test substance.

HISTOPATHOLOGY (PARENTAL ANIMALS): One possible exposure-related finding was increased minimal alveolar histiocytosis in males in the 400 ppm exposure group. This is a common non-specific finding in inhalation studies; however, the minimal severity and fact that only one sex was affected made the significance of the finding uncertain. There were no other exposure-related in other tissues.

FOB: There appeared to be no functional or neurological effects of the test substance on the rats.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant treatment-related effects on males or toxicity phase females.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
There were no adverse effects for the pups up to postpartum day 4.
Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
>= 400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects on pups.
Reproductive effects observed:
no
Conclusions:
In a combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted using a protocol comparable to OECD 422 and to GLP (reliability score 1) the NOAEC for general and reproductive toxicity was at least 400 ppm (the only concentration tested) according to the study report. However, it should be noted that three female rats in the 400 ppm group with evidence of copulation failed to deliver a litter. One of these three females showed signs of parturition (blood discharge) on gestation day 25, but no pups were found. However, seven implant sites were present. The remaining females produced litters that were similar to the controls.
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
5 083 mg/m³
Study duration:
subacute
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There is a reliable OECD 422 screening study available for decamethyltetrasiloxane. There are no other studies relating to reproductive toxicity. In the oral 28-day and inhalation 90-day studies the reproductive organs were weighed and were the subject of histopathological examinations, and there were no adverse findings.

In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted by the inhalation route using a protocol comparable to OECD 422 and to GLP (Dow Corning Corporation, 2007) the NOAEC for reproductive toxicity was at least 400 ppm (the only concentration tested) according to the study report. However, it should be noted that three female rats in the 400 ppm group with evidence of copulation failed to deliver a litter. One of these three females showed signs of parturition (blood discharge) on gestation day 25, but no pups were found. However, seven implant sites were present. The remaining females produced litters that were similar to the controls.

Two reliable reproductive toxicity studies with hexamethyldisiloxane (L2; CAS 107-46-0) are read-across as supporting data. Both L2 and L4 are members of the siloxanes analogue group; they are methylated siloxanes containing no reactive functional groups, and have similar physico-chemical, toxicokinetic and toxicological properties. L2 and L4 have high log Kow (5.1 and 8.1 respectively) and low water solubility (0.93 mg/L and 0.0067 mg/L).

In a two-generation reproductive toxicity study (WIL Research Laboratories, 2006) conducted to OECD 416 and in compliance with GLP, Sprague-Dawley rats (30 animals/sex/dose) were exposed to the structurally-related substance L2 at a concentration of 100, 400, 1600 or 5000 ppm, 6 hours/day, 7 days/week. No treatment-related effects were observed on fertility or parturition. The NOAEC for L2 for parental reproductive toxicity is considered to be at least 5000 ppm (33200 mg/m³). An additional one-generation reproductive toxicity study Corporation, 1999) conducted to EPA OPPTS 870.3800 and in compliance with GLP, supports the finding that L2 does not have an adverse effect on reproductive parameters, as there were no adverse effects in Sprague-Dawley rats up to a concentration of 5000 ppm.

L2 has a shorter chain length, lower molecular weight, higher water solubility that L4 and hence greater bioavailability than L4, and may therefore be considered a worst-case. Consequently, whilst effects were observed during the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test with L4, the results from the full reproductive toxicity studies with L2 do not indicate that these are the result of an effect on fertility. The NOAEC for L4 of at least 400 ppm is therefore considered to be reliable.




Effects on developmental toxicity

Description of key information

In the key combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted by the inhalation route using a protocol comparable to OECD 422 and to GLP (Dow Corning Corporation, 2007) the developmental NOAEC was 400 ppm (the only concentration tested).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27.10.2006 to 21.12.2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Only one concentration tested.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: 9 weeks
- Weight at study initiation: (P) Males: 300.7-350 g; Females: 195.5-240 g
- Fasting period before study: No
- Housing: Individually housed in suspended wire-mesh cages. Except during mating, gestation and lactation periods. Mating: home cage of the male; Gestation: shoebox cages; Lactation: dams housed with litters.
- Diet (e.g. ad libitum): Ad libitum (except during inhalation exposure or FOB.
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.95-21.71
- Humidity (%): 31-69
- Air changes (per hr): 12.1
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 27.10.2006 To: 21.12.2007
Route of administration:
inhalation: vapour
Vehicle:
clean air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 litre stainless steel and glass, TSE-system style, whole-body inhalation exposure chambers.
- Method of holding animals in test chamber: In cages
- Source and rate of air: Nash Air Compressor (rate not specified).
- Method of conditioning air: Series of filters to remove contaminants.
- Temperature, humidity, pressure in air chamber: Temp: 19-25oC (no other information, but it was stated that conditions were maintained according to the protocol).
- Air change rate: No data
- Treatment of exhaust air: No data

TEST ATMOSPHERE
- Brief description of analytical method used: No data
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
None given (apparent Annex missing)
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Continuous until evidence of copulation observed.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged (how): Shoebox cages.
Duration of treatment / exposure:
Males: 30 days
Toxicity group females: 29 days
Reproductive group females: 15 days prior to mating, through the mating period and up to day 19 of gestation.
Frequency of treatment:
Daily (seven days/week)
Duration of test:
Approximately 7 months
Dose / conc.:
5.1 mg/L air
Remarks:
target concentration equivalent to 400 ppm
No. of animals per sex per dose:
Ten
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results from previous study.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily in their cages for mortality, morbidity and moribundity throughout the in-life phase of the study. General clinical observations were made at least once per day, beginning on the first day of treatment (except on days of detailed examinations). Clinical observations were also performed on all animals on the day of, but prior to, scheduled necropsy.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals, once before the first exposure and weekly thereafter. Examinations included but were not limited to changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity. Changes in gait, posture and response to handling as well as the presence of clonic or tonic movement, stereotypies, difficult or prolonged parturition or bizarre behaviour.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined beginning with randomisation into test groups, on the first day of exposure, at least weekly thereafter, and the day of necropsy. During gestation, the females were weighed (at a minimum) on gestation days 0, 7, 14 and 20 within 24 hours after parturition, and day 4 postpartum.

FOOD CONSUMPTION: Individual animal food consumption was recorded at least weekly on an individual animal basis for the periods listed: Reproductive female rats: two week pre-mating period, gestation and postpartum (feeder weights were taken on days 1, 8, 15 and on gestation days 0, 7, 14, 20 and on day 0 and 4 postpartum).

WATER CONSUMPTION: No

OTHER: The duration of gestation was calculated from Day 0 gestation for each female. From Day 20 after evidence of mating, pregnant animals were checked at least three times daily for evidence of parturition.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- 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 pups
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No
Statistics:
All data analyses was conducted using SAS version 9.1.3. Statistically significant probabilities were reported for p-values of <0.05, <0.02 and <0.01.
Indices:
Gestation length, mean number of implantation sites, mean number of corpora lutea, mean mating and fertility indices. Mean litter size, mean live litter size, mean litter weight, mean ratio live births/litter size.
Details on maternal toxic effects:
Maternal toxic effects:no effects
Key result
Dose descriptor:
NOAEC
Effect level:
>= 400 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOAEC
Effect level:
>= 400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant treatment-related effects on fetuses
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
In a combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted using a protocol comparable to OECD 422 and to GLP (reliability score 1) the NOAEC for general and developmental toxicity was at least 400 ppm (the only concentration tested) according to the study report.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
5 083 mg/m³
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In a combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted by the inhalation route using a protocol comparable to OECD 422 and to GLP (Dow Corning Corporation, 2007) the NOAEC for developmental toxicity was at least 400 ppm (the only concentration tested)..


Justification for classification or non-classification

Based on the available OECD 422 screening study L4 is not classified for effects on reproduction or development according to Regulation (EC) No 1272/2008.