1,1,3,3-tetramethyl-1,3-divinyldisiloxane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The key study for reproductive toxicity is a combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted using a protocol comparable to OECD Test Guideline 422 and in compliance with GLP (WIL, 2011). The NOAEL for reproductive toxicity was concluded to be 600 mg/kg bw/day based on no adverse effects observed.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Inc., Raleigh, NC
- Age at study initiation: approximately 63 days
- Weight at study initiation: male 310-396g, female 212-225g
- Fasting period before study: No
- Housing: Individually in wire mesh cages. Follwoing positive evidence of mating females transferred to plastic maternity cages with nesting material and bedding
- Diet : Certified Rodent LabDiet 5002 (PMI Nutrition International LLC), ad libitum (except during fasting prior to blood collection for clinical pathology for males as part of toxicological assessment)
- Water: Reverse osmosis-purified (on-site) water ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 8 July to 29 August 2011

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0, 10, 30, 120 mg/mL
- Amount of vehicle (if gavage): 5mL/kg
- Lot/batch no. (if required): ZT1301, 2AD0465, 2AE0415

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: until positive evidence of mating
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- If evidence of copulation was not detected after 14 days of pairing, any females that had not shown evidenceof mating were palced in plastic maternity cages.
- After successful mating each pregnant female was caged in a plastic maternity cages with nesting material and bedding

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability and resuspension homogeneity of the test substance in formulation following 10 days of refrigerated storage at concentrations of 1 and 200 mg/mL were established in a previous study so stability and resuspension homogeneity analyses were not conducted on this study.

Samples for homogeneity and concentration determinations were collected from the top, middle, and bottom strata of the first dosing formulations prepared during the study (study week 0), including the control group. In addition, samples for concentration analyses were collected from the middle stratum of each test substance formulation prepared during study weeks 1, 2, 3, and 7. One set of samples from each collection was subjected to the appropriate analyses. The remaining set of samples was stored refrigerated (2°C - 8°C) as back-up. All analyses were conducted by the WIL Research Analytical Chemistry Department using a validated gas chromatography method with flame ionization detection

Duration of treatment / exposure:

Males dosed during study days 0-30 (total of 31 doses)
Females with viable pups were dosed during study days 0 through the day prior to euthanasia (14 days prior to pairing through lactation day 3) for a total of 39-47 doses. Females with no evidence of mating or that failed to deliver were dosed through the day prior to euthanasia (post-mating or post-cohabitation day 25) for a total of 40 or 52 doses. Females with total litter loss received 38 or 40 doses.

Frequency of treatment:

Once daily

Details on study schedule:

- Age at mating of the mated animals in the study: approximately 12.5 weeks

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

150 mg/kg bw/day (nominal)

Dose / conc.:

600 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dosage levels were selected based on the results of a previous 28-day toxicity study in which severe toxicity was noted at 1000 mg/kg/day, including mortality, moribundity, adverse clinical signs, mean body weight losses, and reduced food consumption during the first week of treatment, which resulted in early termination of the 1000 mg/kg/day group on study day 7 and the subsequent early termination of the study on study day 13

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily and approximately 1 hour after dosing

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Males weekly. Females weekly until positive evidence of mating then gestational days 0, 4, 7, 11, 14, 17 and 20 and on lactation days 1 and 4

FOOD CONSUMPTION:
Males - weekly
Females - Weekly until positive evidence of mating then gestational days 0, 4, 7, 11, 14, 17 and 20 and on lactation days 1 and 4.
- Food consumption not recorded for paired animals during mating period.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animals/day and g food/kg body weight/day: Yes


OTHER:

Oestrous cyclicity (parental animals):

Not examined

Sperm parameters (parental animals):

Not examined

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, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: After up to 31 doses
- Maternal animals: Lactation day 4 (after 39-47 doses)

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively

Postmortem examinations (offspring):

None - discarded without examination

Statistics:

Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group by sex.

Parental mating, fertility, conception, and copulation indices were analyzed using the Chi square test with Yates’ correction factor (Hollander and Wolfe, 1999). Mean parental body weights (weekly, gestation, and lactation), body weight changes, and food consumption, offspring body weights and body weight changes, gestation length, numbers of former implantation sites and corpora lutea, number of pups born, live litter size on PND 0, unaccounted-for sites, absolute and relative organ weights, pre coital intervals, and FOB data values were subjected to a parametric one way ANOVA (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance-treated groups to the control group. Mean litter proportions (percent per litter) of males at birth, and postnatal survival were subjected to the Kruskal Wallis nonparametric ANOVA (Kruskal and Wallis, 1952) to determine intergroup differences. If the ANOVA revealed significant (p<0.05) intergroup variance, Dunn’s test (Dunn, 1964) was used to compare the test substance-treated groups to the control group.

Reproductive indices:

Male and female fertility, male and female copulation index.
Number of former implantation sites and corpora lutea.
Number of pups/litter size

Offspring viability indices:

Mean litter size, postnatal survival between birth and postnatal day 0 or 4, postnatal survival for all other intervals

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical findings of clear material around the mouth were noted in the 150 and 600 mg/kg/day groups in a dose related manner at approximately 1 hour following dose administration. In addition, red material around the mouth was noted for the 600 mg/kg/day group at approximately 1 hour following dose administration and salivation prior to dosing was noted in this group . The aforementioned clinical findings generally occurred throughout the treatment period and were considered test substance related. Other clinical findings noted in the test substance treated groups, including hair loss on various body surfaces, occurred infrequently, at similar frequencies in the control group, and/or in a manner that was not dose-related.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

All males and females survived to the scheduled necropsies.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

A test substance-related, significant (p<0.01) mean body weight loss during study days 0-7 and lower (not statistically significant) mean body weight gain during study days 7-13 were noted for males in the 600 mg/kg/day group. As a result, mean body weight gains in this group were significantly (p<0.01) lower than the control group when the pre-mating (study days 0-13) and entire treatment (study days 0-27) periods were evaluated and mean body weights in this group were 10.3% to 12.3% lower than the control group during study days 7-30; the differences in mean body weight were significant (p<0.01 or p<0.05). Mean body weight gains in this group were similar to the control group during study days 13-30. Mean body weights and body weight gains for males in the 50 and 150 mg/kg/day groups were unaffected by test substance administration throughout the treatment period. Differences from the control group were slight and not statistically significant.

Mean body weights and body weight gains for treated females were unaffected by test substance administration throughout the pre-mating period, gestation and lactation periods. Differences from the control group were slight and not statistically significant.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Mean food consumption, evaluated as g/animal/day and g/kg/day, for males in the 600 mg/kg/day group was significantly (p<0.01 or p<0.05) lower than the control group during study days 0-7, corresponding to a mean body weight loss noted for these males during this period. Mean food consumption for these males was generally similar to the control group throughout the remainder of the treatment and post-treatment evaluation periods. Mean food consumption for males in the 50 and 150 mg/kg/day groups was unaffected by test substance administration throughout the treatment period. Differences from the control group were slight and not statistically significant.

Mean food consumption for treated females was unaffected by test substance administration throughout the pre-mating period, gestation and lactation periods. Differences from the control group were slight.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Test substance-related alterations in hematology parameters included significantly (p<0.05) lower mean hemoglobin concentration and lower mean corpuscular hemoglobin concentration (MCHC) in the 600 mg/kg/day group males. In addition, significantly (p<0.01 or p<0.05) lower mean hemoglobin concentration, hematocrit, mean corpuscular hemoglobin (MCH), and MCHC were observed in the 600 mg/kg/day group females. All changes were of small magnitude and were not associated with gross observations, organ weight changes, or microscopic observations, and were considered nonadverse. The prothrombin time was lower in the 600 mg/kg/day group males. This change was in a direction of no known toxicologic significance.
Test substance-related changes in hematology and coagulation parameters persisted at the recovery necropsy in the 600 mg/kg/day group males and females. Significantly (p<0.01 or p<0.05) lower mean hemoglobin concentration, lower mean hematocrit, lower MCH, lower MCHC, higher mean absolute reticulocyte count, higher mean percent reticulocytes, and higher mean red cell distribution width (RDW) were observed in the 600 mg/kg/day group males at the recovery necropsy. Significantly (p<0.01 or p<0.05) higher mean hematocrit, lower MCHC, lower mean absolute monocyte count, and lower mean hemoglobin distribution width (HDW) were observed in the 600 mg/kg/day group females. The changes were of small magnitude, not associated with gross observations, organ weight changes, or microscopic observations, and were considered nonadverse.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Test substance-related changes in serum chemistry values occurred in the 600 mg/kg/day group males and females. Significantly (p<0.01 or p<0.05) higher mean serum total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase (GGT), and cholesterol levels were observed in the 600 mg/kg/day group males. Significantly (p<0.01) higher mean serum globulins, total protein, GGT, and cholesterol levels were observed in the 600 mg/kg/day group females. The changes in bilirubin, ALT, AST, and GGT levels were associated with absolute and relative liver weight changes and microscopic observations in the liver, and were considered adverse.
There were no other test substance-related effects on serum chemistry parameters. However, significantly (p<0.01) lower mean serum alkaline phosphatase (ALP) was observed in the 600 mg/kg/day group females. This change was in a direction of no known toxicological significance.
At the recovery necropsy, significant (p<0.05 or p<0.01) differences were noted when the control and test substance-treated groups were compared. Higher mean serum albumin, higher mean serum A/G ratio, lower mean serum creatinine, lower glucose levels, and lower AST levels were observed in the 600 mg/kg/day group males. Higher serum ALP level was observed in the 600 mg/kg/day group females. Changes were of small magnitude, the values fell within the WIL Research historical control database reference range, and the changes were considered a result of individual animal variation rather than test substance administration and were indicative of recovery.

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Home cage, handling, open field, sensory, neuromuscular and physiological parameters were unaffected by test substance administration.
Significant (p<0.001), test substance-related increases in mean cumulative total and ambulatory counts were noted for males in the 600 mg/kg/day group. Males in this group exhibited slower habituation over the entire test session. Locomotor activity patterns (total activity as well as ambulatory activity counts) for males in the 50 and 150 mg/kg/day groups and toxicology phase females at all dosage levels were unaffected by test substance administration when evaluated at study week 4; values obtained from the 6 subintervals evaluated (0-10, 11-20, 21-30, 31-40, 41-50 and 51 60 minutes) and the overall 60 minute test session values were comparable to the concurrent control values and/or the WIL historical control data, with the following exception. A significant (p≤0.045) increase in mean total counts during 51-60 minutes and decrease in mean ambulatory counts during 21-30 minutes were noted for females in the 600 mg/kg/day group; however, these results were transient and discordant. Other differences from the control group were slight, not statistically significant when analyzed by a repeated measures analysis, within the WIL historical control data ranges and/or did not occur in a dose-related manner. No remarkable shifts in the pattern of habituation occurred for males in the 50 and 150 mg/kg/day groups and toxicology phase females at all dosage levels when evaluated at study week 4.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Test substance-related microscopic findings were noted in the liver of the 600 mg/kg/day group males and females and the kidneys, adrenals, and pituitary of the 600 mg/kg/day group males.

Minimal to mild hepatocellular hypertrophy was observed in the liver of all dose groups. In the males, the distribution was diffuse. A centrilobular pattern was apparent in the females. In addition to hepatocellular hypertrophy, increased numbers of bile duct profiles were observed in the 600 mg/kg/day group males and the 150 and 600 mg/kg/day group females (bile duct hyperplasia). In the 600 mg/kg/day group only, the bile ducts often contained brown pigment and were surrounded by few concentric layers of fibrous connective tissue (peribiliary fibrosis). Under polarised light some pigment accumulations show birefringence, but this finding was not consistent in size or between animals. Microscopic observations in the liver correlated to the higher absolute liver weight and higher liver weight relative to body weight and brain weight in the males and females. Hepatocellular hypertrophy was considered adaptive and nonadverse. Biliary hyperplasia with peribiliary fibrosis and brown pigment were considered adverse in the 600 mg/kg/day group males and females.

Minimal to mild increased concentrations of eosinophilic proteinaceous intracytoplasmic and intraluminal droplets (hyaline droplets) were observed in the proximal convoluted tubules of the kidneys in treated males. Hyaline droplets are considered a normal finding in male rats; however, the aggregation and condensation pattern of the droplets was more prominent in the test substance-treated rats. This progressed to hyaline droplet nephropathy in 1 of 4 in the 50 mg/kg/day group males, 4 of 7 in the 150 mg/kg/day group males and 3 of the 7 males in the 600 mg/kg/day group with hyaline droplets. Hyaline droplet nephropathy was characterized by dilated tubules with flattened epithelium in the inner stripe of the outer medulla. Tubules contained lightly eosinophilic granular cell debris (granular casts). The combination of granular casts and hyaline droplets was characteristic of hyaline droplet nephropathy (Hard, 2008). Immunohistochemical staining for alpha-2u globulin of the kidneys of males was negative. Hyaline droplet nephropathy was considered an adverse finding in the males in all dose groups.

Minimal to mild adrenal cortical atrophy was observed in treated males. Atrophy was characterized by decreased overall size. Adrenal cortical atrophy correlated to the lower absolute adrenal gland weight and lower adrenal gland relative to brain weight observed at the primary necropsy in the 600 mg/kg/day group males. This finding was not associated with gross observations and was considered nonadverse.

Minimal to mild vacuolation of the pituitary was observed in treated males. Pituitary vacuolation was not associated with gross observation or organ weight changes, and was considered nonadverse.

Moderate decreased corpora lutea were observed in the ovaries in one 600 mg/kg/day group female. This finding only occurred in 1 female, can occur sporadically in rats, and the relationship to test substance administration was unlikely.

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):

No test substance-related effects on reproductive performance were observed at any dosage level. No statistically significant differences were noted between the control and test substance treated groups. Males that did not sire a litter numbered 1, 0, 1, and 2 in the control, 50, 150, and 600 mg/kg/day groups, respectively. Females that had evidence of mating but did not deliver numbered 1, 0, 0, and 1 in the same respective groups. The mean numbers of days between pairing and coitus in the test substance-treated groups were similar to the control group value; the difference from the control group was slight and not statistically significant.
Mean gestation lengths in treated groups were similar to those in the control group. No statistically significant differences were noted. No signs of dystocia were noted in these groups.

Key result

Dose descriptor:

NOAEL

Remarks:

Reproductive Tox

Effect level:

600 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed

Critical effects observed:

no

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

The general physical condition of F1 pups in the 50 and 150 mg/kg/day groups were unaffected by test substance administration. Pups that were found dead in the 50 and 150 mg/kg/day groups numbered 7 and 2, respectively. One, 2, and 0 pups in the control, 50, and 150 mg/kg/day groups, respectively, were missing and presumed to have been cannibalized.

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Postnatal survival in the 600 mg/kg/day group was lower than the control group during PND 0-1 and 1-4 and from birth to PND 4. Although not statistically significantly different from the concurrent control group, the values of postnatal survival were below the minimum mean values in the WIL historical control data. These results were primarily due to 2 total litter losses noted on PND 1 and 3, respectively, and were considered test substance-related and adverse. Postnatal survival, the number of pups born, live litter size, and percentage of males at birth in the 50 and 150 mg/kg/day groups were unaffected by test substance administration.
Higher numbers of pups found dead (19 pups) and missing (7 pups) were noted in the 600 mg/kg/day group compared to the control group (11 pups found dead and 1 pup missing). This was primarily due to 2 test substance related total litter losses. In addition, increased incidences of pups with cool and pale bodies were noted.
The numbers of pups (litters) found dead during PND 0-4 numbered 11(3), 7(4), 2(2), and 19(4) in the control, 50, 150, and 600 mg/kg/day groups, respectively.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Slightly lower F1 pup birth weights were noted for male and female pups in the 600 mg/kg/day group. Slightly lower mean pup body weight gains were noted for these pups during PND 1-4, resulting in mean pup body weights that were 9.4% (males) and 7.0% (females) lower than the control group on PND 4. Although the mean body weight gain for females in the 600 mg/kg/day group (2.8 g) was higher than that noted in the 150 mg/kg/day group (2.7 g), the value at 600 mg/kg/day was slightly skewed by 1 litter with a high mean body weight gain; with this litter excluded, mean body weight gain during PND 1-4 for females in the 600 mg/kg/day group was 2.4 g. These results were considered test substance-related and adverse.
Mean male and female pup body weights and body weight changes in the 50 and 150 mg/kg/day groups were unaffected by test substance administration during PND 1-4.

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):

One pup in the 150 mg/kg bw/day group had the malformation ectopia cordis; however, this finding was not noted in the 600 mg/kg bw/day group. In addition, one pup in the control group had the variation anophthalmia. Aside from the presence or absence of milk in the stomach, no other internal findings were noted.

Histopathological findings:

not examined

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

As a result of the lower number of implantation sites noted for females in the 600 mg/kg/day group the mean number of pups born and live litter size in this group were lower (not statistically significant) than the control group.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Total litter loses, effects on postnatal survival, pup body weights and pup clinical findings at 600 mg/kg/day.

Critical effects observed:

not specified

Reproductive effects observed:

no

Table 1 - Reproductive performance

	Dosage Level (mg/kg/day)				WIL HC^a
Parameter	0	50	150	600	Mean (Range)
Male Mating Index	100.0	100.0	90.0	90.0	96.8 (84.0-100.0)
Female Mating Index	100.0	100.0	90.0	90.0	98.2 (86.7-100.0)
Male Fertility Index	90.0	100.0	90.0	80.0	91.1 (60.0-100.0)
Female Fertility Index	90.0	100.0	90.0	80.0	93.2 (60.0-100.0)
Male Copulation Index	90.0	100.0	100.0	88.9	94.4 (71.4-100.0)
Female Conception Index	90.0	100.0	100.0	88.9	95.0 (65.2-100.0)
Pre-Coital Interval (days)	3.1	2.4	3.3	2.3	2.9 (1.8-4.8)

^a= WIL historical control data
None significantly different from control group.

Table 2 - Organ Weights

Test Substance-Related Organ Weight Changes at Necropsy
Parameter	Direction and magnitude of change	Dosage level (mg/kg/day)	Sex
Liver   Absolute   Relative to body weight   Relative to brain weight     Absolute   Relative to body weight   Relative to brain weight	↑18.6%*/21.2%**/40.5%** ↑11.1%*/18.7%**/61.9%** ↑14.8%/22.0%**/46.0%**   ↑15.2%*/30.6%** ↑13.8%**/40.6%** ↑14.5%**/33.0%**	50/150/600 50/150/600 50/150/600   150/600 150/600 150/600	M M M   F F F
Adrenal Gland   Absolute   Relative to brain weight	↓25.9%** ↓23.6%**	600 600	M M

* =   Significantly different from the control group at 0.05 using Dunnett's test

** = Significantly different from the control group at 0.01 using Dunnett's test

Table 3 - Microscopic Findings

Incidence of Selected Histopathologic Findings at the Primary Necropsy
	Males				Females
Dosage (mg/kg/day):	0	50	150	600	0	50	150	600
Liver^a	10	10	10	10	10	10	10	10
Fibrosis, Peribiliary	0	0	0	3	0	0	0	1
Minimal	-	-	-	1	-	-	-	1
Mild	-	-	-	2	-	-	-	0
Hyperplasia, Bile Duct	0	0	0	4	0	0	2	1
Minimal	-	-	-	1	-	-	2	0
Mild	-	-	-	3	-	-	0	1
Hypertrophy, Hepatocellular	0	3	8	10	0	6	10	10
Minimal	-	3	4	2	-	6	10	5
Mild	-	0	4	8	-	0	0	5
Pigment, Brown	0	0	0	5	0	0	0	1
Minimal	-	-	-	3	-	-	-	0
Mild	-	-	-	2	-	-	-	1
Kidney^a	10	10	10	10	10	0	0	10
Droplet, Hyaline	0	4	7	7	0	-	-	0
Minimal	-	3	4	3	-	-	-	-
Mild		1	3	4	-	-	-	-
Nephropathy, Hyaline Droplet	0	1	4	3	0	-	-	0
Minimal	-	1	3	2	-	-	-	-
Mild	-	0	1	1	-	-	-	-
Adrenal Cortex^a	10	10	10	10	10	0	0	10
Atrophy	0	1	2	6	0	-	-	0
Minimal	-	1	2	5	-	-	-	-
Mild	-	0	0	1	-	-	-	-
Pituitary^a	10	10	10	10	10	0	0	10
Vacuolation, Cytoplasmic	0	4	6	8	0	-	-	0
Minimal	-	4	6	5	-	-	-	-
Mild	-	0	0	3	-	-	-	-

^a Number of tissues examined from each group.

Conclusions:

Based on the lack of adverse effects on any reproductive parameter evaluated, a dosage level of 600 mg/kg/day, the highest dosage level evaluated, was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive toxicity of the test substance when administered orally by gavage to Crl:CD(SD) rats.

Executive summary:

In a well-conducted, GLP compliant, OECD 422 study (reliability score 1), all animals survived to their scheduled euthanasia. Clinical findings noted in the test substance treated groups included clear material around the mouth noted in a dose-related manner for the 150 and 600 mg/kg/day groups, red material around the mouth for the 600 mg/kg/day group at approximately 1 hour following dose administration, and salivation prior to dosing in this group. These findings were considered test substance-related.

Test substance-related mean body weight losses or reduced mean body weight gains were generally noted for males throughout the treatment period, resulting in reductions in mean body weights. Corresponding reductions in mean food consumption were noted for males in the 600 mg/kg/day group during study days 0-7. Mean body weights, body weight gains, and food consumption for males in the 50 and 150 mg/kg/day groups and for females at all dosage levels throughout the study, were unaffected by test substance administration.

A reduction (not statistically significant) in the mean number of implantation sites was noted in the 600 mg/kg of body weight/day group. This value (13.0 sites) was attributed to 1 female (no. 17852) with only 3 implantation sites that delivered 2 pups; the value for this group with this female excluded (14.4 sites) was similar to the WIL historical control data mean of 14.7 sites. Therefore, these results were not attributed to test substance administration. The mean numbers of implantation sites in the 50 and 150 mg/kg of body weight/day groups and mean numbers of unaccounted-for sites and corpora lutea in the 50, 150, and 600 mg/kg of body weight/day groups were unaffected by test substance administration.

Test substance-related organ weight alteration at necropsy included higher absolute and relative (to final body weight and brain weight) liver weights for treated males and females in the 150 and 600 mg/kg/day groups and lower absolute and relative to brain weight adrenal gland weights for males in the 600 mg/kg/day group. Test substance-related macroscopic findings were limited to pale kidneys for 1 male in the 600 mg/kg/day group; this finding corresponded to microscopic findings of hyaline droplet nephropathy for this male.

Bile duct hyperplasia, peribiliary fibrosis, and brown pigment in the bile duct were noted microscopically for males and females in the 600 mg/kg/day group; bile duct hyperplasia was also noted for females in the 150 mg/kg/day group and were considered adverse. Examination of the brown pigment by polarized light revealed red birefringence with “Maltese cross” formation, consistent with porphyrin pigment.  In addition, hepatocellular hypertrophy was noted in the liver of males and females in the 50, 150, and 600 mg/kg/day groups at the primary necropsy; this finding was considered nonadverse. 

 

Microscopic findings of hyaline droplets (nonadverse) were noted in the kidney for males at all dosage levels at the primary necropsy. This finding progressed to hyaline droplet nephropathy (adverse) at all dosage levels. Immunohistochemistry for alpha-2u globulins was positive in the male rats with changes in distribution and morphology of the positive staining consistent with alpha-2u globulin hyaline droplet nephropathy. The hyaline droplet nephropathy persisted at the recovery necropsy. Alpha-2u globulin nephropathy is a male rat specific finding and renal effects induced in the male rats are unlikely to occur in humans.Adrenal cortical atrophy and cytoplasmic vacuolation of the pituitary were noted for males at all dosage levels at the primary necropsy; these findings were considered nonadverse. The adrenal cortical atrophy corresponded to lower absolute and relative adrenal gland weights for males in the 600 mg/kg/day group at the primary necropsy. The cytoplasmic vacuolation observed in the pituitary at the primary necropsy wasobserved at the recovery necropsy with decreased incidence and severity, indicating a trend toward recovery. Adrenal cortical changes were not observed at the recovery necropsy.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

600 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

In a combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted using a protocol comparable to OECD Test Guideline 422 and in compliance with GLP (WIL, 2011) no treatment-related effects were noted on the mean numbers of implantation sites, numbers of pups born, or live litter sizes at all dosage levels. Based on the results of this study the NOAEL for 1,1,3,3-tetramethyl-1,3-divinyldisiloxane for reproduction was considered to be at least 600 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

In the key prenatal developmental toxicity study, conducted according to OECD Test Guideline 414 and in compliance with GLP, the NOAEL for maternal and developmental toxicity was 150 mg/kg bw/day based on lower maternal body weight gain and lower fetal body weights at 600 mg/kg bw/day (Charles River, 2020). The effects on fetal weight occurred together with maternal toxicity effects, but were not considered to be a secondary non-specific consequence of maternal toxicity effects.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05 August 2019 to 21 January 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: controlled temperature area set to maintain 18°C to 24°C, in a flame-proof cabinet, capped with nitrogen
- Stability under test conditions: Stable
- Solubility and stability of the test substance in the solvent/vehicle: Test substance formulations have been previously shown to be stable and homogenous over the range of concentrations used in in this study for at least 10 days when stored in a refrigerator set to maintain a target of 5°C.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The vehicle, corn oil, was dispensed approximately weekly for administration to Group 1 control animals and preparation of the test substance formulations, which were stored at room temperature (18°C to 24°C), protected from light, until use. The vehicle was stirred continuously during dosing. Test substance dosing formulations were prepared at appropriate concentrations to meet dose level requirements.
- Preliminary purification step (if any): none

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:CD

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Age at study initiation: 11–13 weeks old
- Weight at study initiation: 200 and 250 g on Gestation Day 0
- Fasting period before study:
- Housing: Animals were individually housed in solid-bottom cages containing appropriate bedding equipped with an automatic watering valve
- Diet (e.g. ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet® 5002 meal was provided ad libitum
- Water (e.g. ad libitum): Municipal tap water after treatment by reverse osmosis and ultraviolet irradiation was freely available to each animal via an automatic watering system
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C to 26°C
- Humidity (%): 30% to 70%
- Air changes (per hr): Ten or greater air changes per hour with 100% fresh air.
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test substance dosing formulations were prepared at appropriate concentrations to meet dose level requirements. The dosing formulations were prepared approximately weekly and an adequate amount of each formulation was dispensed into daily aliquots, which were stored refrigerated (target of 5°C), protected from light, until use.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil was chosen as the appropriate vehicle based on the test substance’s characteristics and
the subsequent relevant OECD testing guidelines.
- Concentration in vehicle: 0, 12.5, 37.5, 150 mg/mL
- Amount of vehicle (if gavage): not specified
- Lot/batch no. (if required): 2IC0148 and 1IG1538
- Purity: not specified

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dose formulation samples were collected for analysis twice during the study period. Concentration analysis was performed on duplicate sets of all dose levels. Concentration results were considered acceptable if mean sample concentration results were within or equal to ± 15% of theoretical concentration. Homogeneity analysis of the dose formulations was performed once during the study on duplicate sets of low and high dose groups. Homogeneity results were considered acceptable if the relative standard deviation of the mean value at each sampling location was ≤ 10% and if mean sample concentration results were within or equal to ± 15% of theoretical concentration. Stability was not assessed as the test substance formulations have been previously shown to be stable and homogenous over the range of concentrations used in in this study for at least 10 days when stored in a refrigerator set to maintain a target of 5°C.

Details on mating procedure:

The females were time-mated and were received on Gestation Day 1, 2, 3, or 4.

Duration of treatment / exposure:

From gestation day 6 to gestation day (GD) 20.

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Remarks:

control group

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Remarks:

low dose group

Dose / conc.:

150 mg/kg bw/day (actual dose received)

Remarks:

medium dose group

Dose / conc.:

600 mg/kg bw/day (actual dose received)

Remarks:

high dose group

No. of animals per sex per dose:

25 females per group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The target exposure concentrations were selected based on a previous 14-day repeated-dose study and an OECD 422 combined repeated dose toxicity study with the reproduction/developmental toxicity screening test.
- Rationale for animal assignment (if not random): random

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked for mortality and moribundity.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed individually on Gestation Days 0 (by supplier) and 5–21 (daily).

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Food consumption was quantitatively measured on Gestation Days 5–21 (daily)

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: Animals were subjected to a complete necropsy examination, which included evaluation of the thoracic, abdominal, and pelvic cavities with their associated organs and tissues as well as the thyroid gland. Furthermore, kidney, liver and thyroid gland were weighed at necropsy. The thyroid gland was examined hystopathologically.

OTHER:
THYROID HORMONES EXAMINATIONS: Yes
- Time schedule for examinations: Blood samples for thyroid hormone analyses (triiodothyronine (Total T3); thyroxine (Total T4); thyroid-stimulating hormone (TSH)) were collected (prior to noon in order to avoid diurnal fluctuations in thyroid hormone levels) from a jugular vein into tubes without anticoagulants on GD 21 from all animals.

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:
- Live and dead fetuses: Yes
- Placeta examination: Yes

Fetal examinations:

- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter ]
- Head examinations: No

Statistics:

Levene’s test11 was used to assess the homogeneity of group variances. The groups were compared using an overall one-way ANOVA F-test if Levene’s test was not significant or the Kruskal-Wallis test if it was significant. If the overall F-test or Kruskal-Wallis test was found to be significant, then pairwise comparisons were conducted using Dunnett’s or Dunn’s test, respectively.
The groups were compared using an overall Kruskal-Wallis test. If the overall Kruskal-Wallis test was found to be significant, then the above pairwise comparison was conducted using Dunn’s test.
A Fisher’s Exact Test16 was used to conduct pairwise group comparisons of interest.

Indices:

Pre-implantation loss, post-implantation loss, sex ratio, litter % of fetuses with abnormalities

Clinical signs:

no effects observed

Description (incidence and severity):

No test substance-related clinical observations were noted at the daily examinations or approximately 1 hour following dose administration at any dosage level.
Observations noted in the test substance-treated groups, primarily including thin fur cover and scabbing on various body surfaces, occurred infrequently, at similar frequencies in the control group, and/or in a manner that was not dose-related.
All females were gravid, with the exception of Female No. 2520 in the 50 mg/kg bw/day group.

Mortality:

no mortality observed

Description (incidence):

All females in the control, 50, 150, and 600 mg/kg bw/day groups survived to the scheduled necropsy on Gestation Day 21.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

A lower (8.1%) mean body weight gain was noted in 600 mg/kg bw/day group when the overall treatment period (Gestation Days 6–21) was evaluated. Although mean absolute body weights in this group were comparable to the control group throughout the treatment period, a statistically significantly lower corrected body weight (5.4%) and corrected body weight gain (24.2%) were noted in this group. The body weight effects noted in the 600 mg/kg bw/day group were considered test substance-related and adverse.
Mean maternal body weights, body weight gains, corrected body weights, and corrected body weight gains in the 50 and 150 mg/kg bw/day groups, and mean gravid uterine weights at all dosage levels were unaffected by test substance administration. Differences from the control group were slight and not statistically significant.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Mean maternal food consumption, evaluated as g/animal/day, in the 50, 150, and 600 mg/kg bw/day groups was unaffected by test substance administration.

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

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Test substance-related higher mean kidney weights (5-7%) were noted in the 50, 150, and 600 mg/kg bw/day groups; higher liver weights (4-7%) were also noted in the 150 and 600 mg/kg bw/day groups. Kidney and liver were not evaluated microscopically, but weight elevations were similar to those noted in the previous 28-day repeat dose study using the same dosage levels. There were no other test substance-related effects on organ weights.

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no observations that were considered to be associated with administration of the test substance at dosage levels of 50, 150, and 600 mg/kg/day

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

There were no test substance-related histologic changes.

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Thyroid hormones: In the 150 and 600 mg/kg bw/day groups, statistically significantly higher (72.7% and 69.7%,respectively) mean TSH concentrations were noted compared to the control group. In addition, a statistically significantly lower (30.0%) mean T3 concentration was noted in the 600 mg/kg bw/day group compared to the control group. Given the lack of any effects on thyroid gland weight at any dosage level or histopathology in the 600 mg/kg bw/day group, the differences in T3 and TSH hormones were considered test substance-related but nonadverse. There were no effects on T4 concentrations at any dosage level. In the 150 mg/kg bw/day group, a statistically significantly higher (18.0%) T4 concentration was noted compared to the control group; however, the difference in T4 concentration was not observed in a dose-dependent manner.

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Mean numbers of corpora lutea and implantation sites and the mean litter proportions of pre-implantation loss were similar across all groups.

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Description (incidence and severity):

Intrauterine survival in all dose levels was unaffected by test substance administration.

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Abnormalities:

effects observed, treatment-related

Localisation:

other: body weight gain

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

In the 600 mg/kg bw/day group, mean male (5.66 g), female (5.33 g), and combined (5.48 g) fetal weights were statistically significantly lower (5.39% to 5.84%) than the concurrent control group values (5.98, 5.66, and 5.81 g, respectively) and the historocal control data (5.955, 5.653, and 5.817 g, respectively). The effects on intrauterine growth at 600 mg/kg bw/day were considered test substance-related and adverse. Intrauterine growth was unaffected by test substance administration at dose levels of 50 and 150 mg/kg bw/day. The effects on fetal weight occurred together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects.

Reduction in number of live offspring:

not examined

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

No external malformations or developmental variations were observed in fetuses in this study.

Skeletal malformations:

no effects observed

Description (incidence and severity):

No test substance-related skeletal malformations were observed in fetuses in this study. Fetus No. 2523-03 in the 50 mg/kg bw/day group was noted with an absent lumbar vertebra. In the absence of malformations in the higher dosage levels, this malformation in a single low-dose fetus was not considered test substance-related.

Visceral malformations:

no effects observed

Description (incidence and severity):

No visceral malformations were observed in fetuses in this study.

Other effects:

no effects observed

Description (incidence and severity):

Mean absolute and relative (to the cube root of fetal body weight) anogenital distances in the 50, 150, and 600 mg/kg bw/day groups were comparable to the control group values. Differences from the control group were slight and not statistically significant.

Key result

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Abnormalities:

effects observed, treatment-related

Localisation:

other: body weight

Description (incidence and severity):

The effects on fetal weight occurred together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects.

Developmental effects observed:

yes

Lowest effective dose / conc.:

150 mg/kg bw/day (actual dose received)

Treatment related:

yes

Relation to maternal toxicity:

developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

not specified

See attachments for result tables.

Conclusions:

In the prenatal developmental toxicity study, conducted according to OECD Test Guideline 414 and in compliance with GLP, the NOAEL for maternal and developmental toxicity was 150 mg/kg bw/day based on lower maternal body weight gain and lower fetal body weights at 600 mg/kg bw/day. The effects on fetal weight occurred together with maternal toxicity effects, but were not considered to be secondary non-specific consequence of maternal toxicity effects.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 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

In the key prenatal developmental toxicity study, conducted according to OECD Test Guideline 414 and in compliance with GLP, the NOAEL for maternal and developmental toxicity was 150 mg/kg bw/day based on lower maternal body weight gain and lower fetal body weights at 600 mg/kg bw/day (Charles River, 2020). The effects on fetal weight occurred together with maternal toxicity effects, but were not considered to be secondary non-specific consequence of maternal toxicity effects.

Animals were dosed via oral gavage once daily during Gestation Days 6–20. Clinical signs, body weights, body weight gains, gravid uterine weights, food consumption, thyroid hormones, gross necropsy findings, organ weights and histopathology, intrauterine growth and survival, anogenital distance, and fetal morphology were evaluated in this study.

All females in the control, 50, 150, and 600 mg/kg bw/day groups survived to the scheduled necropsy on Gestation Day 21. There were no test substance-related clinical observations noted at the daily examinations or approximately 1 hour after dose administration in the 50, 150, and 600 mg/kg bw/day groups.

In the 600 mg/kg bw/day group, a greater mean body weight loss and slightly lower mean body weight gains were noted during Gestation Days 6-9, resulting in a lower (43.0%, not statistically significant) mean body weight gain for this period. Mean body weight gains in the 600 mg/kg bw/day group were comparable to the control group during Gestation Days 9–12 and 12–15, but lower again during Gestation Days 15–21 (10.8%). As a result of the decrements noted during the early and late portions of gestation, a lower (8.1%) mean body weight gain was noted in the 600 mg/kg bw/day group when the overall treatment period (Gestation Days 6–21) was evaluated. Although mean absolute body weights in this group were comparable to the control group throughout the treatment period, a lower corrected body weight (5.4%) and corrected body weight gain (24.2%) were noted in the 600 mg/kg bw/day group. The body weight effects noted in the 600 mg/kg bw/day group were considered test substance-related and adverse. Mean maternal body weights, body weight gains, corrected body weights, and corrected body weight gains in the 50 and 150 mg/kg bw/day groups, and gravid uterine weights and food consumption in the 50, 150, and 600 mg/kg bw/day groups were unaffected by test substance administration.

At the scheduled necropsy, no test substance-related macroscopic findings were noted at any dose level.

In the 600 mg/kg bw/day group, a lower (30.0%) mean T3 concentration was noted compared to the control group. In addition, higher (72.7% and 69.7%) mean thyroid stimulating hormone (TSH) concentrations were noted in the 150 and 600 mg/kg bw/day group, respectively, compared to the control group. In the absence of effects on thyroid gland weight (any dosage level) or histopathology in the 600 mg/kg bw/day group, the differences in T3 and TSH hormones were considered test substance-related but nonadverse. There was no test substance-related effect on T4 concentration.

Test substance-related higher mean absolute liver weights were noted in the 150 and 600 mg/kg bw/day groups, and higher mean absolute kidney weights were noted in the 50, 150, and 600 mg/kg bw/day groups compared to the control group. These differences were not considered adverse due to the low magnitude of change.

In the 600 mg/kg bw/day group, lower fetal weights (mean male, female and combined), were noted in comparison to the concurrent control group and the minimum mean values in the Charles River Ashland historical control data; these differences were considered test substance-related and adverse. Intrauterine growth at 50 and 150 mg/kg bw/day, and intrauterine survival, fetal anogenital distance, and fetal morphology at all dosage levels were unaffected by test substance administration.

In a supporting combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted using a protocol comparable to OECD 422 and to GLP (WIL, 2011) neonatal toxicity of the test substance was noted in the 600 mg/kg bw/day group, as two test substance-related total litter losses were noted. As a result, lower postnatal survival was noted during the postnatal period and an increased number of pups found dead and missing were noted in this group. In addition, clinical findings of cool body were noted for pups in this group. Slightly lower (not statistically significant) mean pup birth weights and body weight gains during post-natal days 1-4 resulted in lower mean male and female pup body weights in the 600 mg/kg bw/day group; these results were considered test substance-related and adverse.

Based on the results of this study the NOAEL for 1,1,3,3-tetramethyl-1,3-divinyldisiloxane for development was considered to be 150 mg/kg bw/day.

Justification for classification or non-classification

Based on the available data, 1,1,3,3-tetramethyl-1,3-divinyldisiloxane requires classification for reproductive and developmental toxicity Category 2, H361 "Suspected of damaging fertility or the unborn child (fetal weights) (oral route)" according to Regulation (EC) No 1272/2008.