Chloro(methyl)silane

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

other: read-across from trimethylsilanol, which is structurally related to the hydrolysis product of chlorodimethylsilane, dimethylsilanol.

Adequacy of study:

key study

Study period:

A least 28 days

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to an appropriate OECD test guideline, and in compliance with GLP, using a closely related test substance.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Hydroxytrimethylsilane

EC Number:

213-914-1

EC Name:

Hydroxytrimethylsilane

Cas Number:

1066-40-6

IUPAC Name:

trimethylsilanol

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 11-12 weeks.
- Weight at study initiation: Males: 341 g to 418 g; Toxicity phase females:231 g to 282 g ; Reproductive phase females: 218 g to 280 g
- Fasting period before study: None
- Housing: F0 animals were housed individually in clean, stainless steel wire mesh cages suspended above cage board. The cage-board was changed at least 3 times per week. The males and reproductive phase females were paired for mating in the home cage of the male. Following positive evidence of mating, the males were housed in suspended wire mesh cages until the scheduled necropsy, and the females were transferred to plastic maternity cages with nesting material, ground corncob bedding
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): Ad libitum except during exposure periods, FOB and fasting period prior to blood sampling.
- Water (e.g. ad libitum): Ad libitum except during exposure periods, FOB and fasting period prior to blood sampling.
- Acclimation period: The males and reproductive phase females were housed for an acclimation period of 16 days prior to the first day of treatment. The toxicity phase females were housed for an acclimation period of 23 days prior to the first day of treatment.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 3
- Humidity (%): 50± 20
- Air changes (per hr): At least 10
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 3 April 2008 To: 31 May 2008

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: 1.0 m3 (1000 L) stainless steel and glass whole-body exposure chambers

- Temperature, humidity in air chamber: 19°C to 26°C; 38% to 68% humidity

- Air change rate: At least 12 per hour

- Trimethylsilanol was generated for exposure as a vapor using a bubbler-type vaporization system located within a heated containment box. Nitrogen flowed into the inlet stem of a gas washing bottle containing an appropriate quantity of test article and bubbled through a fritted disc at the bottom of the bottle in order to create vapors of the test article. The concentrated vapors were piped to the heated chamber inlet where the concentration was reduced by mixing with chamber ventilation air.


TEST ATMOSPHERE

- Brief description of analytical method used: Gas chromatography

- Samples taken from breathing zone: yes

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: Until evidence of mating
- Proof of pregnancy: vaginal copulatory plug or the presence of sperm following a vaginal lavage defined as Day 0.
- Females with no evidence of mating or that failed to deliver were housed in plastic maternity cages until post-cohabitation or post-mating day 25.
- After successful mating each pregnant female was caged (how): plastic maternity cages with nesting material, ground corncob bedding.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Actual exposure concentrations within each chamber were measured at approximately 35 minute intervals during each daily exposure period by a validated gas chromatographic method. Exposure atmosphere samples were delivered to the gas chromatograph from the approximate middle of each chamber by a pump and multi-port sampling valve. At least 1 standard was analyzed each day prior to exposure to confirm gas chromatographic calibration.
Homogeneity and temporal stability of the exposure concentrations were evaluated during the method development phase of the study. Four test locations and a reference location were used for these determinations. The test locations were top rear, top front, bottom rear and bottom front. Samples were collected and analyzed on the GC as rapidly as possible by alternating from the reference location to a test location. The measured concentration was calculated as a percent difference for each position from the reference location. Homogeneity was performed in triplicate for each test article exposure chamber.

Duration of treatment / exposure:

Six hours per day, seven days per week.

Frequency of treatment:

Males and reproductive phase females were exposed daily for at least 14 days prior to mating and continuing throughout mating for a minimum of 34 days (males) or through gestation day 20 (reproductive phase females). Toxicity phase females were exposed daily for a minimum of 28 days.

Details on study schedule:

Three test article exposed groups and one control group, each composed of 10 males, 10 toxicity phase females and 10 reproductive phase females. F0 males and reproductive phase females were exposed daily for 14 days prior to mating, throughout the mating period and continuing through the day prior to euthanasia (males) or gestation day 20 (reproductive phase females), for a total of 34 and 35-48 consecutive days, respectively. F0 reproductive phase females with no evidence of mating or that failed to deliver were exposed through post-mating or post-cohabitation day 24 (the day prior to euthanasia) for a total of 52 consecutive days. F0 toxicity phase females were exposed for 28 consecutive days.
All females were allowed to deliver naturally and rear their young to PND 4. During the period of expected parturition, the females were observed twice daily for initiation and completion of parturition and for signs of dystocia. On the day parturition was initiated (PND 0), pups were sexed and examined for gross malformations, and the numbers of stillborn and live pups were recorded. Individual gestation length was calculated using the date delivery started.
Females that delivered were euthanized (by carbon dioxide inhalation) on lactation day 4. Females that failed to deliver were euthanized on post mating day 25 (females with evidence of mating) or post-cohabitation day 25 (females with no evidence of mating).

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 61, 303 and 602 ppm (males), 0, 61, 304 and 604 ppm (toxicity phase females) and 0, 61, 304 and 603 ppm (reproductive phase females)
Basis:
analytical conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 60, 300 and 600 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

Ten

Control animals:

other: Filtered air only

Details on study design:

- Dose selection rationale: 2-week range-finding study

- Rationale for animal assignment: Random

Positive control:

No

Examinations

Parental animals: Observations and examinations:

CAGE SIDE AND DETAILED CLINICAL OBSERVATIONS: Yes
All rats were observed twice daily for moribundity and mortality. Individual clinical observations were recorded daily. Once prior to the initiation of exposure, on the first day of exposure and on a weekly basis throughout the study, all rats were observed outside the home cage in a standard arena and evaluated for changes in gait, posture and response to handling, as well as the presence of clonic or tonic movements, stereotypies or bizarre behavior. Observations were conducted prior to test article exposure during the treatment period and were not performed on the day of Functional Observational Battery (FOB) assessments. Animals visible in the exposure chamber were also observed for signs of toxicity at the mid-point of exposure (3 hours following beginning of exposure) and any positive findings were recorded. All animals were observed for signs of toxicity approximately 1 hour following the exposure period.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual male and toxicity phase female body weights were recorded weekly, beginning 1 week prior to test article exposure, on the first day of exposure and weekly thereafter until the scheduled euthanasia. Body weights were also recorded for the toxicity phase animals assigned to FOB and locomotor activity assessments on the days of these evaluations. Individual reproductive phase female body weights were recorded weekly, beginning 1 week prior to test article exposure, on the first day of exposure and on a weekly basis thereafter until evidence of copulation was observed. Once evidence of mating was observed, reproductive phase female body weights were recorded on gestation days 0, 4, 7, 11, 14, 17 and 20 and on lactation days 1 and 4.

FOOD CONSUMPTION:
Individual food consumption was recorded on the corresponding weekly body weight days until pairing. Once evidence of mating was observed, reproductive phase female food consumption was recorded on gestation days 0, 4, 7, 11, 14, 17 and 20 and on lactation days 1 and 4.

WATER CONSUMPTION: No

FUNCTIONAL OBSERVATION BATTERY (FOB) observations were recorded for all F0 males and toxicity phase females during the week prior to initiation of test article exposure (baseline evaluation) and prior to exposure during study week 4 (the last week of the study), following a minimum of 28 days of exposure (females) or 34 days of exposure (males). See Table 1 for parameters investigated.

LOCOMOTOR ACTIVITY was assessed for all F0 males and toxicity phase females during the week prior to initiation of exposure (baseline evaluation) and prior to exposure during study week 4, following a minimum of 28 days (females) or 34 days (males) of test article exposure.

HAEMATOLOGY AND CLINICAL CHEMISTRY: Blood samples for clinical pathology evaluations (hematology, serum chemistry and coagulation parameters) were collected from all F0 males and toxicity phase females at the scheduled necropsies (study day 34 for males and study day 35 for females). The animals were fasted overnight prior to blood collection. Blood for serum chemistry and hematology was collected from the retro orbital sinus following isoflurane anesthesia. Blood for coagulation parameters was collected from the vena cava at the time of necropsy. Parameters assessed are summarised in Table 2.

MATING, FERTILITY AND COPULATION INDICES: The following were calculated: male and female mating index, male and female fertility index, male and female copulation index.

Oestrous cyclicity (parental animals):

Not examined.

Sperm parameters (parental animals):

Microscopic examination of male tissues placed special emphasis on stages of spermatogenesis in the male gonads and histopathology of interstitial cell structure. Male fertility and copulation indices were calculated.

Litter observations:

STANDARDISATION OF LITTERS - Not performed.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: Survival and any adverse changes in appearance or behavior, nursing behaviour, body weight, number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies and length of gestation.

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

Histopathologic examination was deemed unnecessary.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals after completion of mating and 34 days of exposure.
- Maternal animals: Females that delivered were euthanized on lactation day 4; the number of former implantation sites and corpora lutea were recorded. Females that failed to deliver were euthanized on post mating day 25 (females with evidence of mating) or post-cohabitation day 25 (females with no evidence of mating).
- Toxicity phase females: All after 28 days of exposure.


GROSS NECROPSY
- MALES AND TOXICITY PHASE FEMALES: Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.


HISTOPATHOLOGY / ORGAN WEIGHTS
- MALES AND TOXICITY PHASE FEMALES: The tissues indicated in Table 3 were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

On PND 4, surviving F1 pups were euthanized via an intraperitoneal injection of sodium pentobarbital and necropsied with emphasis on developmental morphology. Organs and tissues with gross lesions were preserved in 10% neutral-buffered formalin for possible future histopathologic examination. All carcasses were then discarded. Histopathologic examination was deemed unnecessary during consultation between the study director and the sponsor; therefore, tissues retained from F1 pups will be discarded upon issuance of the final report.

Statistics:

Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test article-treated group to the control group by sex. Each mean was presented with the standard deviation, standard error and the number of animals used to calculate the mean. Data obtained from nongravid females were excluded from statistical analyses following the mating period. Where applicable, the litter was used as the experimental unit. Parental mating, fertility, conception and copulation indices were analyzed using the Chi square test with Yates’ correction factor. Mean body weights (weekly, gestation and lactation), body weight changes and food consumption, precoital intervals, offspring body weights and body weight changes, gestation length, numbers of corpora lutea and implantation sites, number of pups born, live litter size on PND 0, unaccounted-for sites, absolute and relative organ weights, clinical pathology values (except gamma glutamyltransferase) and FOB data values were subjected to a parametric one way analysis of variance (ANOVA) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test was used to compare the test article-exposed groups to the control group. FOB parameters that yielded scalar or descriptive data and qualitative histopathological findings in the test article exposed groups were compared to the control group using Fisher’s Exact test. Mean litter proportions (% per litter) of males at birth and postnatal survival, as well as gamma glutamyltransferase values, were subjected to the Kruskal-Wallis nonparametric ANOVA to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test was used to compare the test article-exposed groups to the control group.

Reproductive indices:

Mating, fertility and copulation/conception indices formulae- See 'Other information on materials and methods' section.

Offspring viability indices:

Litter parameter formulae - See 'Other information on materials and methods' section.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

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:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY:
F0 males: All F0 males survived to the scheduled necropsy.
Toxicity phase females: One toxicity phase female in the 300 ppm group was found dead on study day 35, the day of scheduled necropsy. The cause of death for this female could not be determined and there were no clinical findings observed for this female during the study. However, because there were no mortalities at 600 ppm, this mortality at 300 ppm was not considered test substance-related.
Reproductive phase females: All reproductive phase females survived to the scheduled necropsy on lactation day 4, post-mating day 25 or post-cohabitation day 25. No test article-related clinical findings were noted.
In all groups no test article-related clinical findings were noted during the daily examinations, at the midpoint of exposure or approximately 1 hour following the end of exposure. Clinical findings were observed in the exposed groups during the daily examinations and approximately 1 hour following the end of exposure, and included hair loss, scabbing and/or red or yellow material on various body surfaces. However, these findings were observed in single animals, similarly in the control group and/or in a manner that was not exposure related. Therefore, no relationship to the test article was apparent.

BODY WEIGHT AND WEIGHT GAIN:
F0 males: Mean body weights and body weight gains for all groups were similar to the control group throughout the premating (study days 0-13) and entire exposure (study days 0-34) periods. No statistically significant differences were observed. During study days 27-34, mean body weight losses were noted for all groups, including the control group. This was likely due to the fasting period (study day 33-34) prior to blood collection for clinical pathology evaluations.
Toxicity phase females: Differences from the control group were slight and not statistically significant. Like males there were fasting period related mean body weight losses in all groups, including the controls.
Reproductive phase females: No differences between control and treated animals.

FOOD CONSUMPTION:
F0 males, toxicity phase and reproductive phase females: No statistically significant differences were noted.

REPRODUCTIVE FUNCTION: Mean mating, fertility and copulation/conception indices for all exposure concentrations were similar to the control group. Mean gestation lengths were similar to the control group.

ORGAN WEIGHTS:
F0 males: No test substance-related changes.
Toxicity phase females: Higher mean adrenal gland, kidney and liver weights relative to final body weight were noted for the 600 ppm group when compared with the control group. Although the differences in mean adrenal gland weight achieved statistical significance (p<0.01), the value for the 600 ppm group (0.031 g) was within the range of the WIL historical control data (0.02 g-0.05 g) and was not considered toxicologically important. The increases in mean liver and kidney weights relative to final body weight were not toxicologically significant and fell within the WIL historical control data range. In addition, the elevation in mean liver and kidney weights in the high dose females may in part be due to one animal with histopathologic findings consistent with Caroli’s disease, which is a combination of polycystic kidney disease and bile duct dilatation. These findings in the liver and kidney of this particular animal were associated with relatively high liver and kidney weights, which would have contributed to the statistically significant higher mean kidney and liver weights (relative to final body weight) in this group.

HAEMATOLOGY:
F0 males: Mean absolute eosinophil and lymphocyte counts for the 600 ppm group males were 42.9% and 26.4% lower, respectively, than the control group. The difference for mean absolute eosinophils was significant (p<0.05). Because these changes were within historical limits for approximately age-matched animals (0.05-0.25 and 5.20-13.78 thousand/µL for eosinophils and lymphocytes, respectively) and did not correlate with any other clinical or pathological consequences, the decreased absolute eosinophil and lymphocyte counts were considered test article-related but nonadverse.
Toxicity phase females: A significantly (p<0.05) higher mean corpuscular volume was noted for the 600 ppm group (55.8 fL) when compared with the control group (53.9 fL). This finding was not considered to be test substance related because there were no correlating clinical pathological findings. Furthermore, the change was considered toxicologically insignificant because the small magnitude of change and because the increase in MCV fell within the WIL historical control data range.

CLINICAL CHEMISTRY:
F0 males: The mean alanine aminotransferase value for the 600 ppm group males was 20.5% higher than the control group. The difference was significant (p<0.05). While this change was considered test article-related, it was not considered adverse because the magnitude of change from the control group was small, the value was within historical limits and it did not correlate with any other clinical or pathological abnormalities.
Toxicity phase females: The mean alanine aminotransferase value for the 600 ppm group females was 11.1% higher than the control group, but did not achieve statistical significance. While this change was considered test substance-related, it was not considered adverse because the magnitude of change from the control group was small, the value was within historical limits and it did not correlate with any other clinical or pathological abnormalities. In addition, a significantly (p<0.05) lower creatinine level was noted for the 300 ppm toxicity phase females when compared with the control group. However, because this decrease was not observed in an exposure-related manner, no relationship to the test substance was apparent.

GROSS PATHOLOGY:
F0 males: No test substance-related internal findings.
Toxicity phase females: One toxicity phase female in the 300 ppm group was found dead on study day 35 (day of scheduled necropsy). This female had no macroscopic findings that indicated a cause of death. There were no test substance-related changes.
Reproductive toxicity phase females: No test substance-related changes.

HISTOPATHOLOGY:
F0 males: No test substance-related changes.
Toxicity phase females: There were no test article-related histopathologic findings in toxicity phase females at any exposure level. One 600 ppm group female was noted with lesions of the kidney and liver compatible with congenital polycystic kidney disease and cystic dilatation of intrahepatic bile ducts. This combination of changes is a congenital autosomal recessive disease recognized in Crl:CD rats and therefore, these occurrences in 1 animal were considered unrelated to test article exposure.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

>= 600 ppm (nominal)

Sex:

male/female

Basis for effect level:

other: No adverse test substance-related effects were observed at any dose in parental animals.

Results: F1 generation

General toxicity (F1)

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

Details on results (F1)

VIABILITY (OFFSPRING):
The mean number of pups born, live litter size and the percentage of males at birth in the 60, 300 and 600 ppm groups were similar to the control group values. Postnatal survival in all groups was unaffected by F0 maternal test substance exposure through gestation day 20.

CLINICAL SIGNS (OFFSPRING):
The general physical condition of all F1 pups in this study was unaffected by F0 maternal test article exposure. Pups (litters) that were found dead numbered 17(4), 14(7), 2(2) and 1(1) in the control, 60, 300 and 600 ppm groups, respectively. Two, 2 and 1 pups in the control, 60 and 300 ppm groups, respectively, were missing and 1 pup in the 60 ppm group was found dead due to a mechanical injury and therefore sent to necropsy.

BODY WEIGHT (OFFSPRING):
Mean F1 male and female pup body weights and body weight changes in the 60, 300 and 600 ppm groups were similar to the control group during PND 1-4. No statistically significant differences were noted.

GROSS PATHOLOGY (OFFSPRING):
One fetus in the 60 ppm group had mandibular micrognathia (skeletally, the mandible was smaller than normal and fused) and anophthalmia (skeletally, the orbit was smaller than normal). However, because these findings were limited to a single fetus in the low-exposure group, these findings were not attributed to parental exposure to the test article.
No internal findings that could be attributed to parental test article exposure were noted at the necropsy of pups euthanized on PND 4. Internal findings in the test article-exposed groups were limited to 4 pups in the 300 ppm group and included dark red areas on the eyes and brain and renal papilla not fully developed (Woo and Hoar Grade 1); one of the pups with renal papillae not fully developed was noted with a developmental variation (ipsilateral distended ureter). The pup with dark red areas on the brain was also noted with with a developmental variation (pale liver). There were no internal findings for the 60 and 600 ppm group pups.

HISTOPATHOLOGY (OFFSPRING):
Not conducted in pups.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 600 ppm (nominal)

Sex:

male/female

Basis for effect level:

other: No test substance-related effects in offspring were observed under the conditions of this study.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In this OECD test guideline 422 screening study, which was conducted to GLP, test substance-related effects were limited to changes in hematology (lower eosinophil and lymphocyte counts for males) and serum chemistry (higher alanine aminotransferase for males and toxicity phase females) at 600 ppm. These changes occurred in the absence of correlating histologic changes and were not considered adverse. There were no effects on reproduction parameters. Therefore, under the conditions of this screening study, an exposure level of 600 ppm was considered to be the no-observed-adverse-effect level (NOAEL) for trimethylsilanol. It is considered appropriate to use this result in support of the reproductive toxicity endpoint for chlorodimethylsilane as this substance is hydrolysed very rapidly in the presence of moisture to dimethylsilanol and hydrogen chloride, and the toxicity of di- and tri-methylsilanol are expected to be similar. Since chlorodimethylsilane is hydrolysed to dimethylsilane and hydrogen chloride, additional local irritation can be expected due to the acidic nature of the HCl.

Executive summary:

Three groups of Crl:CD(SD) rats, each group consisting of 10 males, 10 toxicity phase females and 10 reproductive phase females, were exposed via whole-body inhalation to vapour atmospheres of the test article, trimethylsilanol, 6 hours/day, 7 days/week. Target exposure concentrations were 60, 300 and 600 parts per million (ppm). A concurrent control group was exposed to filtered air on a comparable regimen. F₀ males and reproductive phase females were exposed daily for 14 days prior to mating, throughout the mating period and continuing through the day prior to euthanasia (males) or gestation day 20 (reproductive phase females). F₀ reproductive phase females with no evidence of mating or that failed to deliver were exposed through post-mating or post-cohabitation day 24 (the day prior to euthanasia) for a total of 52 consecutive days. F₀ toxicity phase females were exposed for 28 consecutive days.

All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights and food consumption were recorded at appropriate intervals.Functional observational battery (FOB) and locomotor activity data were recorded for all males and toxicity phase females prior to initiation of exposure for each sex (baseline evaluation)and near the end of exposure. F₀males were euthanized following completion of the mating period and F₀toxicity phase females were euthanized following 28 days of exposure. Clinical pathology evaluations (hematology and serum chemistry) were performed on all F₀males and toxicity phase females at necropsy. Complete necropsies were conducted on all F₀males and toxicity phase females, and selected organs were weighed; selected tissues in the control and high‑exposure groups were examined microscopically.

All F₀reproductive phase females were allowed to deliver and rear their pups until lactation day 4. F₁clinical observations and body weights were recorded on postnatal days (PND) 1 and 4. Reproductive phase dams and pups were euthanized and examined on lactation day/PND 4.

One F₀toxicity phase female in the 300 ppm group was found dead on study day 35, the day of scheduled necropsy. While the cause of death for this female was not determined, there were no mortalities in the 600 ppm group. Therefore, this mortality at 300 ppm was not attributed to test article exposure. All other toxicity phase females and all F₀males and reproductive phase females survived to the scheduled necropsies. There were no test article-related macroscopic findings or effects on organ weights. There were no remarkable clinical observations noted at any exposure level. Mean body weights, body weight gains and food consumption for males and females at all exposure levels were similar to the control group for all phases. There were no test article-related effects on FOB parameters, including home cage, handling, open field, sensory, neuromuscular or physiological observations and no effects on locomotor activity patterns for males and toxicity phase females. No remarkable shifts in the pattern of habituation occurred during locomotor activity assessments in any of the test article‑exposed groups when the F₀males and toxicity phase females were evaluated prior to the initiation of exposure or during the study week 4 evaluation.

Decreased mean eosinophil and lymphocyte counts were noted for the 600 ppm group F₀ males. In addition, increased mean alanine aminotransferase values were noted for F₀males and toxicity phase females in the 600 ppm group when compared with the control group. Although these changes were considered test article‑related, they were not considered adverse in the absence of correlating histopathology.

Mean mating, fertility and copulation/conception indices for all exposure concentrations were similar to the control group.  Mean gestation lengths, postnatal survival and F₁body weights were similar to the control group.  There were no test article-related macroscopic findings observed for pups.

Test article-related effects were limited to changes in hematology (lower eosinophil and lymphocyte counts for males) and serum chemistry (higher alanine aminotransferase for males and toxicity phase females) at 600 ppm. These changes occurred in the absence of correlating histologic changes and were not considered adverse. Therefore, under the conditions of this screening study, an exposure level of 600 ppm was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive, systemic and neonatal toxicity of trimethylsilanol when administered via whole-body inhalation exposure to Crl:CD(SD) rats. It is considered appropriate to use this result in support of the reproductive toxicity endpoint for chlorodimethylsilane as this substance is hydrolysed very rapidly in the presence of moisture to dimethylsilanol and hydrogen chloride, and the toxicity of di- and tri-methylsilanol are expected to be similar. Since chlorodimethylsilane is hydrolysed to dimethylsilane and hydrogen chloride, additional local irritation can be expected due to the acidic nature of the HCl