1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2020-04-17 to to 2021-02-08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2016

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Deve lopmental Toxicity Screening Test

Version / remarks:

2000

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane

EC Number:

222-613-4

EC Name:

1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane

Cas Number:

3555-47-3

Molecular formula:

C12H36O4Si5

IUPAC Name:

tetratrimethylsilyl silicate

Test material form:

liquid

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

The Wistar Han rat was chosen as the animal model for this study as it is an accepted rodent species for toxicity testing by regulatory agencies. Charles River Den Bosch has general and reproduction/ developmental historical data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Males: 10 to 11 weeks old; Females: 11 to 12 weeks old
- Weight at study initiation: Males: 250 to 325 g; Females: 194 to 244 g
- Fasting period before study: No
- Housing: Main animals were randomly group housed (up to five animals of the same sex and same dosing group together) in Makrolon polycarbonate cages on arrival and during the pre-mating period. Main males and females were cohabitated on a 1:1 basis in Makrolon plastic cages during the mating phase. Main males and females were housed in Makrolon plastic cages during the post-mating phase, with a maximum of five/cage for males and individually for females. During the lactation phase, pups were housed with the dam in Makrolon plastic cages except during locomotor activity monitoring of the dams. Each cage was clearly labeled with a colour-coded cage card indicating Test Facility Study No., group, animal number(s), and sex.
- Diet : ad libitum , except during locomotor activity
- Water: ad libitum, except during locomotor activity
- Acclimation period: Males: six days before commencement of dosing; Females: 7 days prior to start of the pretest period
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22°C
- Humidity (%): 46 to 78%
- Air changes: 10 per hour minimum
- Photoperiod: 12-hour light/12-hour dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The test item was administered as received. An adequate amount of the test item was dispensed into daily aliquots, which were stored the same as for the bulk test item until use. Test item dosing formulations were kept at room temperature until dosing. If practically possible, the dosing formulations and vehicle were continuously stirred until and during dosing. Adjustment was made for specific gravity of the test item (0.87). No correction was made for the purity/composition of the test item.

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: until evidence of mating (maximum of 14 days)
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 post-coitum
- After successful mating each pregnant female was caged (how): individually, in Makrolon plastic cages (MIII type, height 18 cm).

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

At least 29 days. Main males and Recovery males were treated for 29 days including a minimum of 14 days prior to mating and during the mating period for Main males. Females that delivered offspring were treated for two weeks prior to mating, during mating, during post-coitum, and at least 13-15 days of lactation (for 52-65 days). Females that failed to deliver pups were treated for 41-52 days. Recovery females were treated during the same period as Main females, until at least the first scheduled necropsy of Main females (55 days).

Frequency of treatment:

Daily, 7 days a week

Details on study schedule:

N/A screening study

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Remarks:

Group 1 (control group)

Doses / concentrations 2

Dose / conc.:

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

Remarks:

Group 2

Doses / concentrations 3

Dose / conc.:

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

Remarks:

Group 3

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

Group 4

No. of animals per sex per dose:

15 males and females for Group 1 and 4 (water and 100 mg/kg/day of undiluted test item, respectively); 10 males and 10 females for Group 2 and 3 (300 and 1000 mg/kg/day of undiluted test item, respectively)

Control animals:

yes

Details on study design:

- Dose selection rationale: Based on the results of a 14-day Dose Range Finder (Test Facility Reference No. 20226169)
- Rationale for animal assignment : random
- Fasting period before blood sampling for clinical biochemistry: Yes for main and recovery males, not for main females
- Rationale for selecting satellite groups: The recovery animals, euthanised following a 14-day treatment-free recovery period, were used to study the potential reversibility of possible toxic effects and were not mated.
- Post-exposure recovery period in satellite groups: Yes

Positive control:

None

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed from the cage during observation, unless necessary for identification or confirmation of possible findings.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
1. Once daily, beginning during the first administration of the test item and lasting throughout the dosing and recovery periods up to the day prior to necropsy. During the dosing period, these observations were performed after dosing at no specific time point, but within a similar time period after
dosing for the respective animals. The time of onset, grade and duration of any observed sign was recorded. Signs were graded for severity and the maximum grade was predefined at 1, 2, 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored.
2. Arena observations were also conducted beginning before the first administration of the test item and then once weekly throughout treatment and recovery. These observations were conducted after dosing.

BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed individually on the first day of treatment (prior to dosing), and weekly thereafter. Mated Main females were weighed on Days 0, 4, 7, 11, 14, 17, and 20 post-coitum and during lactation on PND 1, 4, 7, and 13. A terminal weight was recorded
on the day of scheduled necropsy.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Food consumption was quantitatively measured weekly, except for Main males and Main females which were housed together for mating and for Main females without evidence of mating. Food consumption of mated Main females was measured on Days 0, 4, 7, 11, 14, 17, and 20 post-coitum and
during lactation on PND 1, 4, 7, and 13.

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

WATER CONSUMPTION: Yes
- Time schedule for examinations: Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no effect was suspected.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: On the day of scheduled necropsy in main and recovery animals
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes for main and recovery males, not for main females
- How many animals: All animals except for animals which were found dead or died during the blood sampling procedure
- Parameters checked in table were examined: yes, see table 1

Oestrous cyclicity (parental animals):

Oestrous cycles were evaluated by examining the vaginal cytology of samples obtained by vaginal lavage. Daily vaginal lavage was performed for all females (Main and Recovery) during 14 days prior to treatment (pretest period) and the first 14 days of treatment. For Main females, daily vaginal lavage was continued during mating until evidence of copulation was observed. On the day of necropsy, a vaginal lavage was also taken from Main females to determine the stage of estrous. This was done for all females, except for females that died spontaneously.

Sperm parameters (parental animals):

Parameters examined in male parental generations:
- testis weight, reduced in size, flaccid
- epididymis weight, reduced in size, nodule(s)

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of eight pups/litter (four/sex/litter as nearly as possible) were selected. The surplus pups were euthanized by decapitation. Blood samples were collected from two of the surplus pups (if possible from one male and one female pup) and samples were pooled to one sample per litter. Selective elimination of pups, e.g. based upon body weight or AGD, was not done. All remaining pups were euthanized on PND 14-16.

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 abnormalities, anogenital distance (AGD), pup weight on the day of AGD, presence of nipples/areolae in male pups. Particular attention was paid to the external reproductive genitals to examine signs of altered development.

GROSS EXAMINATION OF DEAD PUPS:
[No. Except for a few missing pups, no pups died during the course of the study]

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals [Following completion of the mating period for Main males which sired or failed to sire; after the recovery period of at least 14 days for Recovery males]
- Female animals: All surviving animals [At PND 14-16 for Main females which delivered; Post-coitum Days 26-27 for Main feamles with evidence of mating which failed to deliver; Approximately 24 days after the last day of the mating period for the one Main female without evidence of mating - note that mating was overlooked as one implantation site was recorded at necropsy; After the recovery period of at least 14 days for Recovery females]

GROSS NECROPSY / HISTOPATHOLOGY / ORGAN WEIGHTS
Gross necropsy consisted of external and internal examinations, including examination of the cranial, thoracic and abdominal cavities and their contents, as well as reproductive organs.
A number of organs from all selected main aninmals and all recovery animales (see table 2) as well as from males that failed to sire and females that failed to deliver (see table 2bis) were prepared for microscopic examination and weighed.
All tissues indicated in these tables were examined by board-certified toxicological pathologist with training and experience in laboratory animal pathology. For the testes of all selected Main males of Groups 1 and 4, and all Main males that failed to sire, a detailed qualitative examination was made, taking into account the tubular stages of the spermatogenic cycle.
A peer review on the histopathology data was performed by a second pathologist.

Postmortem examinations (offspring):

SACRIFICE
- Pups younger than 7 days were euthanized by decapitation.
- All remaining pups (PND 14-16), except for the two pups per litter selected for blood collection were euthanized by an intraperitoneal injection of sodium pentobarbital.
- The pups selected for blood collection on PND 14-16 were anesthetized using isoflurane followed by exsanguination.

GROSS NECROPSY / HISTOPATHOLOGY
Sex was determined both externally and internally. Descriptions of all external abnormalities were recorded. Particular attention was paid to the external reproductive genitals to examine signs of altered development.
In addition, blood was collected from two pups per litter, and the thyroid from two pups per litter (if possible one male and one female pup) was preserved in 10% buffered formalin. The pups selected for blood sampling were the same pups as selected for thyroid preservation.

Statistics:

Mean values of the following were evaluated appropriately: body weights and body weight gain, food consumption and relative food consumption, grip fore and grip hind, total movements and ambulations, haematology and serum chemistry, terminal organ weights and body weight ratios, precoital time, implantation sites, gestation length, deads pups and living pups, litter weight, ratio of live births/litter size, anogenital distance and nipple retention, thyroid hormone values and thyroidweight, litter sex ratio, mating, fertility and gestation index.

Reproductive indices:

Reproductive-type parameters evaluated were evidence of mating, pregnancy and duration of gestation. In particular, the number of corpora lutea and the number of uterine implantation sites were determined for all females.

Offspring viability indices:

Pups were examined daily for survival, external abnormalities and clinical signs during the lactation period. Each litter was examined as soon as possible after delivery (within 24 hours) to determine the number and sex of the pups, the number of pups alive, number of pups dead, runts and the pres ence of any gross abnormalities. All pups were counted, weighed, sexed and the sex ratio calculated . Litter weights were taken within 24 hours of completion of parturition and on post-partum day 4 or earlier if the dam was euthanised prior to post-partum day 4. Developmental parameters evaluated included mean litter size, offspring survival, sex ratio and offspring body weight gain.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related clinical signs were noted during daily detailed clinical observations or during weekly arena observations. Any clinical signs noted during the treatment period occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment. No toxicologically relevant clinical signs were observed in Recovery animals.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

No mortality occurred during the study period that was considered to be related to treatment with the test item. Female No. 59 (control) died at blood sampling on the day of scheduled necropsy. No clinical signs were noted. Slightly low body weight gain was recorded on the days preceding its death. At necropsy many reddish foci on the thymus were recorded. As this was a control animal which died during the blood sampling procedure, this death was considered not treatment-related. Female No. 80 (300 mg/kg/day) was found dead on Day 15 post-coitum. No clinical signs or body weight changes were noted on the days preceding death. At macroscopy reddish fluid in the trachea, not collapsed lungs and reddish discoloration of the lungs were recorded, suggesting that death was related to the gavage procedure.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weights and body weight gain of treated animals up to 1000 mg/kg/day remained in the same range as controls over the treatment period (Main and Recovery animals) and in the recovery period thereafter (Recovery animals only).

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption before or after correction for body weight was similar to the control level over the treatment period up to 1000 mg/kg/day (Main and Recovery animals) and in the recovery period ther eafter (Recovery animals only).

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

No statistically significant changes were recorded at the end of the treatment period. Any statistically significant differences recorded at the end of the recovery period (but not at the end of the treatment period) were considered not related to treatment with the test item. Coagulation parameters of treated rats were considered not to have been affected by treatment with
the test item.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

No toxicologically relevant changes were noted in clinical biochemistry parameters after treatment with the test item up to 1000 mg/kg/day.
Any (statistically significant) changes noted were considered to be unrelated to treatment based on the small magnitude of change and/or as these changes occurred in the absence of a dose-related trend, or were recorded at the end of the recovery period only. Thyroid hormone analyses: Serum levels of T4 in Main males (F0-generation) were considered unaffected by treatment with the test item up to 1000 mg/kg/day.

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, non-treatment-related

Description (incidence and severity):

Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all examined animals.
Motor activity in males at end of treatment was similar between control and treated animals. Motor activity in Main females at end of treatment was increased at 300 and 1000 mg/kg/day, for total movements as well as and ambulations. As this difference was caused by one animal in each group (Nos. 84 and 88), this was considered not toxicologically relevant.
In Recovery females at the end of treatment total movements and ambulations were similar between treated and control animals. A similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period was noted in all groups and sexes.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

There were microscopic observations of note in the lungs of some animals after treatment with the test item at all dose levels.
At the end of the treatment period, main finding in the lungs of both sexes consisted of granulomatous inflammation (varying from minimal to marked degree). This was recorded in three males and two females at 100 mg/kg/day, two males and two females at 300 mg/kg/day and in one male and three females at 1000 mg/kg/day. The multifocal granulomatous inflammatory processes contained multinucleated foreign body giant cells, a varying amount of vacuolated material (mainly in macrophages) and granulocytic inflammatory cells. This inflammatory process was seen in one or more lung lobes and was in most cases located close to the main stem bronchi.
Additional findings in the lungs included, alveolar (vacuolated) macrophage aggregations (varying from minimal to marked degree) and an increased incidence and severity of perivascular/peribronchial mixed inflammatory cell infiltrate (minimal to slight degree). There was no dose relationship for the incidences and severities of these lung alterations.
After the 14-day treatment-free recovery period two males and three females of the 1000 mg/kg/day group showed granulomatous inflammation (minimal-slight). The alveolar (vacuolated) macrophage aggregations and/or perivascular/peribronchial mixed inflammatory cell infiltrates were recorded for some animals but didn’t exceed a minimal degree. The alterations in the lungs of the recovery animals were recorded at lower severities compared to the animals at the end of the treatment period, suggesting partial, ongoing recovery. These alterations were attributed to accidental aspiration of non-lethal amounts of test item formulation resulting in local inflammatory lesions in the lungs.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

Length and regularity of the estrous cycle were considered not to have been affected by treatment with the test item. Most females had regular cycles of 4 to 5 days.
Female Nos. 73 (100 mg/kg/day) and 89 (1000 mg/kg/day) were observed with an irregular cycle, while for Female No. 90 (1000 mg/kg/day) regularity could not be determined.
Extended estrous was recorded for female No. 82 (300 mg/kg/day). All females had a normal litter. Given their absence of an apparent correlation to pregnancy status, these findings did
not indicate a relation with treatment with the test item.

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

Stage dependent qualitative evaluation of spermatogenesis in the testis was performed. The testes revealed normal progression of the spermatogenic cycle and the expected cell associations and proportions in the various stages of spermatogenesis were present.

Reproductive performance:

no effects observed

Description (incidence and severity):

Mating index was unaffected by treatment. All females showed evidence of mating. Precoital time was considered not to be affected by treatment with the test item. Most females mated within 4 days. Fertility index was considered not to be affected by treatment. The fertility index was 100, 80, 70 and 100% for the control, 100, 300 and 1000 mg/kg/day groups, respectively. A total of two females at 100 mg/kg/day and three females at 300 mg/kg/day were not pregnant. In the absence of a dose-related incidence of non-pregnancy, this was considered not to be related to treatment with the test item.
Gestation index and duration of gestation were considered not to be affected by treatment with the test item. Except for one female in the control group (Female No. 51, one implantation only) and one female at 300 mg/kg/day (Female No. 80, found dead on post-coitum Day 15), all pregnant females had live offspring. The gestation index was 90, 100, 86 and 100% for the control, 100, 300 and 1000 mg/kg/day groups, respectively.
There were 1/10 couples of the control group (Male No. 1 and Female No. 51), 2/10 couples at 100 mg/kg/day (Male Nos. 19, 20 and Female Nos. 69, 70) and 3/10 couples at 300 mg/kg/day day (Male Nos. 28, 33, 35 and Female Nos. 78, 83, 85) with no offspring. No abnormalities were seen in the reproductive organs, which could account for their lack of offspring.

Details on results (P0)

No reproduction toxicity was observed up to the highest dose level tested (1000 mg/kg/day). No treatment-related changes were noted in any of the reproductive parameters investigated
in this study (i.e. mating and fertility indices, precoital time, number of implantations, estrous cycle, spermatogenic profiling, and histopathological examination of reproductive organs).

Effect levels (P0)

1

Key result

Dose descriptor:

NOAEL

Remarks:

Reproductive effects in P0 animals

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

2

Dose descriptor:

NOAEL

Remarks:

Systemic toxicity in P0 animals

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No systemic parental toxicity was observed up to 1000 mg/kg/day

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs occurred among pups that were considered to be related to treatment with the test item.
The nature and incidence of clinical signs remained within the range considered normal for pups of this age and were therefore considered not to be toxicologically relevant.

Mortality / viability:

no mortality observed

Description (incidence and severity):

Viability indices were 100, 99, 100 and 99% for the control, 100, 300 and 1000 mg/kg/day groups, respectively.
There were two pups missing between PND 2 and 3 (Pup No. 5 of Litter No. 74 of the 100 mg/kg/day group and Pup No. 4 of Litter No. 88 of the 1000 mg/kg/day group). For pup No. 5 of Litter No. 74 pale appearance was recorded at first litter check. Pups missing were most likely cannibalized. No toxicological relevance was attributed to these dead/missing pups since the mortality incidence did not show a dose-related trend and remained within the range considered normal for pups of this age.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Serum T4 levels in male and female PND 14-16 pups were considered not to be affected by treatment up to 300 mg/kg/day.
The increased serum T4 levels at 300 mg/kg/day in females and 1000 mg/kg/day in males (1.14x of control) were considered not treatment-related as the magnitude of change was less than 20% and no statistical significance was reached. Increased serum T4 levels in females at 1000 mg/kg/day (1.20x of control) were considered test item-related. Mean values remained within the historical control range.

Urinalysis findings:

not examined

Sexual maturation:

not examined

Anogenital distance (AGD):

no effects observed

Description (incidence and severity):

Anogenital distance (absolute and normalized for body weight) in male and female pups was considered not to be affected by treatment with the test item.
Both absolute and normalized anogenital distance in male and female pups at 300 mg/kg/day was higher compared to concurrent control, however without reaching statistical significance. In the absence of a dose response, this was considered to be unrelated with the test item.

Nipple retention in male pups:

no effects observed

Description (incidence and severity):

Treatment up to 1000 mg/kg/day had no effect on areola/nipple retention. For none of the examined male pups nipples were observed at PND 13.

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

No macroscopic findings were noted during necropsy of F1 pups.

Histopathological findings:

not examined

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Remarks:

Reproductive toxicity in F1 animals

Generation:

F1

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Any other information on results incl. tables

Table 3: Correlation of Histopathology Findings with In-Life Reason for Males that Failed to Sire and Females that

Failed to Deliver Healthy Pups.

Group	Dose level (mg/kg bw/day)	No. Female/Male	In-life reason	Histopathology
1	0	51/01	Not mated	No histopathological correlate
2	100	69/19 70/20	Not pregnant Not pregnant	No histopathological correlate No histopathological correlate
3	300	78/28 83/33 85/35	Not pregnant Not pregnant Not pregnant	No histopathological correlate No histopathological correlate No histopathological correlate
4	1000	-	-	-

Applicant's summary and conclusion

Conclusions:

In a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening test with the registered substance 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane, conducted according to OECD Test Guideline 422 and in compliance with GLP, a NOAEL for male and female reproductive toxicity was concluded to be > 1000 mg/kg bw/day based on no treatment-related effects observed in any of the reproductive parameters evaluated.