Reaction mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no available fertility studies for the registered substance "Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane". Therefore, data have been read-across from three of its constituents: HMDS, L3 and L4.

- In a Two-Generation Reproductive Toxicity study with HMDS, conducted to GLP (WIL Research Laboratories, 2006) the NOAEC for reproductive toxicity is considered to be at least 5000 ppm.

- In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted to OECD 422 and to GLP (Dow Corning Corporation, 2008) via inhalation route, the NOAEC for the reproductive toxicity of L3 was at least 3146 ppm.

- In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted using a protocol comparable to OECD 422 and to GLP (reliability score 1) (Dow Corning Corporation, 2007) performed with L4, the NOAEC for general and reproductive toxicity was at least 400 ppm.

Link to relevant study records

Reference

Reference 1

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

09.12.2003 to 20.06.2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3800 (Reproduction and Fertility Effects)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.6300 (Developmental Neurotoxicity Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: 7 weeks
- Weight at study initiation: Males (P): 243 - 313 g; Females: 141 - 196 g; Males (F1): 381 - 603 g; Females: 223 - 362 g
- Fasting period before study: None
- Housing: Individually in stainless steel wire-mesh cages, mating in home cage of male, following mating females were removed to plastic maternity cages until lactation day 21, then transferred back to wire-mesh cages.
- Diet (e.g. ad libitum): Ad libitum (except during exposure)
- Water (e.g. ad libitum): Ad libitum (except during exposure)
- Acclimation period: 21 days


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


IN-LIFE DATES: From: 03.12.2003 To: 12.12.2005

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: 2.0 m3 stainless steel and glass whole body inhalation chambers
- Method of holding animals in test chamber: None
- Source and rate of air: No data
- Method of conditioning air: No data
- Temperature, humidity, pressure in air chamber: 19-27°C, 34-66%, slight negative pressure, respectively
- Air flow rate: No data
- Air change rate: 12-15 changes/hour
- Treatment of exhaust air: No data


TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatography
- Samples taken from breathing zone: yes, samples were taken from the approximate middle of each chamber

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: 21 days (or until evidence of mating)
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): in a plastic maternity cages

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Gas chromatography

Duration of treatment / exposure:

At least 70 days prior to mating, throughout mating, gestation through gestation day 20. After parturition, exposure of the F0 and F1 females was re-initiated on lactation day 5 and continued through the day prior to euthanasia . Premating exposure period (males): 70 days.
Premating exposure period (females): 70 days. Duration of test: appproximately 18 months.

Frequency of treatment:

6 hours/day, 7 days/week

Details on study schedule:

- F1 parental animals not mated until approximately 11 weeks (not stated) after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 3 weeks of age.
- Age at mating of the mated animals in the study: 14 -16 weeks.

Dose / conc.:

100 ppm

Dose / conc.:

400 ppm

Dose / conc.:

1 600 ppm

Dose / conc.:

5 000 ppm

No. of animals per sex per dose:

30

Control animals:

yes

Details on study design:

- Dose selection rationale: based on the results of a previous study (no details given)
- Rationale for animal assignment (if not random): random

Positive control:

None

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed twice daily for appearance, behavior moribundity and mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT AND FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly body weights and food consumption were recorded on gestation days (GD) 0, 4, 7, 11, 14 and 20 and on Postnatal days (PND) 1, 4, 7, 14 and 21 for females in the F0 and F1 generations.

WATER CONSUMPTION: No

Oestrous cyclicity (parental animals):

Vaginal lavages were performed daily for determination of estrous cycles beginning 21 days prior to pairing. Ovarian primordial follicle counts were recorded for all F1 females in the control and high exposure groups. 

Sperm parameters (parental animals):

Spermatogenic endpoints (sperm motility [including progressive motility], morphology and numbers) were recorded for all F0 and F1 males. 

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 10 pups/litter (5/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring: Each litter was examined to determine the number of fetuses, sex, still births runts, survival, litter viability and death. 

GROSS EXAMINATION OF DEAD PUPS: yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead.

Forty pups/sex/group from the F2 generation were selected for evaluation of surface-righting (PND 5 to day of positive response) and air-righting (PND 13, 17, 21 and 61) reflexes; of these, 20 F2 pups/sex/group were selected for FOB (PND 4, 11, 21, 45 and 60), auditory startle response (PND 20 and 60), locomotor activity (PND 13, 17, 21 and 61) and/or learning and memory assessment (PND 22 or 62). 

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals as soon as possible after the last litters in each generation were produced.
- Maternal animals: All surviving animals after the last litter of each generation was weaned.

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

HISTOPATHOLOGY / ORGAN WEIGHTS

Organs examined at necropsy (macroscopic and microscopic): Complete detailed necropsy was conducted. Organ weights: Adrenal glands, brain, epididymis (total and cauda), kidneys, liver, lungs, ovaries, pituitary gland, prostate gland, seminal vesicles with coagulating glands and accessory fluids, spleen, testes, thyroid gland, uterus with oviducts and cervix. Histopathologic evaluation: Adrenal glands, brain, cervix, coagulated glands, epididymis (right), kidneys, liver, lungs, ovaries, oviducts, pituitary gland, prostate gland, seminal vesicles, testes, thyroid gland, uterus, vagina, vas deferens, all gross (internal) lesions. 

Postmortem examinations (offspring):

Nonselected F1 pups were necropsied on PND 21 or 28, and nonselected F2 pups were necropsied on PND 21.  Selected organs were weighed from F1 and F2 pups (one/sex/litter) that were necropsied on PND 21.  Selected F2 rats not allocated for neuropathology and brain dimension measurements were necropsied following completion of reflex ontogeny evaluations (PND 61) or at study termination (PND 72).  Each surviving  F1 parental animal received a complete detailed gross necropsy following the completion of weaning of the F2 pups; selected organs were weighed.  

Organs examined at necropsy (macroscopic and microscopic): Complete detailed necropsy was conducted. Organ weights: Adrenal glands, brain, epididymis (total and cauda), kidneys, liver, lungs, ovaries, pituitary gland, prostate gland, seminal vesicles with coagulating glands and accessory fluids, spleen, testes, thyroid gland, uterus with oviducts and cervix. Histopathologic evaluation: Adrenal glands, brain, cervix, coagulated glands, epididymis (right), kidneys, liver, lungs, ovaries, oviducts, pituitary gland, prostate gland, seminal vesicles, testes, thyroid gland, uterus, vagina, vas deferens, all gross (internal) lesions. 

Statistics:

Statistical methods: Parametric analysis was screened for homogeneity of variance using Levene's test and normality using Shapiro-Wilk's test. If the data was not homogenous and normal, then the data were analyzed using nonparametric statistics (Kruskal-Wallis ANOVA test followed by the Mann-Whitney U-test). Homogeneous data was analyzed by Chi-Square test with Yates correction factor, One-way ANOVA with Dunnett's test and Kolmogorov-Smirnov test (one-tailed test).  FOB data and histopathological findings were compared to the control group using a two-tailed Fisher's Exact test.  P< 0.05 or P < 0.01.

Reproductive indices:

Reproductive parameters (days between pairing and coitus, length of gestation, evidence of parturation difficulties, mating, fertility, copulation and conception indices, testicular and epididymal sperm counts, sperm production rate sperm motility and morphology, ovarian primordial follicle count), developmental landmarks (e.g., balanopreputial separation and vaginal patency).

Offspring viability indices:

Mean litter size, postnatal survival (postnatal day 0 to 4), postnatal survival for other intervals up to day 21.

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not examined

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No test article-related mortalities or clinical findings were observed in this study. One female in the F1 generation (highest dose group) died of dystocia (17 dead fetused in utero).

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Lower weekly body weight gains were noted for F0 males and females in the 1600 and 5000 ppm groups and F1 males in the 5000 ppm group.  Mean body weights in the 1600 ppm group for both the F0 and F1 generations were generally similar to control group values, while those in the 5000 ppm group were reduced throughout the majority of both the F0 and F1 generations. Food consumption was lower for the 5000 ppm group males during the premating period (F0) and throughout the entire generation (F1).  Food consumption for F1 females in the 5000 ppm group was reduced during the first week following weaning (week 17-18) only. 

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): No adverse effects.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): No adverse effects.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): No adverse effects.

ORGAN WEIGHTS (PARENTAL ANIMALS): Test article-related higher kidney weights were noted for F0 and F1 males in the 1600 and 5000 ppm groups.  Corresponding histopathological effects of HMDS in this study were similar to those previously reported in rats. Higher mean relative liver weights were noted for the F1 males in 1600 and 5000 ppm groups.

GROSS PATHOLOGY (PARENTAL ANIMALS): No adverse treatment-related findings.

HISTOPATHOLOGY (PARENTAL ANIMALS): Test article-related higher kidney weights were noted for F0 and F1 males in the 1600 and 5000 ppm groups.  Corresponding histopathological effects of HMDS in this study were similar to those previously reported (Cassidy et al., 2001) in rats following long-term inhalation exposure at 593 and 5012 ppm.  These findings included hyaline droplets (F0 and F1 males at 5000 ppm) and increased incidence and severity of basophilic tubules in the kidneys (F0 males, F1 males and F1 females at 5000 ppm).  Male rat-specific hyaline droplet (consistent with alpha 2 urinary globulin) nephropathy was associated with the increase in basophilic tubules.  Other test article related microscopic findings, including golden-brown pigment in the periportal areas of the liver for F0 males in the 5000 ppm group and F1 males and females in the 1600 and 5000 ppm groups.  This pigment was accompanied by infiltration of primarily mononuclear inflammatory cells and/or bile duct hyperplasia in the liver in the F0 and F1 5000 ppm groups, and corresponded to higher mean relative liver weights for the F1 males in the 1600 and 5000 ppm groups.  The golden-brown pigment demonstrated bright red birefringence with a central dark Maltese cross under polarized light, characteristic of porphyrin (Churukian, 2002).  In the 5000 ppm group F1 males and females, golden brown pigment was also noted in the medullary macrophages of the mesenteric lymph nodes and alveolar macrophage aggregates were noted for F0 and F1 males and females in the 5000 ppm group. Effects in the lungs were diagnosed as idiopathic rat respiratory syndrome, and were not therefore related to treatment.

Dose descriptor:

NOAEC

Effect level:

400 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: General toxicity: Based on effects in the liver.

Dose descriptor:

NOAEC

Effect level:

>= 5 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Reproductive toxicity: No reproductive toxicity in the parent animals of the P and F1 animals.

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

VIABILITY (OFFSPRING): There were no treatment-related effects in postnatal survival of the F1 litter.


CLINICAL SIGNS (OFFSPRING): None


BODY WEIGHT (OFFSPRING): Offspring body weight gains were decreased for F1 pups in the 5000 ppm group from PND 4-21 and F2 pups in the 1600 and 5000 ppm groups from PND 4 to 14.  In the 5000 ppm group, these reduced body weight gains resulted in substantially lower mean body weights on PND 14 and 21 in both generations (approximately 6% to 7% lower by PND 21); lower body weights continued to be observed for the F2 males and females through PND 56 and PND 35, respectively.  In the F2 pups in the 1600 ppm group, the lower body weight gain during PND 4-14 resulted in significantly lower mean body weights on PND 14 (approximately 7% and 5% for male and female pups, respectively); lower body weights were also observed for the F2 males and females in this group through PND 49 and 35, respectively.


SEXUAL MATURATION (OFFSPRING): Balanopreputial separation and vaginal patency were not affected in the F1 pups.


ORGAN WEIGHTS (OFFSPRING): On PND 21, decreased thymus weights were noted for F2 male pups in the 1600 and 5000 ppm groups and F2 female pups in the 5000 ppm group only. There were no such findings in the F1 pups.


GROSS PATHOLOGY (OFFSPRING): There were no remarkable findings in the F1 and F2 pups that were found dead or euthanised in extremis. There were no abnormal findings in the F1 and F2 pups.


HISTOPATHOLOGY (OFFSPRING): No treatment-related effects.


OTHER FINDINGS (OFFSPRING): F1 adult females and their offspring exhibited no exposure-related effects during the FOB assessments. No test article related effects on air-righting reflex or learning and memory were noted for F2 offspring. The only test substance-related effect on attainment of developmental landmarks noted for F2 pups was a slight delay in attainment of the surface righting response for females in the 5000 ppm group (65% attained the response on PND 5 versus 90% in the control group).

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

400 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: General toxicity: Based on effects in the liver.

Dose descriptor:

NOAEC

Generation:

F2

Effect level:

1 600 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on decreased body weight gains in the F2 generation animals at 5000 ppm.

Reproductive effects observed:

not specified

There were no statistically significant offspring weights at any dose level. Statistically significant (p<0.05 or p<0.01) lower mean pup body weight gains were noted for males in the 400, 1600 and 5000 ppm groups and for females in the 400 and 5000 ppm groups from PND 4 to PND 7. Male and female pup weight gain in the 5000 ppm group continued to be slightly lower (not statistically significant) than the control group during PND 7 to 14 and 14 to 21. As a result of the lower weight gain, mean pup body weights in the 5000 ppm group were lower (7.2% to 7.3%) than control group values on PND 21; the difference from the control group for the females was statistically significant (p<0.05). Because the lower weight gain in the 400 and 1600 ppm groups did not persist, the lower mean body weight gains in these groups during PND 4 to 7 were not considered test article-related. No other differences in pup body weight or body weight gain relative to the control group were noted in the 400, 1600 or 5000 ppm groups. Mean male and female pup body weights and body weight changes in the 100 ppm group were unaffected by test article exposure throughout the postnatal period. The NOAEC for F1 developmental toxicity was 1600 ppm due to decreased offspring weights at 5000 ppm. There were no gross anomalies in the pups. The NOAEC for developmental neurobehavioral endpoints was 1600 ppm due to the lack of habituation exhibited in the locomotor activity assessments and delayed attainment of the surface righting response in the 5000 ppm group F2 females, and decreases in average and peak acoustic startle response on PND 20 in the 5000 ppm group F2 males and females. The NOAEC for neuropathologic endpoints was 5000 ppm.

Table 1 - SUMMARY OF OFFSPRING WEIGHTS (F1- pre-weaning) [G] (LITTER AS EXPERIMENTAL UNIT)      

GROUP:	0 PPM	100 PPM	400 PPM	1600 PPM	5000 PPM
PND 1
MALES
MEAN	7.0	6.9	7.1	7.0	6.9
S.D.	0.59	0.54	0.90	0.49	0.70
N	27	29	26	27	25
FEMALES
MEAN	6.6	6.5	6.7	6.6	6.6
S.D.	0.60	0.58	0.78	0.47	0.67
N	27	29	26	27	25
PND 4 (BEFORE SELECTION)
MALES
MEAN	10.0	9.9	10.5	9.8	10.2
S.D.	1.08	1.00	1.44	0.99	1.12
N	27	29	26	27	25
FEMALES
MEAN	9.6	9.4	9.8	9.3	9.7
S.D.	1.06	1.0.4	1.32	0.98	1.23
N	27	29	26	27	25
PND 7
MALES
MEAN	14.3	14.0	14.3	13.7	13.6
S.D.	1.63	1.79	1.82	1.59	1.25
N	27	28	26	27	25
FEMALES
MEAN	13.7	13.2	13.4	13.0	13.1
S.D.	1.57	1.80	1.78	1.56	1.31
N	27	28	26	27	25
PND 14
MALES
MEAN	25.8	26.0	26.1	24.9	24.4
S.D.	2.33	2.18	2.46	2.88	2.09
N	27	27	25	27	25
FEMALES
MEAN	24.9	25.0	24.8	24.0	23.6
S.D.	2.28	1.93	2.43	2.56	2.27
N	27	27	25	27	25
PND 21
MALES
MEAN	41.3	42.0	40.9	39.5	38.3
S.D.	4.42	4.19	5.09	4.22	4.13
N	27	27	25	27	25
FEMALES
MEAN	40.1	40.2	38.8	37.9	37.2*
S.D.	4.30	3.91	4.62	3.99	4.06
N	27	27	25	27	25

PND = POSTNATAL DAY 

MODIFIED STATISTICS USED. 

* = Significantly different from the control group at 0.05

 

  Table 2 - SUMMARY OF OFFSPRING WEIGHT CHANGES [G] (F1- pre-weaning) (LITTER AS EXPERIMENTAL UNIT)

GROUP:	0 PPM	100 PPM	400 PPM	1600 PPM	5000 PPM
PND 1-4 (BEFORE SELECTION)
MALES
MEAN	3.0	3.0	3.3	2.8	3.2
S.D.	0.62	0.67	0.75	0.64	0.74
N	27	29	26	27	25
FEMALES
MEAN	2.9	2.8	3.1	2.7	3.1
S.D.	0.62	0.68	0.75	0.64	0.79
N	27	29	26	27	25
PND 4 TO 7
MALES
MEAN	4.4	4.1	3.8+	3.9+	3.5++
S.D.	0.68	1.09	0.97	0.95	0.71
N	27	28	26	27	25
FEMALES
MEAN	4.2	3.8	3.6+	3.7	3.4++
S.D.	0.67	1.01	0.89	0.93	0.67
N	27	28	26	27	25
PND 7 TO 14
MALES
MEAN	11.4	11.9	11.9	11.2	10.8
S.D.	1.42	1.44	1.28	1.83	1.11
N	27	27	25	27	25
FEMALES
MEAN	11.2	11.6	11. 4	11.0	10.5
S.D.	1.41	1.20	1.22	1.64	1.23
N	27	27	25	27	25
PND 14 TO 21
MALES
MEAN	15.5	16.0	14.8	14.6	13.9
S.D.	2.61	2.74	3.17	2.06	2.48
N	27	27	25	27	25
FEMALES
MEAN	15.2	15.2	14.1	14.0	13.6
S.D.	2.41	2.66	2.85	2.28	2.28
N	27	27	25	27	25

PND = POSTNATAL DAY MODIFIED STATISTICS USED. 

* INDICATES PARAMETRIC ANALYSIS AND + INDICATES NON-PARAMETRIC ANALYSIS. 

Conclusions:

In a two-generation reproductive toxicity study on HMDS, conducted to GLP (reliability score 1) the NOAEC for parental toxicity relevant to humans was 400 ppm based on microscopic liver findings in the F0 males of the 5000 ppm group and F1 males and females in the 5000 and 1600 ppm groups. F0 and F1 reproductive performance was not affected at any concentrations. In the F2 generation, offspring body weight gains were persistently decreased in the 5000 ppm groups from PND 4-14, and this lead to decreased body weights at late as PND 49 in male offspring. The few “findings” at the 1600 ppm and lower exposure levels lacked consistency (along the time line), were of insufficient magnitude, and insufficiently dose-responsive. F1 adult females and their offspring exhibited no exposure-related effects during the FOB assessment. Based on the results of this study the NOAEC for HMDS for parental reproductive toxicity was considered to be at least 5000 ppm. The NOAEC for neonatal toxicity was considered to be 1600 ppm due to decreased offspring weights at 5000 ppm.

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

27.10.2006 and 11.04.2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

other: US EPA Health Effects Test Guidelines OPPTS 870.3650 Combined repeated dose toxicity study with reproduction/developmental toxicity screening test

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, MI
- Age at study initiation: at least 9 weeks
- Weight at study initiation: males: 270.1-346.6 g; females: 195.9-242.5 g
- Fasting period before study: no
- Housing: individually in suspended wire-mesh cages, except during mating, gestation and lactation
- Diet (e.g. ad libitum): ad libitum (except during inhalation exposure)
- Water (e.g. ad libitum): ad libitum (except during inhalation exposure)
- Acclimation period: five days prior to randomisation, 3 days acclimation to exposure caging and chambers (for 2.5 to 3.5 h (day1) or 5.5 to 6.5 h (days 2 and 3))

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.81-23.24
- Humidity (%): 28-64
- Air changes (per hr): 10-20
- Photoperiod (hrs dark / hrs light): 12:12

IN-LIFE DATES: From: 21 November 2006 To: 17 December 2007

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

clean air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposures were conducted in 1000-litre stainless steel and glass, TSE-system style, whole-body inhalation exposure chambers.
- Method of holding animals in test chamber: Animals were individually positioned within stainless steel exposure caging specifically designed for use in the TSE-system chambers (three levels of 24 compartments).
- Source and rate of air: dilution air stream building conditioned air; carrier air stream- compressed air filtered through a series of particulated filters prior to use in vapour generation.
- Method of conditioning air: Activated carbon and HEPA filters for dilution air stream and particulate filters (Matheson Model 460/461; Balston Models 100-18-DX and 100-18-BX) for carrier air stream.
- System of generating particulates/aerosols: heated stainless steel J-tubes where mixed with a constant stream of filtered compressed air for vaporization. J-tubes heated to 60-110°C.
- Temperature, humidity, pressure in air chamber: Continuously monitored and recorded once every 30 minutes. Temperature: 22± 2 °C; Humidity: 36-39 %.
- Air flow rate: approximately 200 LPM
- Air change rate: 10-15 chamber air changes per hour
- Method of particle size determination: no data
- Treatment of exhaust air: No data

TEST ATMOSPHERE
- Brief description of analytical method used: See below.
- Samples taken from breathing zone: yes


TEST ATMOSPHERE
- Brief description of analytical method used:
- Samples taken from breathing zone: yes

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: Continuous until evidence of mating (maximum of 14 days).
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): Home cage

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chamber concentrations of test substance were evaluated a minimum of once per hour for each chamber throughout the daily exposure intervals, using gas chromatography:
Instrument: Varian model 3800 Gas Chromatograph.
Column: J&W Scientific DB-1, 30m x 0.53mm with 1.5um film thickness.
Carrier Gas: Helium, constant flow of 31.0 ml/min.
Sampling System: Electronically actuated VICI 12-port stream selector and VICI single injection valve with a 250 µl stainless steel sample loop.
Oven Ramp: Initial 125 °C for 1.0 min, ramp to 150 °C at 50 °C/min. hold for 1.0 min, total run time 2.5 min.
Detection: Flame ionization detector (FID), 300 °C isothermal.
Sampling Valve: Temperature 50 °C isothermal.

Duration of treatment / exposure:

Six hours/day

Frequency of treatment:

Daily. Treatment of males and females began two weeks prior to initiating mating and continued through the mating period. Males were treated for 29 days and euthanised the day after the last treatment. Toxicity phase females were treated for 28 days then euthanised. Reproductive phase females were treated up to and including Day 19 of gestation. Dams were not exposed during the lactation period.

Details on study schedule:

Not applicable (screening test)

Dose / conc.:

836 ppm (nominal)

Dose / conc.:

1 651 ppm (nominal)

Dose / conc.:

3 135 ppm (nominal)

Dose / conc.:

806 ppm (analytical)

Dose / conc.:

1 623 ppm (analytical)

Dose / conc.:

3 146 ppm (analytical)

No. of animals per sex per dose:

10 per phase

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on previous (unspecified) studies.

Positive control:

Not applicable.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily in their cages for mortality, morbidity and moribundity. General clinical observations were made at least once per day, beginning on the first day of treatment.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure and weekly thereafter. The observations were made outside the home cage in a standard arena at approximately the same time each day. Examinations included, but were not limited to, changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity. Changes in gait, posture and response to handling as well as the presence of clonic or tonic movement, stereotypies, difficult or prolonged parturition or bizarre behaviour were recorded.

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

FOOD CONSUMPTION: yes
- Individual animal food consumption was recorded at least weekly calculated as grams/animal/day.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

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

WATER CONSUMPTION: No

Oestrous cyclicity (parental animals):

Not applicable (screening test)

Sperm parameters (parental animals):

Parameters examined in P male parental generations: testes weight, and epididymis weight.

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: immediately after birth the number and sex of pups, the number of live pups, number of dead pups, runts and presence of any gross abnormalities were noted. Live pups were counted, sexed and the sex ratio calculated. Litter weights were taken within 24 hours of parturition and on postpartum day 4.

GROSS EXAMINATION OF DEAD PUPS: yes, for external abnormalities; possible cause of death was not determined for pups born or found dead.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals on Day 30.
- Maternal animals: Post-partum day 4.

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 2 (Section 7.5.2) were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

SACRIFICE
- Day 4 post-partum.

GROSS NECROPSY
- Gross necropsy consisted of external examinations.

HISTOPATHOLOGY / ORGAN WEIGHTS: not conducted.

Statistics:

ANOVA, Kruskal-Wallis test, Dunnett's test, Wilcoxon test. All data analysis was conducted using SAS version 9.1.3. Statistically significant probabilities were reported for p-values of <0.05, <0.02 and <0.01.

Reproductive indices:

Mating and fertility indices. Plus calculated reproductive parameters were mean gestation length, mean litter size, mean number of implantation sites, mean number of corpora lutea, mean mating and fertility indices.

Offspring viability indices:

Mean live litter size, mean litter weight, mean ratio live births/litter size

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
See Section 7.5.2. Repeated dose toxicity: inhalation

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
See Section 7.5.2. Repeated dose toxicity: inhalation

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS):
See Section 7.5.2. Repeated dose toxicity: inhalation

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS):
Not evaluated

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Testes weight, absolute (g): 3.624 (0.180), 3.464 (0.231), 3.426 (0.230), 3.483 (0.301)
Testes weight, relative to body weight: 0.00882 (0.00060), 0.00856 (0.00063), 0.00865 (0.00131), 0.00864 (0.00116)
Seminal vesicle weight, absolute (g): 1.828 (0.190), 1.665 (0.185), 1.531 (0.285), 1.638 (0.204)
Seminal vesicle weight, relative to body weight: 0.00444 (0.00043), 0.00411 (0.00045), 0.00388 (0.00086), 0.00405 (0.00060)
Epididymides weight, absolute (g): 1.302 (0.109), 1.223 (0.121), 1.236 (0.085), 1.182 (0.104)
Epididymides weight, relative to body weight: 0.00317 (0.00028), 0.00302 (0.00030), 0.00311 (0.00042), 0.00293 (0.00036)
Prostate weight, absolute (g): 0.886 (0.133), 0.789 (0.116), 0.944 (0.379), 0.847 (0.174)
Prostate weight, relative to body weight: 0.00216 (0.00035), 0.00195 (0.00028), 0.00233 (0.00074), 0.00209 (0.00042)

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Number of females allowed to deliver: 10/10, 8/10, 10/10, 10/10
Number of gravid females: 10, 8, 10, 10
Days gestation: 22 (1), 22 (0), 22 (0), 22 (0)
Total pups: 16 (2), 15 (1), 16 (2), 15 (2)
On female in the 800 ppm group failed to mate during the mating period. A second 800 ppm group female had no evidence of copulation; however, when euthanised had 15 pups in utero. The eight remaining females produced litters that were similar in all respects to control litters.

ORGAN WEIGHTS (PARENTAL ANIMALS)
See Section 7.5.2. Repeated dose toxicity: inhalation
See REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS) above

GROSS PATHOLOGY (PARENTAL ANIMALS):
See Section 7.5.2 Repeated dose toxicity: inhalation

HISTOPATHOLOGY (PARENTAL ANIMALS):
See Section 7.5.2 Repeated dose toxicity: inhalation
KEY EFFECT: Hepatic brown pigment was observed only in males at 1600 and 3200 ppm. Under polarized light the material was birefringent, with a highly distinctive pathognomonic appearance that identifies it as brown pigment: it appeared bright red with dark maltese crosses in each globule. Additionally, in the more severe cases viewed under polarized light, tiny specs of birefringent material were observed scattered across the hepatocellular portion of the tissue. The pigment accumulation was accompanied by bile duct proliferation and chronic inflammation.

In the kidney of the male rats there was protein droplet nephropathy. In the minimal degree, there were occasional renal proximal tubule cells that contained protein droplets which were angular in shape. At 800 ppm, this was the only indication of an effect. At higher concentrations these cystalline droplet shapes were more common, and the portion of the cortex with visible droplet accumulation increased, along with individual cell necrosis and tubular basophilia. At 3200 ppm, moderate to marked nephropathy was observed in some animals, which included the above changes, as well as granular casts, which are accumulations of necrotic cell debris, at the cortical-medullary border. Although not definitive, the sex selectivity and histomorphological features are consistent with alpha-2-U-globulin nephropathy.

OTHER FINDINGS (PARENTAL ANIMALS):
None

Dose descriptor:

NOAEC

Effect level:

>= 3 146 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effects on any of the reproductive parameters evaluated

Critical effects observed:

no

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

(Mean (and standard deviation) for control, low-, mid- and high-exposure groups, respectively)

VIABILITY (OFFSPRING):
Day 4 viable pups: 15 (2), 15 (1), 15 (2), 14 (2)
Viable/Total: 0.98 (0.04), 0.99 (0.02), 0.94 (0.07), 0.98 (0.04)

CLINICAL SIGNS (OFFSPRING):
No adverse effects (except - see gross pathology)

BODY WEIGHT (OFFSPRING):
Initial litter weight (g): 95.4 (14.6), 98.0 (11.8), 99.7 (15.8), 98.3 (8.5)
Inital average pup weight (g): 6.2 (0.5), 6.4 (0.6), 6.4 (0.5), 6.8 (0.4)
Final litter weight (g): 153.1 (19.7), 159.2 (17.7), 154.3 (22.3), 153.9 (11.1)
Final average pup weight (g): 10.1 (0.9), 10.6 (1.1), 10.5 (1.0), 10.9 (0.9)

SEXUAL MATURATION (OFFSPRING):
Not evaluated

ORGAN WEIGHTS (OFFSPRING):
Not evaluated

GROSS PATHOLOGY (OFFSPRING)
In the low-exposure group, one male pup was born without a tail, penile and anal opening.

HISTOPATHOLOGY (OFFSPRING):
Not evaluated

OTHER FINDINGS (OFFSPRING):
None reported

One male pup was born without a tail, penile and anal opening. There were no changes observed in the litter size, male-to-female ratio, pup body weights or the pup survival. Differences in group mean values for the treated groups relative to the control group were small and none were found to be statistically significant.

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

>= 3 146 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no statistically significant treatment-related adverse effects seen at any tested concentration

Critical effects observed:

no

Reproductive effects observed:

no

No statistically significant differences in any of the reproductive parameters measured in any treatment groups.

Tables 24 - Summary of mean reproductive parameter for reproductive group female rats

Tables 25 - Summary of reproductive performance for reproductive group female rats

Conclusions:

In an inhalation Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted to OECD 422 and to GLP (reliability score 1) the NOAEC for the reproductive toxicity of octamethyltrisiloxane was at least 3146 ppm as no adverse effects were observed on reproductive parameters in rats. The NOAEC for general toxicity was <806 ppm based on protein droplet nephropathy and hepatic brown pigment.

Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD Guideline 422), performed to GLP, the potential inhalation toxicity of octamethyltrisiloxane was evaluated in Sprague-Dawley rats. Animals were exposed to target concentrations of 0, 800, 1600 or 3200 ppm for 6 hours/day for 29 days in the toxicity test and up to 42 days in the reproductive/developmental screening test.

No treatment-related effects were observed in any of the reproductive parameters evaluated. Differences in mean values for the treated groups relative to the control group were small and none were found to be statistically significant.

The NOAEC for the reproductive toxicity of octamethyltrisiloxane was 3146 ppm on the basis of this screening test.

Reference 3

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

27.10.2006 to 21.12.2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

Only one concentration tested.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: 9 wks
- Weight at study initiation: (P) Males: 300.7-350 g; Females: 195.5-240 g
- Fasting period before study: No
- Housing: Individually housed in suspended wire-mesh cages. Except during mating, gestation and lactation periods. Mating: home cage of the male; Gestation: shoebox cages; Lactation: dams housed with litters.
- Diet (e.g. ad libitum): Ad libitum (except during inhalation exposure or FOB.
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days

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

IN-LIFE DATES: From: 27.10.2006 To: 21.12.2007

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

clean air

Details on exposure:

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

TEST ATMOSPHERE
- Brief description of analytical method used: No data
- Samples taken from breathing zone: yes

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: Continuous until evidence of copulation observed.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged (how): Shoebox cages.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

None given (apparent Annex missing)

Duration of treatment / exposure:

Males: 30 days
Toxicity group females: 29 days
Reproductive group females: 15 days prior to mating, through the mating period and up to day 19 of gestation.

Frequency of treatment:

Daily (seven days per week)

Dose / conc.:

5.1 mg/L air

Remarks:

target concentration equivalent to 400 ppm

No. of animals per sex per dose:

Ten

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on previously conducted study.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily in their cages for mortality, morbidity and moribundity throughout the in-life phase of the study. General clinical observations were made at least once per day, beginning on the first day of treatment (except on days of detailed examinations). Clinical observations were also performed on all animals on the day of, but prior to, scheduled necropsy.

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

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

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

WATER CONSUMPTION: No

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

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

Clinical pathology assessments on all adult male and toxicity group females - See section 7.5.2.

Oestrous cyclicity (parental animals):

No evidence that estrous cyclicity was investigated.

Sperm parameters (parental animals):

Parameters examined in male parental generations: testis weight and epididymis weight.

Litter observations:

STANDARDISATION OF LITTERS:
- Performed on day 4 postpartum: no

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

GROSS EXAMINATION OF DEAD PUPS: yes, for external abnormalities. Possible cause of death was not determined for pups born or found dead.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals after 30 days exposure.
- Maternal animals: Day 4 postpartum.

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

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

Postmortem examinations (offspring):

SACRIFICE: Day 4 post-partum.

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

HISTOPATHOLOGY / ORGAN WEIGHTS: Not conducted.

Statistics:

All data analyses was conducted using SAS version 9.1.3. Statistically significant probabilities were reported for p-values of <0.05, <0.02 and <0.01.

Reproductive indices:

Gestation length, mean number of implantation sites, mean number of corpora lutea, mean mating and fertility indices. Mean litter size, mean live litter size, mean litter weight, mean ratio live births/litter size.

Offspring viability indices:

Survival to postpartum day 4.

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No deaths and no significant treatment-related clincal signs of toxicity.

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

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

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

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

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

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

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

FOB: There appeared to be no functional or neurological effects of the test substance on the rats.

Key result

Dose descriptor:

NOAEC

Effect level:

>= 400 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant treatment-related effects on males or toxicity phase females.

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

There were no adverse effects for the pups up to postpartum day 4.

Key result

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

>= 400 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects on pups.

Reproductive effects observed:

no

Conclusions:

In a combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted using a protocol comparable to OECD 422 and to GLP (reliability score 1) the NOAEC for general and reproductive toxicity was at least 400 ppm (the only concentration tested) according to the study report. However, it should be noted that three female rats in the 400 ppm group with evidence of copulation failed to deliver a litter. One of these three females showed signs of parturition (blood discharge) on gestation day 25, but no pups were found. However, seven implant sites were present. The remaining females produced litters that were similar to the controls.

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

33 200 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

In the key reproductive toxicity study (WIL Research Laboratories, 2006) in Sprague-Dawley rats, the NOAEC for HMDS for parental reproductive toxicity is considered to be at least 5000 ppm (33200 mg/m³).

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

There are no available developmental toxicity studies for the registered substance "Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane". Therefore, data have been read-across from three of its constituents: HMDS, L3 and L4.

- In an inhalation two-generation reproductive toxicity study (WIL Research Laboratories, 2006) in rats conducted to OECD test 416 and GLP with HMDS, the NOAEC for developmental effects is 1600 ppm.

- In a developmental toxicity study (Dow Corning Corporation, 2017b) carried out according to OECD Test Guideline 414 via oral (gavage) route with L3, the NOEL was determined to be 750 mg/kg/day, the highest dose level tested.

- In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted by the inhalation route using a protocol comparable to OECD 422 and to GLP (Dow Corning Corporation, 2007) with L4, the developmental NOAEC was 400 ppm (the only concentration tested).

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

09.12.2003 to 20.06.2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 416, January 22, 2001, and Revised Draft Guideline 426, October, 1999

Qualifier:

according to guideline

Guideline:

other: EPA Test Guidelines 870.3800-Reproduction and Fertility Effects, August, 1998 and 870.6300, Developmental Neurotoxicity Study, August, 1998

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: 7 weeks
- Weight at study initiation: Males (P): 243 - 313 g; Females: 141 - 196 g; Males (F1): 381 - 603 g; Females: 223 - 362 g
- Fasting period before study: None
- Housing: Individually in stainless steel wire-mesh cages, mating in home cage of male, following mating females were removed to plastic maternity cages until lactation day 21, then transferred back to wire-mesh cages.
- Diet (e.g. ad libitum): Ad libitum (except during exposure)
- Water (e.g. ad libitum): Ad libitum (except during exposure)
- Acclimation period: 21 days


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


IN-LIFE DATES: From: 03.12.2003 To: 12.12.2005

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: 2.0 m3 stainless steel and glass whole body inhalation chambers
- Method of holding animals in test chamber: None
- Source and rate of air: No data
- Method of conditioning air: No data
- Temperature, humidity, pressure in air chamber: 19-27°C, 34-66%, slight negative pressure, respectively
- Air flow rate: No data
- Air change rate: 12-15 changes/hour
- Treatment of exhaust air: No data


TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatography
- Samples taken from breathing zone: yes, samples were taken from the approximate middle of each chamber

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Gas chromatography

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: 21 days (or until evidence of mating)
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): in a plastic maternity cages

Duration of treatment / exposure:

At least 70 days prior to mating, throughout mating, gestation through gestation day 20. After parturition, exposure of the F0 and F1 females was re-initiated on lactation day 5 and continued through the day prior to euthanasia.
Premating exposure period (males): 70 days prior to mating
Premating exposure period (females): 70 days prior to mating

Frequency of treatment:

6 hours/day, 7 days/week

Duration of test:

approximately 18 months

Dose / conc.:

100 ppm

Dose / conc.:

400 ppm

Dose / conc.:

1 600 ppm

Dose / conc.:

5 000 ppm

No. of animals per sex per dose:

30

Control animals:

yes

Details on study design:

No further details.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed twice daily for appearance, behavior moribundity and mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT AND FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly body weights and food consumption were recorded on gestation days (GD) 0, 4, 7, 11, 14 and 20 and on Postnatal days (PND) 1, 4, 7, 14 and 21 for females in the F0 and F1 generations.

WATER CONSUMPTION: No

SACRIFICE
- Maternal animals: All surviving animals after the last litter of each generation was weaned.

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

HISTOPATHOLOGY / ORGAN WEIGHTS: Organs examined at necropsy (macroscopic and microscopic): Complete detailed necropsy was conducted. Organ weights: Adrenal glands, brain, epididymis (total and cauda), kidneys, liver, lungs, ovaries, pituitary gland, prostate gland, seminal vesicles with coagulating glands and accessory fluids, spleen, testes, thyroid gland, uterus with oviducts and cervix   Histopathologic evaluation: Adrenal glands, brain, cervix, coagulated glands, epididymis (right), kidneys, liver, lungs, ovaries, oviducts, pituitary gland, prostate gland, seminal vesicles, testes, thyroid gland, uterus, vagina, vas deferens, all gross (internal) lesions. 

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes, but this being a two-generation study, the pregnancies were not interrupted as would be done in a purely developmental study.
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: No
- Number of early resorptions: No
- Number of late resorptions: No

Fetal examinations:

The treatment regimen for this study was previously described in section 7.8.1.  This study was also conducted to determine the potential of HMDS to cause functional and/or morphological changes to the nervous system of the developing rat (F2 generation) following the exposure of the F0 and F1 generations.  Developmental landmarks (balanopreputial separation and vaginal patency) were evaluated for the selected F1 and F2 rats.  10 F2 pups/sex/group were selected for neurobehavioral testing, neuropathology, brain weights and/or brain dimension measurements (PND 21 or 72).  Designated tissues from F2 pups selected for neuropathological evaluation or exhibiting developmental abnormalities suggestive of an exposure related effect, were examined microscopically.

Statistics:

Parametric analysis was screened for homogeneity of variance using Levene's test and normality using Shapiro-Wilk's test. If the data was not homogenous and normal, then the data were analyzed using nonparametric statistics (Kruskal-Wallis ANOVA test followed by the Mann-Whitney U-test). Homogeneous data was analyzed by Chi-Square test with Yates correction factor, One-way ANOVA with Dunnett's test and Kolmogorov-Smirnov test (one-tailed test).  FOB data and histopathological findings were compared to the control group using a two-tailed Fisher's Exact test.  P< 0.05 or P < 0.01.

Indices:

Reproductive parameters (days between pairing and coitus, length of gestation, evidence of parturation difficulties, mating, fertility, copulation and conception indices, testicular and epididymal sperm counts, sperm production rate sperm motility and morphology, ovarian primordial follicle count), developmental landmarks (e.g., balanopreputial separation and vaginal patency). Mean litter size, postnatal survival (postnatal day 0 to 4), postnatal survival for other intervals up to day 21.

Historical control data:

No data

Details on maternal toxic effects:

Maternal toxic effects:no effects

Dose descriptor:

NOAEL

Effect level:

>= 5 000 ppm

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEC

Effect level:

1 600 ppm

Based on:

test mat.

Basis for effect level:

other: other:

Dose descriptor:

other: NOAEC

Effect level:

1 600 ppm

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The attainment of landmarks of sexual development (balanopreputial separation and vaginal patency) were unaffected by HMDS exposure.  No test article related effects on anogenital distance were noted for F2 offspring.  Brain size and weight for F2 animals on PND 21 and 72 were unaffected by parental test article exposure; no macroscopic, histopathological or morphometric evidence of neuropathology was observed.  The only test article-related effect on attainment of developmental landmarks noted for F2 pups was a slight delay in attainment of the surface righting response for females in the 5000 ppm group.  Effects on developmental neurobehavioral endpoints consisted of increased motor activity for F2 females in the 5000 ppm group on PND 13 and 21. The higher total activity counts on PND 21 were the result of an attenuated habituation.  By PND 61, a normal pattern of habituation was observed for these females.  No effects on motor activity were observed for F2 males at any exposure level.  Decreases in the average and peak responses to the acoustic startle response stimulus (VAVE and VMAX, respectively) were observed on PND 20 for F2 males and females at 5000 ppm.  However, no effects on the time from latency to peak response to the acoustic startle response stimulus (TMAX) were observed.   Grossly visible abnormalities, external, soft tissue and skeletal abnormalities:  No treatment-related gross external malformations were reported.

Dose descriptor:

NOAEL

Effect level:

>= 5 000 ppm

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Lower weekly body weight gains were noted for F0 males and females in the 1600 and 5000 ppm groups and F1 males in the 5000 ppm group. Mean body weights in the 1600 ppm group for both the F0 and F1 generations were generally similar to control group values, while those in the 5000 ppm group were reduced throughout the majority of both the F0 and F1 generations. Food consumption was lower for the 5000 ppm group males during the premating period (F0) and throughout the entire generation (F1).  Food consumption for F1 females in the 5000 ppm group was reduced during the first week following weaning (week 17-18) only. 

Conclusions:

Based on the results of an inhalation two-generation reproductive toxicity study in rats conducted to OECD test 416 and GLP, the NOAEL for developmental neurobehavioral endpoints was considered to be 1600 ppm. This was based on a lack of habituation exhibited in the locomotor activity assessments and delayed attainment of the surface righting response in the 5000 ppm group F2 females, and decreases in average and peak acoustic startle response on PND 20 in the 5000 ppm group F2 males and females. The NOAEL for neuropathologic endpoints was considered to be 5000 ppm. In the F2 generation, offspring body weight gains were persistently decreased in the 5000 ppm group from PND 4-14, and this lead to decreased body weights at late as PND 49 in male offspring. The few "findings" at the 1600 ppm and lower exposure levels lacked consistency (along the time line), were if insufficient magnitude and insufficiently dose-responsive. In the F1 generation, effects on body weights were only observed in the 5000 ppm group. The NOAEC for developmental effects was therefore 1600 ppm.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

17 March 2017 to 21 September 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF, the Japanese Ministry of Agriculture, Forestry and Fisheries, Notification of 12 NohSan-8147, Guideline 2-1-18, Teratogenicity study, 24 November 2000.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

Species and Sex: Rats, time-mated females
Strain and Justification: Crl:CD(SD) rats were selected because of their general acceptance and suitability for toxicity testing, the availability of historical background data, and the reliability of the commercial supplier.
Supplier and Location: Charles River Laboratories (CRL) (Raleigh, North Carolina, USA)
Age and Weight at Study Start: Sexually mature adult, weighing approximately 200-250 g

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

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

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

Feed and water: LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in meal form. Feed and municipal water were provided ad libitum.

Route of administration:

oral: gavage

Vehicle:

corn oil

Remarks:

(dried and deacidified corn oil)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

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

VEHICLE
- dried and deacidified corn oil

The rats were ordered and mated in six different replicates from the supplier to stagger cesarean sections over a period of two weeks.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration Verification and Homogeneity:
Dose solutions were prepared for analysis. Dosing solutions were shipped and stored at room temperature. Dose confirmation analyses of all dose levels, plus control, were determined from the first mix prior to exposure. The homogeneity of the low-dose and the high-dose test solutions was determined concurrent with dose confirmation. Additional samples of the low-dose and mid-dose concentrations were sent to the Lab to be analysed for dose confirmation and homogeneity following the start of dosing.
The initial analytical dose check for the low-dose and mid-dose solutions were below the acceptable range of targeted concentration from the first mix; therefore, no solutions from this mix were used to dose the animals and samples from the low-dose and mid-dose of the second mix were analysed. The method used for analysing the test material in dried and deacidified corn oil was gas chromatography with flame ionization detector (GC/FID) (Vogel, 2016) and followed the Lab's Standard Operating Procedures.
Octamethyltrisiloxane in dried and deacidified corn oil has been shown to be stable for up to 14 days at concentrations ranging from 12.5 - 250 mg/mL (Vogel, 2016). Dose solutions were prepared and used within these ranges; therefore, additional stability analyses were not conducted.
Retainer Samples. A sample of each lot number of the bulk test material was retained. No samples of dose solutions were retained.

Details on mating procedure:

The rats were ordered and mated in six different replicates from the supplier to stagger caesarean sections over a period of two weeks.

Duration of treatment / exposure:

GD 6-20

Frequency of treatment:

Daily

Duration of test:

Test material administration began on March 20, 2017 and the last group of rats were necropsied on April 19, 2017.

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

75 mg/kg bw/day

Dose / conc.:

250 mg/kg bw/day

Dose / conc.:

750 mg/kg bw/day

No. of animals per sex per dose:

24

Control animals:

yes, concurrent vehicle

Details on study design:

Groups of 24 Crl:CD(SD) rats were administered octamethyltrisiloxane in dried and deacidified corn oil by gavage at dose levels of 0, 75, 250, or 750 mg/kg bw/day on GD 6-20. The rats were ordered and mated in six different replicates from the supplier to stagger cesarean sections over a period of two weeks.

Route, Method of Administration, Frequency, Duration, and Justification: Test material was administered daily by oral gavage from GD 6-20. Oral administration is the preferred route of exposure specified in the relevant test guideline.
Dose Levels and Justification: Dose levels for this study were selected based on the 28-day and KMD studies discussed in the Previous Toxicity Information section above. The high-dose of 750 mg/kg/day was expected to induce overt signs of maternal toxicity (i.e., increased liver weights and histopathology). The lower dose levels were selected to provide dose response data for any toxicity observed among the high-dose group rats.

Maternal examinations:

Daily Observations: A cage-side examination (including morbidity, mortality, and the availability of feed and water) at least twice daily, at approximately the same time each day.
Clinical Observations: At least once daily.
Body weights: On GD 0 by the supplier and daily from GD 6-21.
Feed Consumption: Recorded and statistically analysed for all animals every 3 days from GD 3-21 by weighing feed containers at the start and end of a measurement cycle.
Necropsy: On GD 21
Histopathology: Histopathological evaluation of the liver on all pregnant animals that survived to the scheduled necropsy.

Ovaries and uterine content:

Gravid uterine weights were recorded, along with the number of corpora lutea, uterine implantations, resorptions, and live/dead foetuses. All foetuses were weighed, sexed, and examined for external alterations. Approximately one half of the foetuses were examined for visceral and craniofacial alterations while skeletal examinations were conducted on the remaining foetuses.

Fetal examinations:

The individual body weight of all viable/dead foetuses and sex of all foetuses was recorded.
Total litter weight was calculated by addition of individual foetal body weights in a litter.
All foetuses were given an external examination that included observations on body proportions, the head and face (including closure of the palate), abdomen, spine, extremities, genitalia, rectum, and tail.
All viable foetuses were euthanized by sublingual oral administration of sodium pentobarbital solution. At least one half of all the foetuses in each litter were chosen randomly via computer for visceral examination conducted by dissection under a low power stereomicroscope for evidence of visceral alterations (Staples, 1974; Stuckhardt and Poppe, 1984).
The visceral examination included observation of the thymus, trachea, esophagus, lungs, great vessels, heart (external and internal), liver, gastrointestinal tract, pancreas, spleen, kidney (sectioned), adrenal glands, ureters, bladder, and reproductive organs.
The heads of these foetuses were removed, placed in Bouin’s fixative and serially sectioned to allow for inspection of the eyes, brain, nasal passages, and tongue (Wilson, 1965). The foetal body was preserved in neutral, phosphate-buffered 10% formalin (to be discarded approximately six months after completion of the final report).
The remaining foetuses not selected for visceral examination were then skinned, eviscerated, preserved in alcohol, and double stained with Alcian Blue and Alizarin Red S for cartilage and bone according to methods based on Trueman et al. (1999) and Zablotny (2002) and a thorough evaluation of the foetal skeleton was conducted (foetal skeletal bodies were archived following completion of the final report). However, a foetus may have been intentionally changed from one selected for visceral examination to one processed for skeletal examination (and vice versa) if it was deemed that such examination would provide more meaningful data about a suspected abnormality.
All foetal alterations were classified as a variation or malformation. A variation is defined as a divergence beyond the normal range of structural constitution that may not adversely affect survival or health. A malformation is defined as a permanent structural change that may adversely affect survival, development or function and/or which occurs at a relatively low incidence in the specific species/strain.
The maternal necropsy and foetal examinations were conducted such that investigators were blind to treatment group assignment

Statistics:

Maternal body weights, maternal body weight gains, organ weights (absolute and relative with the exception of only absolute weight for gravid uterus), total litter weights, foetal body weights, and feed consumption were evaluated by Bartlett’s test (alpha = 0.01; Winer, 1971) for homogeneity of variance. Based on the outcome of Bartlett's test, a parametric (Steel and Torrie, 1960) or nonparametric (Hollander and Wolfe, 1973) analysis of variance (ANOVA) was performed. If the ANOVA was significant at alpha = 0.05, analysis by Dunnett's test (alpha = 0.05; Winer, 1971) or the Wilcoxon Rank-Sum test (alpha = 0.05; Hollander and Wolfe, 1973) with Bonferroni's correction (Miller, 1966) was performed, respectively.
Frequency of pre- and post-implantation loss (calculated), and foetal alterations (if any) were analysed using a censored Wilcoxon test (Haseman and Hoel, 1974) with Bonferroni’s correction applied when the incidence was greater than 5%. The number of corpora lutea, implantations, and litter size were evaluated using a nonparametric ANOVA (alpha = 0.05) followed by the Wilcoxon Rank-Sum test (alpha = 0.05) with Bonferroni's correction.
Pregnancy rates were analysed using the Fisher exact probability test (alpha = 0.05; Siegel, 1956) with Bonferroni’s correction. Foetal sex ratios were analysed using a binomial distribution test. Non-pregnant females, females with resorptions only, or females found to be pregnant after staining of their uteri were excluded from the appropriate analyses. Statistical outliers (alpha = 0.02) were identified by the sequential method of Grubbs (1969) and were routinely excluded from feed consumption only. Other outliers, if excluded, were excluded from analysis for documented, scientifically sound reasons. Both Dunnett’s test and Bonferroni’s correction corrected for multiple comparisons to the control and were reported at the corrected alpha level.

Clinical signs:

no effects observed

Description (incidence and severity):

Examinations performed on all animals revealed no treatment-related findings throughout the duration of the study.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

There was a treatment-related 19.8% decrease in body weight gain of animals in the 750 mg/kg bw/day group from GD 6-9 (Table 1). This decrease recovered and was similar to control for the remainder of the study.

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

Body weight gains of animals in the 250 mg/kg bw/day group were higher than control and statistically significant over the GD 6-21 and GD 0-21 measured intervals. These higher body weight gains were considered unrelated to treatment with Octamethyltrisiloxane as the differences were minimal, there was no effect in body weight at any dose level, and corrected body weights on GD 21 were similar to control. Body weights of animals in all dose groups and body weight gains of animals in the 75 mg/kg bw/day dose group were similar to control throughout the duration of the study.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There were no treatment-related differences in the amount of feed consumed by any treated groups when compared to controls. Feed consumption of animals in the 250 and 750 mg/kg bw/day groups were higher and statistically significant from GD 15-21 with concomitant increases in body weight gains (Table 2). These higher feed consumption values were considered unrelated to treatment with octamethyltrisiloxane. Feed consumption was similar to controls for animals in the 75 mg/kg bw/day group throughout the duration of the study.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

There were treatment-related, statistically significant increases in mean absolute and relative liver weights at all dose levels tested (Table 3) with correlating histopathological observations. The mean relative liver weights of females given 75, 250, or 750 mg/kg bw/day were 9.3%, 13.5%, or 29.5% higher than controls, respectively.

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no treatment-related gross pathologic observations.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Treatment-related very slight hypertrophy of centrilobular/midzonal hepatocytes was present in 12/24 females given 75 mg/kg bw/day and in 17/24 females given 250 mg/kg bw/day (Table 4). Treatment-related slight hypertrophy of centrilobular/midzonal hepatocytes was present in 7/24 females given 250 mg/kg bw/day and in 24/24 females given 750 mg/kg bw/day. The hepatocellular hypertrophy corresponded to the doserelated increases in liver weights of females given 75, 250 or 750 mg/kg bw/day. Two females given 750 mg/kg/day had treatment-related very slight multifocal chronic inflammation in periportal regions of the liver, and one of the females with chronic inflammation also had treatment-related very slight increased number of mitotic figures in hepatocytes. Treatment-related pigment deposits were present in the intrahepatic bile ducts, hepatocytes and/or Kupffer cells of six females given 750 mg/kg bw/day. The pigment deposits were brown when examined with a light microscope and birefringent with some deposits featuring Maltese cross formations when examined with polarized light. All of the treatment-related liver effects were consistent with a previously conducted 28-day oral gavage toxicity study with octamethyltrisiloxane (Braun, 2010). The pigment deposits in animals 471, 475, 478, and 482 were negative for the presence of bile when processed with Fouchet’s bile stain.

Histopathological findings: neoplastic:

no effects observed

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

not specified

Details on maternal toxic effects:

No effercts noted.

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: Based on the decreased body weight gain and liver weight increases combined with the chronic inflammation of the liver noted in animals in the 750 mg/kg bw/day group

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Foetal body weights of males in the 750 mg/kg bw/day group, females in the 250 and 750 mg/kg bw/day groups, and sexes combined in the 250 and 750 mg/kg bw/day groups were higher than control and statistically identified. These higher body weights were considered unrelated to treatment with octamethyltrisiloxane as they were within recent historical control values.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

No effects noted.

Dose descriptor:

NOEL

Effect level:

750 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: There was no indication of embryo/fetal toxicity or teratogenicity at any dose level tested.

Abnormalities:

no effects observed

Developmental effects observed:

no

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

Dose (mg/kg bw/day)	Day of Gestation
	6 -9	9 -12	15 -18	18 -21	6 -21	0 -21
0	12.1	19.0	37.0	50.4	139.9	171.2
75	14.0	21.4	40.7	55.8	153.7	184.9
250	13.2	21.6	43.2*	59.1*	159.3*	190.8*
750	9.7	20.6	42.5*	59.2*	152.8	184.9

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

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

Table 2. Feed Consumption (g/day)

Dose (mg/kg bw/day)	Day of Gestation
	6 -9	15 -18	18 -21
0	17.4	21.0	19.8
75	17.7	22.6	21.5
250	17.6	24.1*	22.3*
750	16.5	24.4*	23.6*

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

Table 3. Liver Weights

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

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

Table 4. Histopathologic Liver Alterations

Sex	Females
Dose level (mg/kg bw/day)/Liver (number examined)	0/24	75/24	250/24	750/24
Hypertrophy, increased eosinophilia, hepatocyte, centrilobular/midzonal (-very slight/-slight)	0/0	12/0	17/7	0/24
Increased Number of Mitotic Figures, hepatocyte, -very slight	0	0	0	1
Inflammation, chronic, periportal, multifocal -very slight	0	0	0	2
Pigment, bile duct, focal -very slight	0	0	0	1
Pigment, bile duct, multifocal -very slight	0	0	0	4
Pigment, hepatocyte, multifocal -very slight	0	0	0	5
Pigment, Kupffer cell, multifocal -very slight	0	0	0	4

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

Conclusions:

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

Executive summary:

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

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

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

Reference 3

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

27.10.2006 to 21.12.2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

Only one concentration tested.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: 9 wks
- Weight at study initiation: (P) Males: 300.7-350 g; Females: 195.5-240 g
- Fasting period before study: No
- Housing: Individually housed in suspended wire-mesh cages. Except during mating, gestation and lactation periods. Mating: home cage of the male; Gestation: shoebox cages; Lactation: dams housed with litters.
- Diet (e.g. ad libitum): Ad libitum (except during inhalation exposure or FOB.
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days

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

IN-LIFE DATES: From: 27.10.2006 To: 21.12.2007

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

clean air

Details on exposure:

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

TEST ATMOSPHERE
- Brief description of analytical method used: No data
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

None given (apparent Annex missing)

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: Continuous until evidence of copulation observed.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged (how): Shoebox cages.

Duration of treatment / exposure:

Males: 30 days
Toxicity group females: 29 days
Reproductive group females: 15 days prior to mating, through the mating period and up to day 19 of gestation.

Frequency of treatment:

Daily (seven days/week)

Duration of test:

Approximately 7 months

Dose / conc.:

5.1 mg/L air

Remarks:

target concentration equivalent to 400 ppm

No. of animals per sex per dose:

Ten

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on results from previous study.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily in their cages for mortality, morbidity and moribundity throughout the in-life phase of the study. General clinical observations were made at least once per day, beginning on the first day of treatment (except on days of detailed examinations). Clinical observations were also performed on all animals on the day of, but prior to, scheduled necropsy.

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

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

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

WATER CONSUMPTION: No

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

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No

Fetal examinations:

- External examinations: Yes all pups
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No

Statistics:

All data analyses was conducted using SAS version 9.1.3. Statistically significant probabilities were reported for p-values of <0.05, <0.02 and <0.01.

Indices:

Gestation length, mean number of implantation sites, mean number of corpora lutea, mean mating and fertility indices. Mean litter size, mean live litter size, mean litter weight, mean ratio live births/litter size.

Details on maternal toxic effects:

Maternal toxic effects:no effects

Key result

Dose descriptor:

NOAEC

Effect level:

>= 400 ppm

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Key result

Dose descriptor:

NOAEC

Effect level:

>= 400 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant treatment-related effects on fetuses

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

In a combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted using a protocol comparable to OECD 422 and to GLP (reliability score 1) the NOAEC for general and developmental toxicity was at least 400 ppm (the only concentration tested) according to the study report.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

10 626 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

In the key reproductive toxicity study (WIL Research Laboratories, 2006) in Sprague-Dawley rats, the NOAEC for developmental toxicity was 1600 ppm (10626 mg/m3) due to decreased offspring weights at 5000 ppm.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Toxicity to reproduction: other studies

Additional information

There are no available reproductive toxicity studies for the registered substance "Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane". Therefore, data have been read-across from three of its constituents:

 

1) HMDS: hexamethyldisiloxane (CAS 107-46-0)

2) L3: octamethyltrisiloxane (CAS 107-51-7)

3) L4: decamethyltetrasiloxane (CAS 141-62-8)

Fertility studies:

In the key reproductive toxicity study (WIL Research Laboratories, 2006) Sprague-Dawley rats (30 animals/sex/dose) were exposed to HMDS at a concentration of 100, 400, 1600 or 5000 ppm, 6 hours/day, 7 days/week. Exposure started at least 70 days prior to mating, throughout mating, during gestation through to gestation day 20. After parturition, exposure of the F0 and F1 females was re-initiated on lactation day 5 and continued through the day prior to euthanasia. F1 parents were selected from litters at 3 weeks of age and mated at between 14 and 16 weeks of age. Observations and examinations were conducted to OECD test guideline 416. The NOAEC for parental toxicity relevant to humans was 400 ppm based on microscopic liver findings (golden-brown pigment in the periportal areas) in the F0 males of the 5000 ppm group and F1 males and females in the 5000 and 1600 ppm groups. F0 and F1 reproductive performance was not affected at any concentration. Based on the results of this study the NOAEC for HMDS for parental reproductive toxicity is considered to be at least 5000 ppm (33200 mg/m³).

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted to OECD 422 and to GLP (Dow Corning Corporation, 2008) via inhalation route, the NOAEC for the reproductive toxicity of L3 was at least 3146 ppm as no adverse effects were observed on reproductive parameters in rats. The NOAEC for male and female general toxicity was <806 ppm and at least 3146 ppm, respectively. The male NOAEC was based on adverse effects in the kidney and liver.

In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted by the inhalation route using a protocol comparable to OECD 422 and to GLP (Dow Corning Corporation, 2007) with L4, the NOAEC for reproductive toxicity was at least 400 ppm (the only concentration tested) according to the study report. However, it should be noted that three female rats in the 400 ppm group with evidence of copulation failed to deliver a litter. One of these three females showed signs of parturition (blood discharge) on gestation day 25, but no pups were found. However, seven implant sites were present. The remaining females produced litters that were similar to the controls.

Developmental studies:

In a reproductive toxicity study (WIL Research Laboratories, 2006) Sprague-Dawley rats (30 animals/sex/dose) were exposed to HMDS at a concentration of 100, 400, 1600 or 5000 ppm, 6 hours/ day, 7 days/week. Exposure started at least 70 days prior to mating, throughout mating, during gestation through to gestation day 20. After parturition, exposure of the F0 and F1 females was re-initiated on lactation day 5 and continued through the day prior to euthanasia. F1 parents were selected from litters at 3 weeks of age and mated at between 14 and 16 weeks of age. Observations and examinations were conducted to OECD test guideline 416.

There were no statistically significant offspring weights at any dose level. Statistically significant (p<0.05 or p<0.01) lower mean pup body weight gains were noted for males in the 400, 1600 and 5000 ppm groups and for females in the 400 and 5000 ppm groups from PND 4 to PND 7. Male and female pup weight gain in the 5000 ppm group continued to be slightly lower (not statistically significant) than the control group during PND 7 to 14 and 14 to 21. As a result of the lower weight gain, mean pup body weights in the 5000 ppm group were lower (7.2% to 7.3%) than control group values on PND 21; the difference from the control group for the females was statistically significant (p<0.05). Because the lower weight gain in the 400 and 1600 ppm groups did not persist, the lower mean body weight gains in these groups during PND 4 to 7 were not considered test article-related. No other differences in pup body weight or body weight gain relative to the control group were noted in the 400, 1600 or 5000 ppm groups. Mean male and female pup body weights and body weight changes in the 100 ppm group were unaffected by test article exposure throughout the postnatal period. The NOAEC for F1 and F1 developmental toxicity was 1600 ppm due to decreased offspring weights at 5000 ppm. There were no gross anomalies in the pups. The NOAEC for developmental neurobehavioral endpoints was 1600 ppm due to the lack of habituation exhibited in the locomotor activity assessments and delayed attainment of the surface righting response in the 5000 ppm group F2 females, and decreases in average and peak acoustic startle response on PND 20 in the 5000 ppm group F2 males and females. The NOAEC for neuropathologic endpoints was 5000 ppm.

In a developmental toxicity study with L3 (Dow Corning Corporation, 2017b) carried out according to OECD Test Guideline 414 via oral (gavage) route, there was no indication of embryo/fetal toxicity or teratogenicity at any dose level tested. The NOEL was determined to be 750 mg/kg/day, the highest dose level tested.

In a combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test conducted with L4 by the inhalation route using a protocol comparable to OECD 422 and to GLP (Dow Corning Corporation, 2007b) the NOAEC for developmental toxicity was at least 400 ppm (the only concentration tested).

Read-across justification

 

A detailed read-across explanation is available in Section 7.5.

 

Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane (EC No 946-797-7) belongs to the structural class of siloxanes. Studies for toxicity endpoints are available for some or all of its constituents. The available studies, as well as key physicochemical properties, are summarised in table below. The most recent and reliable studies for the substance’s constituents were chosen for weight of evidence.

 

Table: Key available data

Substance	HMDS	L3	L4	L5
Chemical name	Hexamethyldisiloxane	Octamethyltrisiloxane	Decamethyltetrasiloxane	Dodecamethylpentasiloxane
CAS number	107-46-0	107-51-7	141-62-8	141-63-9
Water solubility	0.93	0.034	6.7E-03	7.5E-05
Log Kow	5.1	6.6	8.1	9.4
Toxicity to reproduction
- Fertility	NOAEC:5000 ppm (OECD 416) (Will Research, 2006)	NOAEC: 3141 ppm (OECD 422) (Dow Corning Corporation, 2008)	NOAEC: 400 ppm (OECD 422) (Dow Corning Corporation, 2007)	-
- Developmental toxicity	NOAEC: 1600 ppm (OECD 416) (Will Research, 2006)	NOAEC:750 mg/kg bw/day ppm (OECD 414) (Dow Corning Corporation, 2017)	NOAEC: 400 ppm (OECD 422) (Dow Corning Corporation, 2007)	-

-         No data

 

 

Conclusion

Overall, HMDS, L3 and L4 have similar toxicological profiles. Following consideration of all of the above studies it is deemed appropriate to read-across data from HMDS, L3 and L4 to Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane as they have the similar toxicological properties and belong to the structural class of siloxanes.

Justification for classification or non-classification

The available studies do not suggest that the reaction mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane (EC No 946-797-7) should be classified for adverse effects on fertility or offspring development according to Regulation (EC) No 1272/2008.