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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproductive toxicity studies are available for the registered substance, amino functional alkoxysilanes, therefore surrogate data for constituents of the substance have been used to address this endpoint.

The key reproductive toxicity study for trimethoxy(methyl)silane is summarised as follows:

No treatment-related effects were observed in any of the reproductive parameters evaluated in an oral OECD 422 study (Dow Corning Corporation, 2005) in rats. Based on the results of this screening study, the NOAEL for reproductive toxicity of trimethoxy(methyl)silane in the rat via oral dosing was determined to be 1000
mg/kg bw/day.

Other constituents are aminofunctional substances, such as 3-aminopropyl(triethoxy)silane (CAS 919-30-2). The key reproductive toxicity data for this substance are as follows:

A well reported repeated dose 90-day oral toxicity study (Momentive, 2001), conducted in the main according to the current guideline for that endpoint and in accordance with GLP, identified a systemic NOAEL value of 200 mg/kg bw/day in male and female rats; mortality, clinical observations and liver effects were evident at 600 mg/kg bw/day. No effects on reproductive organs, oestrus cycle or sperm parameters were evident at the highest tested dose of 600 mg/kg bw/day. This study would have only limited potential to detect all possible reproductive effects.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19.11.2003 to 19.05.2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to guideline
Guideline:
other: USEPA OPPTS 870.3650
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: No data
- Age at study initiation: Nine weeks
- Weight at study initiation: Males: 294.2-351.5; Females: 200.2-260.2 g
- Fasting period before study: None
- Housing: individually housed in suspended wire-mesh cages (pregnant rats in shoebox cages)
- Diet (e.g. ad libitum): Ad libitum (except during FOB)
- Water (e.g. ad libitum): Ad libitum (except during FOB)
- Acclimation period: Six days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2-22.5
- Humidity (%): 36.0-62.0
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 09.02.2004 To: 19.04.2005
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Conducted over nitrogen atmopshere. Test substance was placed into a volumetric flask and corn oil added to achieve the desired volume. The weight of the test substance added to the flask was used to calculate nominal dose solution concentrations. Dosing solutions were prepared at least once every two weeks consistent with the previously determined 15-day stability. The concentration, homogeneity and stability of the test substance in vehicle for at least 15 days.

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: Various
- Amount of vehicle (if gavage): Up to 3 ml/kg
- Lot/batch no. (if required): 122K0131
- Purity: Considered 100%
Details on mating procedure:
A 1:1 mating ratio was used. After dosing on study day 14, the animals were paired by placing the lowest numbered ear tag reproductive group female within each group in the home cage of the male with the lowest numbered ear tag from the same group. Female animals were housed continuously with the same male until evidence of copulation was obtained. Females were evaluated daily for evidence of copulation, as indicated by either a vaginal copulatory plug or sperm in the vaginal smear. Day 0 of gestation was defined as the day evidence of copulation was obtained, at which time the female was returned to her home cage (shoebox cage).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of methyltrimethoxysilane (MTMS) in corn oil dosing solutions was determined prior to the beginning of the definitive study.
Duration of treatment / exposure:
Toxicity group females and males were treated for 28 and 29 days, respectively. Reproductive group females were treated for 14 days prior to the mating period, during the mating period, and then up to and including post partum day 3, for a total of up to 51 days.
Frequency of treatment:
Daily, seven days/week
Details on study schedule:
No further relevant details.
Remarks:
Doses / Concentrations:
0 (corn oil), 50, 250, and 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on a range-finding study
Parental animals: Observations and examinations:
Mortality/Morbidity: Animals were observed at least twice daily in their cages for moribundity and mortality throughout the in-life phase of the study.
Clinical observations:
Daily Observations: General clinical examinations were made at least once a day and were conducted immediately after dosing. The examinations included, but were not limited to, changes in the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system functions, motor activity and behavior patterns. Findings were recorded for individual animals. General clinical examinations were not performed on days when detailed physical examinations were performed.
Detailed Physical Examinations: All animals received a detailed physical examination once before the first dose administration (to allow for within-subject comparisons), and weekly thereafter. Examinations were made outside the home cage in a standard arena at approximately the same time each day. Observations were detailed and carefully recorded. 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 behavior were recorded. The presence or absence of findings was recorded for individual animals.

Body weights and food consumption were recorded weekly. Additional body weights for reproductive group females were obtained on gestational day 0, 7, 14, and 20, and within 24 hours of parturition, and on postnatal day 4. Individual food consumption was determined for each group following group specific schedules. In addition, detailed clinical observations (functional observational battery [FOB] conducted out of the home cage) and locomotor activity were evaluated for all adult male and toxicity phase females once prior to the start of test article administration (baseline evaluations) and again during the last week of the test article administration. Blood samples were collected from males and toxicity group females on the day of scheduled termination for analysis of hematology and serum chemistry parameters.
Litter observations:
All reproductive phase females were allowed to deliver and rear their offspring to lactation day 4; surviving dams and pups were euthanized and examined on lactation day 4.On the day parturition was initiated (PND 0), the pups were sexed and examined for gross malformations, and the numbers of still born and live pups were recorded. Individual gestation length was calculated using the date delivery started. Abnormal behavior of the offspring was recorded. The dam and litter remained together until PND 4.

Mean measured parameters were calculated for:
Days of gestation
Undetermined sex
Male pups/litter
Female pups/litter
Males/Females per litter
Total pups/litter
Viable (live) pups/litter
Viable/Total pups per litter

Initial litter weight at parturition (g)
Initial average pup weight at parturition (g)
Final litter weight at PND 4 (g)
Final average pup weight at PND 4 (g)

Total number of implants
Corpora counts
Postmortem examinations (parental animals):
Clinical pathology assessments (hematology and serum chemistry) and macroscopic and microscopic examinations (including organ weights) were also performed on the appropriate groups of adult males and toxicity phase females. For females that delivered or had macroscopic evidence of implantation, the numbers of former implantation sites and corpora lutea were recorded. Recognizable fetuses for the females euthanized in extremis were examined externally and preserved in 10% neutral-buffered formalin. For females that failed to deliver, a pregnancy status was determined. Uteri with no macroscopic evidence of implantation were opened and subsequently placed in a 10% ammonium sulfide solution for detection of early implantation loss.
Postmortem examinations (offspring):
Intact offspring dying from PND 0 to 4 were necropsied. Cannibalized pups were discarded without necropsy. Tissues were preserved in 10% neutral-buffered formalin for possible future histopathologic examination only as deemed necessary by gross findings. The carcass of each pup was then discarded.
Statistics:
Reproductive parameters with the exception of litter size were analyzed using an ANCOVA (Analysis of Covariance) with liter size as the covariate. Litter size was analyzed using an ANOVA.
Reproductive indices:
Male (Female) Mating Index (%)
Male Fertility Index (%)
Male Copulation Index (%)
Female Fertility Index (%)
Female Conception Index (%)
Offspring viability indices:
On the day parturition was initiated (PND 0), the pups were sexed and examined for gross malformations, and the numbers of still born and live pups were recorded.
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Reproductive performance:
no effects observed
"Mortality and day of death:         None.
"Number pregnant per dose level:  10
"Number aborting:  0 "Number of resorptions, early/late if available:  None detected.
"Number of implantations: Group Mean (standard deviation):  Control:  15 (2.2);    50 mg/kg: 16 (2.0);    250 mg/kg: 16 (1.4);  1000 mg/kg: 16 (1.9) 
"Number of corpora lutea: Group Mean (standard deviation): Control: 19(4.7); 50 mg/kg: 19(3.1); 250 mg/kg:18(2.0); 1000 mg/kg:  17(3.9)
"Duration of Pregnancy:  Group Mean (standard deviation):        Control: 21  (0.5); 50 mg/kg: 21(0.5); 250 mg/kg: 22(0.5);   1000 mg/kg: 22(0.5)
"Body weight:  No statistically significant differences in treatment group maternal body weight relative to control group animals.
"Food/water consumption:  No statistically significant differences in treatment group maternal food consumption relative to control group animals.
"Description, severity, time of onset and duration of clinical signs:  Thirty percent of the animals in the 50 m/kg/day dose group and 100 % of the animals in the 250 and 1000 mg/kg/day dose groups exhibited a transient period of salivation and/or abnormal inactivity at least once over the course of treatment  immediately after dosing.
"Gross pathology incidence and severity:  Gross pathology of the  reproductive/developmental group animals was not an endpoint for this study.
"Organ weight changes, particularly effects on total uterine weight:   Organ weight was not assessed in the reproductive/developmental group animals.
"Histopathology incidence and severity:  Histopathology was not assessed in the reproductive/developmental group animals. No treatment-related effects were observed in any of the reproductive parameters evaluated. All females bred successfully and delivered live litters. 

There were no treatment-related effects apparent for any of the reproductive endpoints. All females bred successfully and delivered live litters. Litter sizes were comparable for all groups. 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:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect at maximum dose
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
No gross abnormalities were found for any of the pups, with the exception of a single runt in the 50 mg/kg/day group.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect at maximum dose
Critical effects observed:
no
Reproductive effects observed:
no

Result: Exposure to methyltrimethoxysilane was not associated with reproductive  toxicity. The findings support a NOAEL of 1000 mg/kg/day.

NOAEL (NOEL) (maternal toxicity): 1000 mg/kg/day
NOAEL (NOEL) (reproductive toxicity): 1000 mg/kg/day
LOAEL (LOEL):        N/A

Conclusions:
Exposure to methyltrimethoxysilane was not associated with reproductive toxicity. The findings support a NOAEL of 1000 mg/kg bw/day.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The use of constituent data to assess mammalian toxicity of the registered substance is described in Section 7.5.

Effects on developmental toxicity

Description of key information

There are no developmental toxicity data for the registered substance, amino functional alkoxysilanes, therefore the following data are included in the dossier in order to conduct an interim risk assessment until approval to conduct OECD 408 and 414 tests is received from ECHA.

No developmental toxicity studies are available for the registered substance therefore surrogate data for constituents of the substance have been used to address this endpoint. The key developmental toxicity study for trimethoxy(methyl)silane is summarised as follows: No treatment-related effects were observed in any of the developmental parameters evaluated in an oral OECD 422 study in rats (Dow Corning Corporation, 2005). Based on the results of this screening study, the NOAEL for reproductive toxicity of trimethoxy(methyl)silane in the rat via oral dosing was determined to be 1000 mg/kg bw/day.

Other constituents are aminofunctional substances, such as 3-aminopropyl(triethoxy)silane (CAS 919-30-2). The key developmental toxicity study for this substance are as follows: A well reported study conducted according to generally accepted scientific standards and in accordance with GLP reported maternal toxicity (increased incidences of mortality, clinical observations, and slight decreases in body weight gain and food consumption) at 600 mg/kg bw/day (Momentive, 1998). The occurrence of maternal toxicity was accompanied by slight fetal toxicity (increased minor skeletal variations). No significant maternal or developmental effects were observed at 20 or 100 mg/kg bw/day. The maternal and developmental NOAEL was 100 mg/kg bw/day. However, the slight fetotoxicity is considered to be secondary to maternal toxicity. 

A pre-natal developmental toxicity study according to OECD 414 is proposed for the surrogate substance trimethoxy(methyl)silane (CAS 1185-55-3).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The use of constituent data to assess mammalian toxicity of the registered substance is described in Section 7.5.

Toxicity to reproduction: other studies

Additional information

The use of constituent data to assess mammalian toxicity of the registered substance is described in Section 7.5.

Justification for classification or non-classification

There are no data to suggest that amino functional alkoxysilanes should be classified for reproductive or developmental toxicity according to Regulation (EC) No 1272/2008.

Additional information