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Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no reproductive toxicity studies with the registered substance, triethoxy(3-isocyanatopropyl)silane or its ultimate hydrolysis product, 3-aminopropylsilanetriol via any route of exposure.

A 90-day oral toxicity study (WIL research Laboratories, 2001) for the intermediate hydrolysis product, 3-aminopropyl(triethoxy)silane (CAS No. 919-30-2), conducted according to OECD Test Guideline 408 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 dose of 600 mg/kg bw/day.

Due to the nature of isocyanates, further reproductive toxicity testing with the parent substance is inappropriate. Given its highly reactive nature, systemic exposure to unchanged parent material will not occur.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no reproductive toxicity studies for the registered substance, triethoxy(3-isocyanatopropyl)silane. No effects on reproductive organs, oestrus cycle or sperm parameters were evident at the highest dose of 600 mg/kg bw/day in a 90-day oral toxicity study (WIL research Laboratories, 2001) for the intermediate hydrolysis product, 3-aminopropyl(triethoxy)silane. The study was conducted according to OECD Test Guideline 408 and in accordance with GLP. The NOAEL for the reproductive endpoints assessed, was considered to be 600 mg/kg bw/day, the highest dose tested. No effects attributable to treatment were recorded on uterine parameters in the developmental toxicity study (MPI, 1998) at doses up to 600 mg/kg/day.

Justification for use of data for the intermediate hydrolysis product:

Triethoxy(3-isocyanatopropyl)silane hydrolyses very rapidly, half-life <1 minute at pH 7 to form an intermediate hydrolysis product 3-aminopropyl(triethoxy)silane which has a measured hydrolysis half-life of 0.8 h at pH 5, 8.5 h at pH7, and 0.15 h at pH 9 and 24.7°C. The ultimate products of the hydrolysis reaction are 3-aminopropylsilanetriol and ethanol.

Therefore due to the rapid hydrolysis exposure would be to the intermediate and further hydrolysis products so the use of reproductive toxicity data from the initial hydrolysis product, 3-aminopropyl(triethoxy)silane, is considered a conservative approach.

The non-silanol hydrolysis product ethanol does not contribute to any adverse effects for reproductive toxicity at the relevant dose levels based on publicly available information (OECD, 2004).

Ethanol is reported to have an effect on male fertility in some rat studies but not others and where noted generally involve sperm parameters. However, where effects are noted they occur only at high doses.


Effects on developmental toxicity

Description of key information

There are no developmental toxicity studies for the registered substance, triethoxy(3-isocyanatopropyl)silane (CAS 24801-88-5) or its ultimate hydrolysis product, 3-aminopropylsilanetriol, via any route of exposure. Therefore data on the intermediate hydrolysis product, 3-aminopropyl(triethoxy)silane (CAS 919-30-2) have been used to address the developmental toxicity endpoint.

The key developmental toxicity study was an oral (gavage) study in male and female rats conducted according to a protocol similar to OECD Test Guideline 414 and in compliance with GLP (MPI, 1998). The study identified maternal and teratogenicity NOAELs of 100 mg/kg bw/day, with the corresponding LOAEL of 600 mg/kg bw/day. Effects at 600 mg/kg bw/day included increased mortality, clinical observations and reduced body weight gain in dams, and increased foetal skeletal variation. Due to the nature of isocyanates, further developmental toxicity testing with the parent substance is inappropriate. Given its highly reactive nature, systemic exposure to unchanged parent material will not occur.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1997-04-14 to 1997-05-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
Version / remarks:
(Similar to OECD 414)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Charles River Crl:CD VAF/Plus
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Labs, Portage, MI, USA
- Age at study initiation: not stated
- Weight at study initiation: 235-240 g (day 0 of study)
- Housing: 1/suspended stainless steel cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72-75 deg F
- Humidity (%): 44-56
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: 1997-04-14 To: 1997-04-28
Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 0.3, 1.5 or 9 g of TS were added to 30 ml vehicle (peanut oil), mixed with magnetic stir bar. Solution said to be stable for 12 h; prepared daily. A constant volume of 2 ml/kg bw of these solutions or the vehicle were administered daily. No tests were conducted on the on homogeneity or stability of prepared solutions.

DIET PREPARATION
no details given

VEHICLE
- Justification for use and choice of vehicle (if other than water): None given (TS hydrolyses in water)
- Concentration in vehicle: 0.3, 1.5 or 9 g of TS in 30 ml vehicle
- Amount of vehicle (if gavage): 2 ml/kg bw
- Lot/batch no.: Sigma Peanut Oil (P-2144); lot 83H0848
- Purity: not stated
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
doses: 20, 100 and 600 mg/kg bw/day
target concentrations: 10, 50, 300 mg/ml
measured average concentration: 9.34, 51.2, 299 mg/ml
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: until copulatory plug or vaginal smear confirmed mating
- Proof of pregnancy: referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6 of gestation to day 17 of gestation [NB the SIAR (2003) report of this study notes treatment from GD 6 to 20]
Frequency of treatment:
once per day
Duration of test:
Observations from gestation day (GD) 6 to GD 20.
Dose / conc.:
20 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
600 mg/kg bw/day
No. of animals per sex per dose:
30 females
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: female
Duration of test: Through day 20 of gestation
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily GD 6-20

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: GDs 0, 6, 9, 12, 15, 18, 20

FOOD CONSUMPTION : Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg bw/day: Yes. determined on GDs 0, 6, 9, 12, 15, 18, 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on GD 20
- Organs examined: laparaohysterectomic examination and necropsy

OTHER:
half of the foetuses from 0 and 600 mg/kg bw/day groups were examined for soft tissue abnormalities
half of the foetuses from all groups were examined for skeletal abnormalities
Ovaries and uterine content:
The ovaries and uterine content were examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half of the foetuses from 0 and 600 mg/kg bw /day groups
- Skeletal examinations: Yes: half per litter from all dose groups
- Head examinations: yes
Statistics:
See ANY OTHER INFORMATION ON MATERIALS AND METHODS, below.
One-way analysis of variance (ANOVA). Pairwise comparison with vehicle control (Dunnet, 1964) if ANOVA significant.
Kruskal-Wallis test. Pairwise comparison with vehicle control using Mann-Whitney U test if Kruskal-Wallis significant (Siegel, 1956).
Pearson chi-square test. Pairwise comparison with vehicle control using Fisher's exact test if chi-square test significant (Siegel, 1956).
Indices:
No data given as indices (see REMARKS ON RESULTS INCLUDING TABLES AND FIGURES for details of reproductive/developmental findings).
Historical control data:
Full historical control data given (Charles River CD).
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Increase in clinical signs of toxicity and 5/30 deaths at 600 mg/kg bw/day.
Clinical signs although not restricted to the animals that died, were predominantly observed in these animals and included hypoactivity, cold to the touch, body surface stained and material around the mouth and nose. In addition respiratory signs included laboured breathing, gasping and rales. No signs were observed in the two lower dose (100 and 20 mg/kg bw/day) groups. No observations made at necropsy were related to these signs. A slight decrease in body weight gain in the high dose group only, which corresponded to statistically significantly reduced food consumption (GD 6-9), was considered to be treatment-related. No significant treatment-related effects were reported on uterine parameters (including gravid uterine weights, mean number of corpora lutea, implantations and resorptions).
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
600 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
600 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
No treatment-related effects on implantations (including pre- and post- implantation losses and resorptions), live foetuses, sex ratios and foetal weights.
There were no significant effects on foetal external or visceral malformations, developmental variations or significant foetal skeletal malformations. Two minor foetal variations (27 presacral vertebrae and sternebra unossified) seen only at 600 mg/kg bw/day were considered to indicate slight foetal toxicity (in the presence of clear maternal toxicity).
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: sternum
skeletal: vertebra
Description (incidence and severity):
27 presacral vertebrae and sternebra unossified
Developmental effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
not specified
Relevant for humans:
not specified

[adapted from SIAR, 2003]

Mortality and day of death: 

Dose (mg/kg bw/day)                 No. Dead   Day of Death (gestation day)

0                                              0/30                              -

20                                             0/30                              -

100                                           0/30                              -

600                                           5/30                              7,7,13,15,17

Number pregnant per dose level:

Dose (mg/kg bw/day)                 No. Pregnant

0                                              29/30

20                                             25/30

100                                           26/30

600                                           22/30

Number aborting: none

Number of resorptions: 

Dose (mg/kg bw/day)                 No. Resorptions (early + late)

0                                              34

20                                             25

100                                           38

600                                           25

Number of implantations:
Dose (mg/kg bw/day)
                             No. Implantations 

0                                                          437

20                                                         368

100                                                       361

600                                                       358

Pre and post implantation loss:

Dose (mg/kg bw/day)                  Preimplantation loss       Postimplantation loss

0                                                          50                                 34

20                                                         67                                 25

100                                                       74                                 38

600                                                       60                                 25

Number of corpora lutea:

Dose (mg/kg bw/day)                 No. Corpora lutea 

0                                                          487

20                                                         435

100                                                       435

600                                                       418

Duration of Pregnancy: 20 days

Body weight: No significant body weight effects at any dose level. The slight decrease in body weight gain observed GDs 6-9 at 600 mg/kg bw/day was considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption.

Dose (mg/kg bw/day)                           Mean body weight, grams (GD 20)

0                                                                      404.7   

20                                                                     405.1

100                                                                   390.4

600                                                                   407.4

Food/water consumption: A statistically significant decrease in food consumption was observed GDs 6-9 at 600 mg/kg bw/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period.

Description, severity, time of onset and duration of clinical signs:

An increased incidence of the following clinical signs were observed in the 600 mg/kg bw/day group: decreased activity; cold to touch; body surface stained; and material around the nose and eye; respiratory signs including laboured breathing, gasping, and rales. Most of these signs were observed in moribund animals.

Gross pathology incidence and severity: No significant findings at any dose level.

Organ weight changes, particularly effects on total uterine weight: No significant effect on gravid uterine weights at any dose level.

Histopathology incidence and severity: No significant findings at any dose level.

Foetal data:

-Litter size and weights: no significant treatment related effect at any dose level.

-Number viable (number alive and number dead): no significant treatment related effect at any dose level.

-Sex ratio: no significant treatment related effect at any dose level.

-Grossly visible abnormalities, external, soft tissue and skeletal abnormalities: no significant effects on foetal external or visceral malformations or developmental variations at any dose level. Statistically significant increases in the incidences of the variations: 27 presacral vertebrae (p0.05) and sternebra unossified (p0.01), observed at 600 mg/kg bw/day were attributed to treatment and considered manifestations of slight foetal toxicity.

NOAEL (NOEL) and LOAEL (LOEL) maternal toxicity:  

NOAEL 100 mg/kg bw/day; LOAEL 600 mg/kg bw/day

NOAEL (NOEL) and LOAEL (LOEL) developmental toxicity:  

NOAEL 100 mg/kg bw/day; LOAEL 600 mg/kg bw/day

Increased incidence of mortality and clinical observations as well as slight decreases in body weight gain and food consumption observed at 600 mg/kg bw/day. No significant maternal effects at 100 or 20 mg/kg bw/day.

403, 343, 323, and 333 foetuses were examined for the 0, 20, 100 and 600 mg/kg bw/day dose groups, respectively. No significant treatment related effects were observed on the following uterine parameters at any dose level: mean number of corpora lutea, implantations and live foetuses; percent pre-implantation losses, resorptions, and post-implantation losses; percent male or female foetuses; or foetal weights.

A statistically significant increase in the mean number of corpora lutea at the 600 mg/kg bw/day dose level was not considered test article related as ovulation and corpora lutea formation occurred prior to exposure.

Slight foetal toxicity, as exhibited by a statistically significant increase in the incidences of minor skeletal variations: 27 presacral vertebrae and sternebra unossified at 600 mg/kg bw/day. No significant developmental effects at 100 or 20 mg/kg bw/day.

Foetal effects exhibited as a statistically significant increase in the incidences of minor skeletal variations: 27 presacral vertebrae and sternebra unossified at 600 mg/kg bw/day. No statistically significant developmental effects at 100 or 20 mg/kg bw/day.

Conclusions:
A well reported study conducted according to generally accepted scientific standards, similar to OECD Test Guideline 414 and in compliance 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. The occurrence of maternal toxicity was accompanied by slight foetal 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.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no developmental toxicity studies for the registered substance, triethoxy(3-isocyanatopropyl)silane (CAS 24801-88-5) or its ultimate hydrolysis product, 3-aminopropylsilanetriol, via any route of exposure. Therefore data on the intermediate hydrolysis product, 3-aminopropyltriethoxysilane (CAS 919-30-2) have been used to address the developmental toxicity endpoint.

The key prenatal developmental toxicity study was an oral (gavage) study in male and female rats conducted according to a protocol similar to OECD Test Guideline 414 and in compliance with GLP with the test substance, 3-aminopropyltriethoxysilane, which was administered at doses of 0, 20, 100 or 600 mg/kg bw/day (MPI 1998).

During the study, 5 rats in the 600 mg/kg bw/day group were found dead and an increased incidence of clinical signs indicative of poor clinical condition, lower food consumption and body weight gain were also recorded at this dose. There were no effects attributable to treatment on uterine parameters. Based on the mortality, body weight and food consumption effects, the maternal No-Observed-Adverse-Effect-Level was considered to be 100 mg/kg bw/day.

There were no effects attributable to treatment on fetal external or visceral malformations or developmental variations. Increased incidence of 2 minor fetal variations (27 presacral vertebrae and unossified sternebra) was recorded at 600 mg/kg bw/day. There were no fetal skeletal malformations noted. Based on the fetal skeletal variations noted at 600 mg/kg bw/day the fetal No-Observed-Adverse-Effect-Level was considered to be 100 mg/kg bw/day.

Justification for use of data for the intermediate hydrolysis product:

Triethoxy(3-isocyanatopropyl)silane hydrolyses very rapidly, half-life <1 minute at pH 7 to form an intermediate hydrolysis product 3-aminopropyl(triethoxy)silane which has a measured hydrolysis half-life of 0.8 h at pH 5, 8.5 h at pH7, and 0.15 h at pH 9 and 24.7°C. The ultimate products of the hydrolysis reaction are 3-aminopropylsilanetriol and ethanol.

Therefore due to the rapid hydrolysis exposure would be to the intermediate and further hydrolysis products so the use of developmental toxicity data from the initial hydrolysis product, 3-aminopropyl(triethoxy)silane, is considered to be appropriate.

The non-silanol hydrolysis product ethanol does not contribute to any adverse effects for developmental toxicity at the relevant dose levels based on publicly available information (OECD, 2004).

Rats and mice maintained on liquid diets containing 5 – 10% ethanol for 5 weeks or longer showed some adverse physical and functional effects on the testes. Some indications of toxicity to the foetus, including deaths, growth retardation and increased malformations have been noted in rats and mice given diets in which 15-35% of the calories were derived from ethanol. However in other studies, no effect on the foetuses were seen in mice and rabbits given drinking water containing up to 15% ethanol, or inhaling up to 20000 ppm ethanol, during pregnancy.


Justification for classification or non-classification

Based on the available read-across data from read-across substance 3-aminopropyl(triethoxy)silane, triethoxy(3-isocyanatopropyl)silane does not require classification for reproductive or developmental toxicity according to Regulation (EC) No 1272/2008.

Additional information

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