hydrolysis products of 3-(triethoxysilyl)propan-1-amine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

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

In accordance with Column 2 of REACH Annex VIII, Section 8.7, Regulation (EC) No 1907/2006, a two generation reproductive toxicity study needs not to be conducted as a prenatal developmental toxicity study is available.

Effects on developmental toxicity

Description of key information

Read-across from 3-(triethoxysilyl)propan-1-amine (CAS 919-30-2)
Calculated NOAEL for hydrolysis products of 3-(triethoxysilyl)propan-1-amine (15%) is based on mixture rules:
Oral (EPA OTS 798.4900), NOAEL (maternal toxicity) = 667 mg/kg bw/day
Oral (EPA OTS 798.4900), NOAEL (developmental toxicity) = 667 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1997-04-14 to 1997-05-01

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline study, tested with the source substance 3-aminopropyltriethoxysilane (CAS 919-30-2). According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

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.

Remarks:

Doses / Concentrations:
20, 100 or 600 mg/kg bw/day
Basis:
actual ingested

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 was 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 fetuses 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-releted effects were reported on uterine parameters (including gravid uterine weights, mean number of corpora lutea, implantations and resorptions).

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

667 mg/kg bw/day

Based on:

other: hydrolysis products of 3-(triethoxysilyl)propan-1-amine (15%)

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Dose descriptor:

NOAEL

Effect level:

667 mg/kg bw/day

Based on:

other: hydrolysis products of 3-(triethoxysilyl)propan-1-amine (15%)

Basis for effect level:

other: developmental toxicity

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 fetuses, sex ratios and fetal weights.
There were no significant effects on fetal external or visceral malformations, developmental variations or significant fetal skeletal malformations. Two minor fetal variations (27 presacral vertebrae and sternebra unossified) seen only at 600 mg/kg bw/day were considered to indicate slight fetal toxicity (in the presence of clear maternal toxicity).

Abnormalities:

not specified

Developmental effects observed:

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

500                                           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.

Fetal 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 fetal 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 fetal 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 fetuses 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 fetuses; percent pre-implantation losses, resorptions, and post-implantation losses; percent male or female fetuses; or fetal 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 copora lutea formation occured prior to exposure.

Slight fetal 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.

Fetal 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 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. 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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

667 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified as 3-(triethoxysilyl)propan-1-amine hydrolyses rapidly in water resulting in the target substance (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7.1, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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 data available on developmental toxicity of “hydrolysis products of 3-(triethoxysilyl)propan-1-amine" (EC No. 939-125-9). In order to fulfil the standard information requirements set out in Annex VIII, 8.7.1, read-across from a structurally related substance is conducted in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

The read-across is based on the hypothesis that the analogue substance, 3-(triethoxysilyl)propan-1-amine, hydrolyses rapidly in water resulting in the target substance. It can be expected that both the target and the source substance have similar behaviour under aqueous conditions. The target substance consists of 3-aminopropylsilanetriol and ethanol which are formed directly after hydrolysis and several condensation products such as dimers, trimers as well as polymers of siloxanes having similar functional groups (-O-Si- or HO-Si-). Therefore, it is considered that the target and the source substance are in one class of compounds and structural differences are not supposed to contribute to significant differences in activity with respect to eco- and human toxicological endpoints. A detailed analogue approach justification is provided in the technical dossier (Please refer to IUCLID Section 13 for further information).

Thirty female rats per group were exposed by gavage from day 6 of gestation through day 20 of gestation to dose levels of 20, 100 or 600 mg/kg bw/day of 3-(triethoxysilyl)propan-1-amine (Breslin, 1998). In order to reduce rapid hydrolysis of the test substance, the test substance was administered in peanut oil sparged with nitrogen. However, it can be assumed that hydrolysis takes place under the acidic conditions in the gastrointestinal tract.Extensive monitoring for embryotoxicity, foetal toxicity and foetal malformations was conducted. Increased incidences of mortality and clinical observations, as well as slight decreases in body weight gain and food consumption, were observed at 600 mg/kg bw/day. The occurrence of maternal toxicity at 600 mg/kg bw/day was accompanied by slight fetal toxicity, as exhibited by 27 presacral vertebrae and sternebra unossified. No significant maternal or developmental effects were observed at 20 or 100 mg/kg bw/day. Therefore, the maternal and developmental NOAEL was 100 mg/kg bw/day. Due to the fact that the hydrolysis product is formed in aqueous solutions of 3-(triethoxysilyl)propan-1-amine where the concentration range of 3-(triethoxysilyl)propan-1-amine is > 0.1 - < 16% (w/w), the available prenatal developmental toxicity study represents a worst case assumption. With respect to mixture rules, the NOAEL for hydrolysis products of 3-(triethoxysilyl)propan-1-amine (15%) is 667 mg/kg bw/day (100 mg/kg bw/day x 100/15 = 667 mg/kg bw/day).

Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

The available data on reproductive toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) No 1272/2008 and are therefore conclusive but not sufficient for classification.