3-(diethoxymethylsilyl)propylamine

Developmental toxicity / teratogenicity

Administrative data

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:

The study was conducted according to an appropriate guideline, in compliance with GLP and was considered to be reliability 1 (reliable without restrictions). Read across to the registered substance is considered scientifically justified; the read across is considered to be reliability 2.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

3-aminopropyltriethoxysilane

EC Number:

213-048-4

EC Name:

3-aminopropyltriethoxysilane

Cas Number:

919-30-2

IUPAC Name:

3-(triethoxysilyl)propan-1-amine

Test animals

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

Administration / exposure

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 treament from GD 6 to 20]

Frequency of treatment:

once per day

Duration of test:

Observations from gestation day (GD) 6 to GD 20.

Doses / concentrations

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

Examinations

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).

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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).

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

LOAEL

Effect level:

600 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

3

Dose descriptor:

LOAEL

Effect level:

600 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

Results (fetuses)

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).

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

[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.

Applicant's summary and conclusion

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. However, the variation can result from maternal stress and is considered to be minor, and not a threat to normal functioning of the animals, and therefore not of significance for humans. The NOAEL for developmental toxicity (including teratogenicity) was therefore ≥600 mg/kg bw/day.