Registration Dossier

Administrative data

Description of key information

There are no repeated dose studies on 3-(diethoxymethylsilyl) propylamine.
The key study is a 90-day oral study (WIL, 2001) in which the related substance, 3-aminopropyltriethoxysilane (919-30-2), was administered by gavage to rats. Following administration of the highest dose of 600 mg/kg bw/day, mortality, clinical observations and liver effects were evident. No such effects were observed at the next dose of 200 mg/kg bw/day, which was concluded to be the NOAEL for this study. This NOAEL was in agreement with the NOAEL derived from the oral 28-day study (Shin-Etsu, 2003) in which the hydrolysis product of 3-(diethoxymethylsilyl) propylamine, 3-aminopropylmethyldihydroxysilane was tested. In this study there were no adverse effects up to a maximum dose of 200 mg/kg bw/day in rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no repeated dose studies for 3-(diethoxymethylsilyl)propylamine; however, there is an oral 28-day study available for the hydrolysis product,3-(dihydroxymethylsilyl)propylamine. The parent substance is rapidly hydrolysed in contact with moisture, and in doing so causes corrosive effects. It is therefore appropriate to use this result on the hydrolysis product. The other hydrolysis product, ethanol, is not expected to contribute to the systemic toxicity of the parent substance at this dose as the lowest available NOAEL for ethanol is 2400 mg/kg bw/day.

There are no studies available that tested for a longer duration for the parent substance, 3-(diethoxymethylsilyl)propylamine, or its hydrolysis product. However, in a well reported 90-day oral study, on the related substance 3-aminopropyltriethoxysilane (CAS 919-30-2), conducted in the main according to the current guideline and in accordance with GLP, a NOAEL value of 200 mg/kg bw/day in male and female rats was derived.

READ-ACROSS JUSTIFICATION

To reduce animal testing REACH recommends to make use of a read-across approach where appropriate based on the high accordance in properties relevant for the specific endpoint. In the case of repeated dose toxicity and reproductive toxicity relevant properties are structural similarity as well as physicochemical and basic toxicological parameters in the same range. In the following paragraphs the read-across approach for 3-(diethoxymethylsilyl)propylamine is evaluated point by point.

Read-across hypothesis

Read-across is based on the presence of a common functional group (3-aminopropyl) in the registered and read-across substances, and the rapid hydrolysis of both substances to produce silanols containing this group. Read-across substances have been selected as the most appropriate based on chemical structure for which data were available.

The read-across substance is believed to be predictive for the toxicological profile of the registered substance as physical chemical parameters indicate similar toxicokinetic behaviour and the fact that one methoxy group in the read-across substance is replaced by a toxicologically inert methyl group in the registration substance and thus reducing reactivity of the parent substance. Rapid excretion via urine can be expected for both substances.

Analogue approach justification

(a) Structural similarity

The registered substance and the read-across substance are members of an analogue group containing amine functional groups (see Section 1.4). Read-across for mammalian toxicology is performed between members of the group which contain a 3-(aminopropyl) group.

The registered substance is a dialkoxysilane, and thus hydrolyses to form a methylsilanediol, whereas the read-across substance is a trialkoxysilane and thus hydrolyses to form the corresponding silanetriol.

 (b) Similar physicochemical properties

A data matrix is attached in Section 13 of the IUCLID dossier, and the key physicochemical parameters are summarised in the table below:

Key physicochemical properties

CAS Number

3179-76-8

919-30-2

Chemical Name

3-(diethoxymethylsilyl)propylamine

3-aminopropyltriethoxysilane

Si hydrolysis product

3-(dihydroxymethylsilyl)propylamine

3-(trihydroxylsilyl)propylamine

Molecular weight

191.35

221.37

log Kow (parent)

2.5

1.7

log Kow (silanol hydrolysis product)

-0.9

-2.9

Water sol (parent)

5900 mg/l

5400 mg/l

Water sol (silanol hydrolysis product))

1E+06 mg/l

1E+06 mg/l

Vapour pressure (parent)

6.9 Pa

2 Pa

Hydrolysis t1/2at pH 7 and 25°C

6 hours

8.5 hours

Hydrolysis t1/2at pH 7 and 37.5°C

2.2 hours

3.1 hours

Hydrolysis t1/2at pH 2 and 37.5°C

ca. 5 seconds

ca. 5 seconds

 

 (c) Toxicokinetics

The read-across substance, 3-aminopropyltriethoxysilane has a predicted log Kow value of 1.7, while the registered substance has a predicted log Kow value of 2.5. Both are therefore favourable for absorption across the respiratory tract.

Once systemic uptake of 3-aminopropyltriethoxysilane has occurred following inhalation exposure, the substance will hydrolyse moderately quickly (half-life predicted to be around 3.1 hours) therefore distribution to tissues will be for a mixture of parent and hydrolysis product. Likewise, with a predicted half-life of 2.2 hours minutes, systemic availability for the registration susbtance is also a mixture of parent and hydrolysis product following inhalation exposure. Based on the respective log Kow and water solubility values, systemic distribution is most significant for parent substances, whereas the silanol hydrolysis products will be rapidly excreted in urine.

Following oral exposure, both substances hydrolyse very quickly to the corresponding silanols, with a half-life of approximately 5 seconds (see Section 5.2.1).Compared to the typical gastric emptying half-life for liquids in the order of 11 - 30 minutes (RIVM,http://www.rivm.nl/interspeciesinfo/intra/human/stomach/db_human_stomach.jsp), many hydrolysis half-lives would therefore have occurred and absorption in the intestine would almost exclusively relate to hydrolysis products in both cases. Rapid excretion of hydrolysis products in urine will occur.

 (d) Acute toxicity

Acute oral and dermal toxicity studies are available for both the registered and read-across substances. In addition, an acute inhalation study is available for the read-across substance. Both substances are classified as corrosive based onin vivodata.

In the key acute oral toxicity study for the registered substance (Hűls AG, 1989), clinical signs included adoption of a prone or squatting position, ruffled fur, altered mobility, diarrhoea or nasal bleeding. One male and one female died between 5 minutes and 48 hours after treatment at 2000 mg/kg bw. All survivors were symptom-free after 48 hours. Post mortem revealed hyperaemia of the gastric mucosa. The LD50was >2000 mg/kg bw.

In the key acute oral toxicity study for 3-aminopropyltriethoxysilane (Myers and Christopher, 1989) the overall LD50was 1490 mg/kg bw (1.57 ml/kg) for females and 2690 mg/kg bw (2.83 ml/kg) for males; no overall LD50was reported although on the basis of these data the substance is classified as acutely harmful by the oral route. There were mortalities at 1.41 (1/5) and 2 ml/kg bw (5/5) in females and at 4 (4/5) and 2 ml/kg bw (1/5) in males. At the 2 ml/kg bw dose level clinical signs includedsluggishness, unkempt appearance, periurogenital brown staining, red encrusted fur around nose and eyes, closed eyelids, emaciation and diarrhoea. Survivors recovered at 5 to 9 days. Post mortem findings for animals that died indicated signs of corrosive effects; there were no remarkable findings in animals surviving to the end of the observation period.

The key dermal study for the registered substance (Mellon Institute, 1956), reported an LD50of 2.52 ml/kg bw (2293 mg/kg bw). Animals treated at 4.0 ml/kg bw died within four days of exposure; one animal in the 2.0 ml/kg bw group died on day three after exposure. Corrosive effects to the skin were apparent.

The key acute dermal study with the read-across substance (Myers and Christopher, 1989) included dose levels far in excess of current guideline limit doses. The overall LD50was 4076 mg/kg bw (4.29 ml/kg bw). There were no deaths at dose levels of 1.0 and 2.0 ml/lg bw although there were mortalities at the higher doses of 4.0 and 8.0 ml/kg. Clinical signs at all dose levels included sluggishness, diaorrhea and bleeding from the rectal area. Post mortem findings were indicative of corrosive effects.

No reliable acute inhalation data are available for the registered substance. For the read-across substance no overt toxicity was detected in rats of either sex exposed (whole body, 6 h) to the neat substantially saturated vapour (BRRC, 1982). Mean measured concentrations of the test material were 5 and 16 ppm (around 45 and 144 mg/m3) for males and females, respectively

These studies indicate that, although the acute toxicity classification of the two substances differ, they are of similar toxicity and show a comparable pattern of systemic effects following uptake, this supporting the read-across of long-term data. With respect to the oral route, the read-across substance represents the worst-case in terms of observed lethality.

Additional data for other members of the analogue group are described in a supporting report attached to Section 13 of the IUCLID dossier (PFA, 2013v).

 (e) Ethanol

The repeated dose toxicity of the non-silanol hydrolysis product, ethanol, has been extensively studied. It is beyond the scope of this assessment to review all of the available data in detail. However, the key findings from the disseminated REACH dossiers and OECD SIAR reports (OECD 2004b) are reported here to support read-across arguments.

Generally in repeat dose studies in animals with ethanol very large doses are used, and often specific endpoints relating to known effects in humans are the primary focus of such studies. However, adverse effects on the liver have been noted in animals but only at very high doses >8 g/kg/day.

Ethanol is not classified for repeated dose toxicity in Annex VI of Regulation (EC) No 1272/2008.

Conclusion

The observed effects in repeated dose toxicity studies with 3-aminopropyltriethoxysilane are not attributable to the non-silanol hydrolysis product, ethanol.

Based on the similar chemical structure, physicochemical properties and acute toxicity, it is considered valid to read-across existing repeated dose toxicity data for 3-aminopropyltriethoxysilane.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The selected study is the study of longest duration available with an appropriate surrogate test substance. It was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

3-(Diethoxymethylsilyl) propylamine is not classified for effects following repeated dosing according to Regulation (EC) No 1272/2008, based on the available read-across data.