Registration Dossier

Administrative data

Description of key information

There are no measured repeated dose toxicity data on (3-chloropropyl)diethoxymethylsilane, therefore, the structural analogue substance (3-chloropropyl)trimethoxysilane (CAS: 2530-87-2) has been used to assess the systemic toxicity potential of (3-chloropropyl)diethoxymethylsilane (MW ratio: target/source = 1.06).
Repeated dose toxicity:
Inhalation, subchronic:
according to OECD TG 413 in rats: NOAEC = 804.6 mg/m³ (99.7 ppm)
MW corrected NOAEC = 853.38 mg/m³
Inhalation, subacute:
according to OECD TG 422 in rats: NOAEC = ≥804.6 mg/m³ (99.7 ppm)
MW corrected NOAEC = ≥ 853.38 mg/m³

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
853.38 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study was carried out in accordance with an appropriate OECD test guideline and in compliance with GLP and is therefore considered to be reliability 1. Read-across of the study itself is considered to be reliability 2.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
853.38 mg/m³
Quality of whole database:
The study was carried out in accordance with an appropriate OECD test guideline and in compliance with GLP and is therefore considered to be reliability 1. Read-across of the study itself is considered to be reliability 2.

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

Mode of Action Analysis / Human Relevance Framework

Additional information

Studies were chosen as key when the available study was of relevance and of sufficient quality for classification, labelling and for risk assessment.

 

No adequate repeated-dose toxicity data are available for (3-chloropropyl)diethoxymethylsilane, therefore good quality inhalation data for the analogue substance (3-chloropropyl)trimethoxysilane (CAS: 2530-87-2) have been read-across. Both substances hydrolyse to produce structurally similar silanol hydrolysis products, (3-chloropropyl)methylsilanediol and (3-chloropropyl)silanetriol, with the other hydrolysis products being ethanol and methanol respectively. Since neither methanol or ethanol would contribute to general toxicity effects in rodents at the dose levels tested, it is considered that the observed toxicological effects are due to the action of the (3-chloropropyl)silyl moiety, although the specific toxicological mechanism cannot be determined from the available information. Both substances have log Kow in the range that is favourable for absorption across the respiratory tract (ethoxy log kow= 4.2 and methoxy log kow= 0.56). No acute inhalation toxicity data are available for either substance, but acute oral and dermal LD50 values for both substances in rats are > 2000 mg/kg. It is therefore considered valid to read-across the results for the trimethoxy analogue to fill data gaps for the registered substance. Additional information is given in a supporting report (PFA, 2013s)attached in Section 13 of the IUCLID 5 dossier. The molecular weight difference between target and source chemical is 210.77/198.72 = 1.06.

A key 90- day whole-body inhalation (vapour) study in rats, which was conducted in accordance with OECD TG 413 with the structural analogue substance (3 -chloropropyl)trimethoxysilane is available. Microscopic examinations did not reveal any adverse findings in females exposed to 0.5 or 5 ppm. Eight of 10 male animals in the 0.5 ppm exposure group were reported as normal. The two remaining male animals exhibited minimal chronic cystitis of the urinary bladder. Nine of 10 male animals were reported as normal in the 5.0 ppm exposure group. The remaining male animals exhibited minimal chronic cystitis of the urinary bladder. Treatment-related histopathological effects were observed in the 99.7 ppm (804.6 mg/m³) group animals. Increased incidence of hyperplasia of the urinary bladder epithelium was noted in both sexes of this group (Dow Corning Corporation, 1993).

It is not known whether the urinary bladder was inflated by a fixative before microscopic examination. Without inflation of the urinary bladder the relevance of the hyperplasia is questionable. Based on the fact that the hyperplasia of the bladder was mild /minimal and in some cases associated with a minimal inflammation (cystitis) it can be presumed that if the stimulus for the hyperplastic changes is removed the hyperplasia will resolve within a matter of weeks and the urinary bladder will return to a normal histological appearance. A minimal/mild change of the urinary bladder not associated with any clinical symptoms or changes in urine parameters does not reflect a marked organ dysfunction. Therefore, the mild/minimal hyperplastic effects are not considered as adverse and the NOAEC is 99.7 ppm (804.6mg/m³).The NOAEC for the target chemical is 853.38 mg/m³.

A supporting 28-day whole body inhalation (vapour) study in rats, which was conducted in accordance with OECD TG 422 with the structural analogue substance(3 -chloropropyl)trimethoxysilane is also available. Rats were exposed up to and including the highest concentration of 99.7 ppm (804.6 mg/m³). There were no signs of general toxicity in the study and therefore based on these results the NOAEC was established to be ≥ 99.7 ppm (≥804.6 mg/m³). The NOAEC for the target chemical is ≥ 853.38 mg/m³ (RCC, 2005).

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 relevant properties are structural similarity as well as physical-chemical and basic toxicological parameters in the same range. In the following paragraphs the read-across approach for (3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3) is evaluated point by point.

Read-across hypothesis

After inhalation exposure, both (3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3) and (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) are supposed to hydrolyse rapidly to similar silanol hydrolysis products, namely (3-chloropropyl)methylsilanediol and (3-chloropropyl)silanetriol. The non-silanol hydrolysis products, ethanol and methanol, are not expected to contribute to any adverse effects for systemic toxicity at the relevant dose levels. This is discussed further below.

The half-lives of (3-chloropropyl)diethoxymethylsilaneat 25°C are3.8 h at pH 7 (see Section 5.1.2).As the hydrolysis reaction may be acid or base catalysed, the rate of reaction is expected to be slowest at pH 7 and increases as the pH is raised or lowered.

Reaction rate increases with temperature therefore hydrolysis will be faster at physiologically relevant temperatures compared to standard laboratory conditions. Under ideal conditions, hydrolysis rate can be recalculated according to the equation:

DT50(X °C) = DT50(T) x e(0.08 (T-X))

Where T = temperature for which data are available and X = target temperature.

Thus, for (3-chloropropyl)diethoxymethylsilane the hydrolysis half-life at 37.5°C and pH 7 (relevant for lungs and blood) is 2.3 hours and 5 s at 37.5°C and pH 2 (relevant for stomach).

For the read-across substance, (3-chloropropyl)trimethoxysilane, the corresponding half-lives are 53 min (20°C, pH 7), 17 min (37°C, pH 7), and 5 s (37.5°C, pH 2), respectively.

Analogue approach justification

(a) Structural similarity

Both the registration and read-across substances are structurally similar, containing a 3-chloropropyl moiety and 2-3 alkoxy (-OX) groups. The two substances hydrolyse rapidly to produce similar hydrolysis products(3-chloropropyl)methylsilanediol and (3-chloropropyl)silanetriol.

These substances are part of an analogue group of chloroalkoxysilanes. The read-across substance was selected as the most appropriate based on chemical structure.

Further information is given in a supporting report attached to Section 13 of the IUCLID5 dossier (PFA, 2013s).

 

(b) Similar physicochemical characteristics

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

CAS Number

13501-76-3

2530-87-2

Chemical Name

(3-chloropropyl)diethoxymethylsilane

(3-chloropropyl)trimethoxysilane

Si hydrolysis product

(3-chloropropyl)methylsilanediol

(3-chloropropyl)silanetriol

Molecular weight (parent substance)

210.77 g/mol

198.72 g/mol

log Kow (parent)

4.2

2.0

log Kow (silanol hydrolysis product)

0.8

-1.1

Water sol (parent)

36 mg/l

1100 mg/l

Water sol (silanol hydrolysis product))

60 000  mg/l

1 000 000 mg/l

Vapour pressure (parent)

6.8 Pa

52 Pa

Hydrolysis t1/2 at pH 7 and 25°C

3.8 hours

53 min

Hydrolysis t1/2 at pH 2 and 37.5°C

5 s

5 s

Hydrolysis t1/2 at pH 7 and 37°C

2.3 hours

17 min

(c) Similar toxicokinetics

(3-chloropropyl)diethoxymethylsilane and (3-chloropropyl)trimethoxysilane have similar vapour pressures, indicating that exposure as a vapour is possible. The predicted water solubility and the log Kow indicate that absorption from the respiratory tract epithelium by passive diffusion is possible.

 

 (d) Similar acute toxicity

A key acute oral limit test which was conducted in compliance with GLP and according to the now deleted OECD TG 401 is available on (3-chloropropyl)diethoxymethylsilane. Two out of five males died when dosed at 2000 mg/kg bw and the macroscopic examination of the two perished animals showed the most severe lesions in the stomach and the intestine. The mucosa of these tissues showed hyperaemia and haemorrhages. No macroscopic abnormalities were observed in animals killed on day 14. All animals showed severe clinical symptoms in the first six hours after treatment with the test substance. The symptoms seen were padding movements, gait abnormality; decreased activity and squatting position. 24 and 48 hours after treatment most of the animals showed still the described clinical signs. Only one male and one female showed these signs 72 hours after treatment with the test substance. Milder clinical signs like piloerection were observed until day 7. After 7 days until the end of the observation period there were no more signs of systemic reaction to treatment. The LD50 to rats of (3-Chloropropyl)diethoxymethylsilane was found to be > 2000 mg/kg bw.

A key acute dermal toxicity study which was conducted in compliance with GLP and according to OECD TG 402 is available on (3-chloropropyl)diethoxymethylsilane, there was no mortality or any systemic effects seen at 2000 mg/kg bw (24 hour exposure) (LD50> 2000 mg/kg bw). 

In an acute oral toxicity study with(3-chloropropyl)trimethoxysilanethe LD50 (rat) was determined to be >2000 mg/kg day. Three older studies support this conclusion, although much higher dose levels were tested than required by current guidelines.In addition theLD50 (rat) was determined to be >2000 mg/kg after dermal exposure. Two older studies support this conclusion, although much higher dose levels were tested than required by current guidelines.

In conclusion, both substances have low potential for acute toxicity.

e) Discussion of repeated systemic toxicity of the non-silanol hydrolysis products

The repeated dose toxicity of the non-silanol hydrolysis products, methanol and 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 2004a and OECD 2004b) are reported here to support read-across arguments.

Methanol

The majority of repeated dose toxicity information for methanol comes from inhalation studies in rats and monkeys.

Generally effects noted include nasal irritation in rats (but not monkeys), CNS depression, effects on body and organ weight and in some cases effects on clinical chemistry parameters. Studies were conducted up to significant doses and generally effects when noted, are considered adverse only at upper end of the dose ranges studied e.g 650 mg/m³ in monkeys, 13 000 mg/m³ in rats.

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

Ethanol

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

In conclusion, the oral NOAEL in rats for methanol is greater than the dose that is expected to be generated from hydrolysis of (3-chloropropyl)trimethoxysilane in the lung. Similarly, ethanol generated from hydrolysis of (3-chloropropyl)diethoxymethylsilane would not be expected to contribute to the observed toxicity in rats at the dose levels used.

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Reliable data are available for the inhalation route.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The key study was selected for assessment.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The key study was selected for assessment.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Reliable data are available for the inhalation route.

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: urinary bladder

Justification for classification or non-classification

Based on the fact that the urinary bladder effects were minimal and are expected to be reversible for the structural analogue substance 3-chloropropyltrimethoxysilane (CAS: 2530-87-2), there is no proposal to classify for specific target organ effects following repeated exposures according to EC Regulation 1272/2008 for the registered substance.