Registration Dossier

Administrative data

Description of key information

There are no repeated dose toxicity data on (3-chloropropyl)dimethoxymethylsilane or its hydrolysis product, (3-chloropropyl)methylsilanediol, so good quality data for the related substance 3-chloropropyltrimethoxysilane (CAS 2530-87-2) have been used to assess the general systemic toxicity of (3-chloropropyl)dimethoxymethylsilane.
In a 90-day inhalation study (DCC, 1993) in rats, conducted in accordance with OECD 413, the NOAEC for 3-chloropropyltrimethoxysilane was determined to be ≥100 ppm (813 mg/m3).
There are no data for the oral and dermal routes.

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:
no adverse effect observed
Dose descriptor:
NOAEC
813 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
813 mg/m³
Study duration:
subchronic
Species:
rat

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 toxicity data on (3-chloropropyl)dimethoxymethylsilane or its hydrolysis product, (3-chloropropyl)methylsilanediol, so good quality data for the related substance 3-chloropropyltrimethoxysilane (CAS 2530-87-2) have been used to assess the general systemic toxicity of (3-chloropropyl)dimethoxymethylsilane.

There are several reliability score 1 studies for repeated inhalation of 3-chloropropyltrimethoxysilane. The 90-day study was selected as the key study as it tested over the longest duration.

In the key study, microscopic examinations did not reveal any adverse findings in females exposed to 0.5 or 5 ppm of the test material. Eight of ten 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 ten 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 histopathologic effects were observed in the 100 ppm group animals. Increased incidence of hyperplasia of the urinary bladder epithelium was noted in both sexes of this group.

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. There is no evidence for genotoxicity of trimethoxy(3-chloropropyl)silane. Therefore it is highly unlikely that the minimal/mild proliferative changes of the bladder are caused by a urinary bladder genotoxic carcinogen. Based on the fact that the hyperplasia of the bladder was mild /minimal and associated with a minimal inflammation (cystitis) it can presumed that if the stimulus for the inflammation is removed the hyperplasia will resolve within a matter of weeks and the urinary bladder will return to a normal histologic appearance. A minimal/mild reversible effect is not adverse. Therefore the NOAEC is ≥100 ppm (≥813 mg/m3).

An additional dose group at 200 ppm was used for a micronucleus assay, reported in Section 5.7.

Hyperplasia was not observed in the second supporting repeated dose toxicity study, an OECD 422 study (RCC, 2005) on 3-chloropropyltrimethoxysilane, in which animals were exposed for about 28 days to concentrations up to 100 ppm.

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-chloropropyl)dimethoxymethylsilane is evaluated point by point.

Read-across hypothesis

Read-across is based on the presence of a common functional group (3-chloropropyl) 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 two substances are structurally similar, with the replacement of a methyl group in the registered substance with an additional methoxy group in the read-across substance.

Analogue approach justification

(a) Structural similarity

The registered substance and the read-across substance are members of a small analogue group containing chloroalkyl functional groups. Read-across for mammalian toxicology is performed between members of the group which contain a (3-chloropropyl) 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 a 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

18171-19-2

2530 -87 -2

Chemical Name

(3-chloropropyl)dimethoxymethylsilane

3-chloropropyltrimethoxysilane

Si hydrolysis product

(3-chloropropyl) methylsilanediol,

(3-chloropropyl) silanetriol

Molecular weight

182.72

198.72

log Kow (parent)

2.1

2.0

log Kow (silanol hydrolysis product)

0.8

-1.1

Water sol (parent)

370 mg/l

1100 mg/l

Water sol (silanol hydrolysis product))

6.0E+04 mg/l

1E+06 mg/l

Vapour pressure (parent)

52

52 Pa

Hydrolysis t1/2at pH 7 and 25°C

1.3 hours

0.88 hours

Hydrolysis t1/2at pH 7 and 37.5°C

29 minutes

19 minutes

 

The read-across substance, 3-chloropropyltrimethoxysilane hydrolyses rapidly at pH 7 and 20-25 °C with a measured half-life of 0.88 hours, generating 3-chloropropylsilanetriol and three moles of methanol.

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(XºC) = DT50(T) x e(0.08. (T-X))

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

Therefore, at 37.5ºC and pH 7 (relevant for conditions following inhalation exposure, the route of available test data), the hydrolysis half-life is approximately 19 minutes.

Similarly, the predicted hydrolysis half-life of the registered substance at 37.5ºC and pH 7 is approximately 29 minutes.

(c) Toxicokinetics

The read-across substance, (3-chloropropyl)trimethoxysilane has a measured log Kow value of 2.0, while the registered substance has a predicted log Kow value of 2.1. Both are therefore favourable for absorption across the respiratory tract.

Once systemic uptake of (3-chloropropyl)trimethoxysilane has occurred, the substance will hydrolyse relatively quickly (half-life predicted to be around 19 minutes) therefore distribution to tissues will be for a mixture of parent and hydrolysis product. Likewise, with a predicted half-life of 28 minutes, systemic availability for (3-chloropropyl)dimethoxymethylsilane is also a mixture of parent and hydrolysis product. 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.

As stated above, the main route of excretion will be via urine. This is consistent with the observed effects on the urinary bladder which drive the NOEL for repeated inhalation exposure.

(d) Acute toxicity

No acute inhalation toxicity data are available for either registered substance or the read-across substance. Acute oral toxicity studies with both 3-chloropropyltrimethoxysilane and 3-chloropropyltriethoxysilane report LD50 >2000 mg/kg bw in the rat. Acute oral toxicity data for the registration substance reported an LD50 value in the range 200-2000 mg/kg bw, whereas another similar substance (3-chloropropyl)diethoxymethylsilane, CAS 13501-76-3)) had LD50(rat) >2000 mg/kg bw respectively. All available dermal toxicity studies (trimethoxy, triethoxy and diethoxymethyl analogues) reported LD50(rat) >2000 mg/kg bw, with no clinical signs or adverse necropsy findings.

Although the registration substance appears to meet different criteria for acute oral toxicity classification purposes compared to the other analogous substances, when mortality data and clinical signs of toxicity in these studies are considered, the apparent differences are less significant. The available results are discussed in more detail in a supporting report attached to Section 13 of the IUCLID5 dossier (PFA, 2013s).

(e) Methanol

The repeated dose toxicity of the non-silanol hydrolysis product, methanol, 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 2004) are reported here to support read-across arguments.

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, 13000 mg/m3 in rats.

Methanol 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-chloropropyl)trimethoxysilane are not attributable to the non-silanol hydrolysis product, methanol.

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-chloropropyl)trimethoxysilane.


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

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

Justification for classification or non-classification

Based on the fact that the urinary bladder effects observed in the read across data were minimal and are expected to be reversible,

(3-chloropropyl)dimethoxymethylsilane is not classified for specific target organ toxicity following repeated exposures according to Regulation (EC) No 1272/2008.