Registration Dossier

Administrative data

Description of key information

Oral: no data available
Inhalation (OECD 413, RA from CAS 2530-87-2, rat): NOAEC=810.32 mg/m³
Dermal: no data available

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

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Remarks:
equivalent to 1627 mg/m³
Sex:
male/female
Basis for effect level:
other: no adverse effects observed up to the highest dose tested
Remarks on result:
other: 90-day study
Critical effects observed:
no

In addition to the 90 -day study a screening study according to OECD 422 is available as well.

Exposure to the source substance (3-Chloropropyl)trimethoxysilane up to and including the high concentration of 100 ppm did not result in any signs of general toxicity of the test item. Based on these results of the OECD 422 the NOEC (no observed effect concentration) was established as 100 ppm (nominal concentration, corresponding to 99.7 ppm mean analytical concentration and equivalent to 810.32 mg/m³).

Conclusions:
In a 90-day inhalation study (RL1) conducted according to OECD 413 and GLP, the NOAEC for male and female rats was reported to be ≥100 ppm for the source substance 2530-87-2. In addition, a screening repeated dose toxicity study with ... according to OECD 422 and GLP the NOAEC for male and female rats was reported to be ≥100 ppm. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in repeated dose toxicity potential.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
806 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1) and consistent studies, from a reference substance with similar structure and intrinsic properties. Read-across is justified based on similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Remarks:
equivalent to 1627 mg/m³
Sex:
male/female
Basis for effect level:
other: no adverse effects observed up to the highest dose tested
Remarks on result:
other: 90-day study
Critical effects observed:
no

In addition to the 90 -day study a screening study according to OECD 422 is available as well.

Exposure to the source substance (3-Chloropropyl)trimethoxysilane up to and including the high concentration of 100 ppm did not result in any signs of general toxicity of the test item. Based on these results of the OECD 422 the NOEC (no observed effect concentration) was established as 100 ppm (nominal concentration, corresponding to 99.7 ppm mean analytical concentration and equivalent to 810.32 mg/m³).

Conclusions:
In a 90-day inhalation study (RL1) conducted according to OECD 413 and GLP, the NOAEC for male and female rats was reported to be ≥100 ppm for the source substance 2530-87-2. In addition, a screening repeated dose toxicity study with ... according to OECD 422 and GLP the NOAEC for male and female rats was reported to be ≥100 ppm. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in repeated dose toxicity potential.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
806 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1) and consistent studies, from a reference substance with similar structure and intrinsic properties. Read-across is justified based on similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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 studies available for the registered substance (chloromethyl)triethoxysilane (CAS 15267-95-5). However, reliable data are available for the structural analogue substance (3-chloropropyl)trimethoxysilane (CAS 2530-87-2). The read-across is justified as follows:

 

 

Repeated dose toxicity: inhalation

In the available key study (Dow Corning Corporation, 1993), conducted according to OECD 413 and in compliance with GLP, groups of 10 Sprague-Dawley rats per sex were exposed to the test item (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) in a whole-body inhalation system at target concentrations of 0.5, 5, and 100 ppm (corresponding to 0.5, 5, and 99 ppm actual overall mean exposure concentrations) for 6 hours/day, 5 days/week. After 13 weeks of exposure, rats were sacrificed and examined for changes in blood, serum chemistry, urine, organ weights and gross and histopathology. At 24 and 48 hours post-exposure, bone marrow was collected from the femur of 5 animals in all groups for a micronucleus assay. An additional group of ten male and ten female rats exposed to a target concentration of 200 ppm (corresponding to 189 ppm actual overall mean exposure concentration) were used for the micronucleus assay only, performed on this group at 24 and 48 hours post-exposure.

Microscopic examinations at study termination 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 100 ppm group animals. Increased incidence of hyperplasia of the urinary bladder epithelium was noted in both sexes of this group: two males and two females showed minimal hyperplasia, two males and 4 females showed mild hyperplasia. None of the animals showed moderate or marked hyperplasia. The minimal and mild hyperplasia was associated in all animals with a minimal cystitis. No clinical symptoms or change of urine parameter were associated with these findings. The epithelium of the normal urinary bladder of rats consists of three cell layers. Lesions may be classified as mild hyperplasia when the epithelium averages four cell layers in thickness, as moderate hyperplasia when it averages five to six cell layers, and marked hyperplasia when it averages seven or more cell layers.

According to these criteria for hyperplasia a differentiation between minimal and mild hyperplasia is not possible. Maybe minimal means in the 90 days study that the pathologists were not convinced and it appeared that there would be sometimes four cell layers.

Furthermore, it is not mentioned in the study whether the urinary bladder of the rats was inflated to its normal size or slightly larger with a fixative before microscopical examination. Microscopic examination of urinary bladders which have not been inflated may lead to a misdiagnosis of hyperplasia, due to the infoldings of the urinary bladder. Without inflation of the urinary bladder objective evaluation of minimal/mild hyperplasia is difficult. This eventually could explain why in the supporting study (conducted according to OECD 422) where animals were exposed only 28 days to substance (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) no hyperplasia of the urinary bladder was reported at the same exposure concentration (RCC, 2005).

No recovery group was included in the 90 day study. Without a recovery group we have no clarity concerning the question of reversibility of the effects. If the hyperplasia is not reversible these proliferative changes could indicate a urinary bladder carcinogen. However, the overall evaluation of the genotoxicity data does not support this mechanism. Furthermore, the hyperplasia was in all cases associated with a minimal inflammation. Inflammatory response of the bladder (cystitis) associated with the administration of xenobiotics is characterized by the presence of inflammatory cells in the epithelial wall of the bladder. This indicates that the applied substance in this study caused a minimal injury of the bladder that caused minimal inflammation.

Most likely the urothelium responded with an increase in mitosis, resulting in a minimal /mild hyperplasia. If the inflammatory stimulus (Xenobiotic) is removed, the hyperplastic changes are expected to regress and the urinary bladder returns to normal histologic appearance. Therefore, the mild/minimal hyperplastic effects are not considered as adverse and the NOAEC was set at 100 ppm (nominal concentration, corresponding to an actual overall mean exposure concentration of 99 ppm).

 

A supporting study is available for the structural analogue substance (3 -chloropropyl)trimethoxysilane (CAS 2530 -87 -2). The study was conducted according to OECD 422, and in compliance with GLP (RCC, 2005). Groups of 10 Sprague-Dawley rats per sex per dose were exposed to the vapour in a whole body inhalation system at doses of 5, 25 and 100 ppm (corresponding to 5.02, 25.44, and 99.7 ppm mean analytical concentration). Untreated animals served as controls. Treatment was carried out for 6 hours daily to male rats for 28 days and to female rats throughout the 14-day pre-pairing, pairing and gestation period until the individual day 19 post coitum. During the pairing period, rats were housed overnight with one male and one female in Makrolon pairing cages. The female was placed with the same male until mating occurred or two weeks elapsed. Animals were observed for mortalities and clinical signs, and detailed clinical observations were performed once per week. A Functional Observational battery (modified Irwin screen test) was performed once during the test (males: shortly before sacrifice; females: on day 3 post-partum). Body weights and food consumption was recorded. Parental generation males were sacrificed after they had been treated for 28 days, parental generation females were sacrificed on day 4 post-partum. A complete gross necropsy was performed on all adult animals. The litters were examined for litter size, live birth, stillbirth and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually on day 0, 1 and 4 post-partum. The pups were observed daily for survival and behavioural abnormalities in nesting and nursing. Dead pups and pups killed on day 4 post-partum were examined macroscopically. No test item-related mortalities or clinical signs that were attributable to exposure to the test item were noted throughout the study. Neither food consumption nor body weight development were affected by exposure to the test item at any concentration. None of the parameters under investigation during the functional observational battery was considered to be affected by exposure to the test item. During necropsy of parent animals no test item-related findings were noted. Mean absolute organ weights as well as organ/body weight ratios and organ/brain weight ratios were not affected by exposure to the test item. There were no findings which distinguished test item-treated animals from controls. Based on the absence of any findings the NOAEC was set at 100 ppm (nominal concentration, corresponding to 99.7 ppm mean analytical concentration).

 

Both available studies result in a NOAEC of 100 ppm nominal vapour concentration. Since the key study was conducted with the longest study duration, this result will be used for the hazard assessment. Thus, a NOAEC of 99 ppm as actual overall mean exposure concentration will be deduced, corresponding to 806 mg/m³.


Justification for classification or non-classification

The available data are reliable and suitable for classification. Based on these data, classification for toxicity after repeated exposure according to EC/1272/2008 is not warranted.