Diethoxy(methyl)silane

Endpoint summary

Description of key information

Combined repeated dose toxicity study with reproductive/developmental toxicity screening test (RA-A CAS 78 -62 -6, OECD 422, oral, rat): NOAEL systemic = 300 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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 for cross-reference:

read-across source

Positive control:

No

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

Critical effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day (actual dose received)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

no

Relevant for humans:

not specified

Critical effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day (actual dose received)

System:

male reproductive system

Organ:

testes

Treatment related:

yes

Dose response relationship:

no

Relevant for humans:

not specified

Conclusions:

A combined repeated dose toxicity study with a reproductive/developmental toxicity screening test was performed with the source substance diethoxy(dimethyl)silane according to OECD TG 422 and GLP at dose levels of 100, 300 and 1000 mg/kg bw/day. The NOAEL for general systemic toxicity can be established at 300 mg/kg bw/day. General systemic toxicity was based on increased mortality, adversely reduced body weight, food consumption, and histopathology effects to the kidney and testes at the highest dose level. 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:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Hazard assessment is conducted by means of read-across based on a read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose.

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

No data on the repeated dose toxicity of diethoxy(methyl)silane (CAS 2031-62-1) are available. Therefore, the risk assessment was performed based on the available data from the source substance diethoxy(dimethyl)silane (CAS 78-62-6). In accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5 “Grouping of substances and read across” and in accordance with the Read across assessment framework (RAAF, ECHA 2017) read across from the analogue substance has been applied to support the human health hazard assessment of diethoxy(methyl)silane (CAS 2031-62-1). Details on read across justifications can be found in the attached justification in the respective target entry and in the overall justification for grouping of substances attached in IUCLID Section 13.

A key study (combined repeated dose toxicity study with reproductive/developmental toxicity screening test (oral)) with diethoxy(dimethyl)silane (CAS 78-62-6) is available and was performed according to OECD TG 422 and in compliance with GLP (Eurofins, 2018). The test substance was administered daily in graduate doses (100, 300, and 1000 mg/kg bw/day) to 3 groups of test animals per gavage, one dose level per group for a treatment period of up to 54 days, i.e. during 14 days of pre-mating and maximum 14 days of mating in both males and females, during gestation period and up to post-natal day 3 in females. Males were dosed after the mating period until the minimum total dosing period of 28-29 days was completed. Animals of an additional control group were handled identically as the dose groups but received corn oil, the vehicle used in this study.

 

In order to allow a detection of possible delayed occurrence or persistence of or recovery from toxic effects, additional animals in recovery groups were observed for a period of 14 days following the last administration. Animals in the recovery groups were not mated and dosed for 28 days (males) or until the first scheduled euthanasia of dams (females).

 

Treatment-related effects were observed at the high dose in both males and females and included increased mortality associated with renal tubular necrosis, decreased body weight, and decreased food consumption. Hematology and clinical chemistry parameters also showed statistical differences at the high- and mid-dose groups; however, none of the changes observed were considered treatment-related. Statistical changes in hematology endpoints included: increased monocytes in high-dose males and females; increased prothrombin time (PT) in mid-dose males; and decreased mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) in the high-dose males and females from the recovery group. Statistically significant but inconsistent changes also were observed in the clinical chemistry parameters. These nontreatment-related changes included: decreased alkaline phosphatase (AP) in mid-dose males and low- and high-dose females; decreased aspartate-aminotransferase (ASAT) in mid- and high-dose males; and decreased sodium levels in mid-dose males. There were no test item-related effects of toxicological relevance during the weekly detailed clinical observation and in the functional observation battery at the end of the treatment and the recovery period. There were no ophthalmoscopic findings in any of the animals of this study.

 

Changes in organ weights correlating to microscopic findings were recorded in testes, liver and thymus. At the end of the treatment period, a toxicologically relevant effect was noted for testes weight in the high-dose group. Mean weight of testes was moderately and statistically significantly reduced in high-dose males (absolute weight 26% below controls, relative (to body weight) weight 20% below controls. At the end of the recovery period, mean absolute and relative testes weight of high-dose males from the recovery group was slightly and statistically significantly below controls (absolute weight 15% and relative weight 11% below controls).

At the end of the treatment period, slightly and statistically higher mean absolute and relative weight of liver was noted in high-dose males and females (absolute weight 23% above controls, respectively). This was related to microscopically observed hepatocellular hypertrophy. Slight effect on liver weight at the end of the recovery period was not considered as toxicologically relevant due to resolving of microscopic findings after the treatment-free recovery period.

At the end of the treatment and the recovery period, a slight tendency (not statistically significant) towards lower thymus weight was observed in all dose levels for males and females and in high-dose males from the recovery group. Reduced thymus weight at the end of the treatment period was related to thymic atrophy of high-dose males and females at histopathological examination. As the finding resolved after the treatment-free period, slight differences at the end of the recovery period were not considered as toxicologically relevant.

Indicators for systemic toxicity consisted of microscopic findings in the testes and kidneys. In testes of high-dose males, there was a moderate tubular degeneration. The elongated and round spermatids of stages V-VII were mainly affected. More mature spermatids and spermia appeared to be almost unaffected. In some tubules, there were reabsorbed apoptotic bodies or Sertoli cell vacuolation. In the epididymides, only a minimal severity of cellular detritus (shedded epitehlia and/or pyknotic sperm cells) was recorded in most high-dose males. After the recovery period, the findings were still present. However, even a partial recovery cannot be judged since the recovery time was much too short for recovery. The sperm cycle in rats takes between 56-58 days.

In kidneys, the severity of tubular hyaline inclusions increased in high-dose males. Furthermore, in both decedent females, there was tubular cell necrosis. This finding affected mainly the distal tubules. It may be considered that these hyaline inclusions represent α2-microglobulin. However, in both decedent females, there was an abnormal color surface of the kidneys associated with moderate tubular cell necrosis. Therefore, a primary renal affection is likely. Under immunohistochemistry evaluation, there was no increase in the α2-microglobulin contents in tubular cells. Therefore, it is considered that the hyaline inclusions in the kidneys represent the test item or a metabolite thereof. The finding was no longer present after the recovery period.

In the liver of most mid- and high-dose animals, there was a minor severity of hepatocellular hypertrophy. In the decedent female no. 91, there was in addition a multifocal moderate necrosis that may be considered to be of agonal nature. No further hepatic lesion was recorded. It is considered therefore, that the hepatocellular hypertrophy is of adaptive nature. Furthermore, the finding resolved after the treatment-free period.

Other findings were related to the vehicle (aspiration and related alveolar macrophages in controls and high dose animals, but also single cases of alveolar/bronchiolar hyperplasia (peribronchiolar) and interstitial, granulomatous inflammation), or were stress-related. The latter consisted of ulceration in the glandular stomach and squamous hyperplasia at the limiting ridge of the forestomach; lymphoid atrophy of the spleen and lymph node; diffuse hypertrophy of the zona fasciculata in the adrenal cortex of two high-dose females; bone marrow atrophy in high-dose females, and an increased atrophy of the thymus in both sexes of the high-dose group. In one surviving and one decedent female of the high-dose group, there were inflammatory/degenerative lesions in the forestomach (ulceration and/or squamous hyperplasia and/or inflammation in the forestomach. These findings may be considered stress-related too.

No adverse effects of diethoxy(dimethyl)silane were found at the lower dose levels tested. Based on mortality and histopathology findings in the kidneys and testes in the high-dose group the NOAEL for general systemic toxicity was 300 mg/kg body weight/day.

Taking into consideration the above results generated from the structurally analogue substance the target substance is expected to show similar toxicity after repeated exposure.

Justification for classification or non-classification

Based on the information from an adequate read-across substance, it is concluded that the available information on repeated dose toxicity does not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and is therefore conclusive but not sufficient for classification.