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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

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 reliable repeated dose toxicity data are available for the registered substance or any other members of the analogue group (see Section 1.54). A 90-day repeated dose toxicity study by the oral route with structurally analogous substance, 3-(triethoxysilyl)propanethiol (CAS 14814-09-6) is proposed. The data will be read-across to the registered substance.

Read-across justification

There are no available long-term toxicity data for 3-trimethoxysilylpropane-1-thiol (4420-74-0). Therefore, read-across data will be used to fulfil Annex requirements. This document describes the analogue approach for fulfilling this endpoint by read-across from the source substance, 3-(triethoxysilyl)propanethiol (CAS 14814-09-6), according to the Read-across Assessment Framework (RAAF)[1].

It should be noted that the testing proposals for the planned read-across strategy were submitted to ECHA with the 2013 registration dossier for that substance. A draft decision accepting these test proposals was received on 29 April 2016 (no decision number given). However, as no final decision has been received it has not yet been possible to contract and initiate the studies.

Read-across is proposed in accordance with RAAF Scenario 2: “This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds which have the same type of effect(s). For the REACH information requirement under consideration, the effects obtained in a study conducted with one source substance are used to predict the effects that would be observed in a study with the target substance if it were to be conducted. The same type of effect(s) or absence of effect is predicted. The predicted strength of the effects may be similar or based on a worst case.”

The read-across justification is presented (Table 5.6.2) according to RAAF scenario 2 assessment elements (AE) as outlined in Table B1 of the RAAF1:

Table 5.6.2: RAAF scenario 2 assessment elements (AE) as given in Appendix B (Table B1) of the RAAF1

AE A.1

Characterisation of source substance

AE A.2

Link of structural similarity and differences with the proposed Prediction

AE A.3

Reliability and adequacy of the source study

AE 2.1

Compounds the test organism is exposed to

AE 2.2

Common underlying mechanism, qualitative aspects

AE 2.3

Common underlying mechanism, quantitative aspects

AE 2.4

Exposure to other compounds than to those linked to the prediction

AE 2.5

Occurrence of other effects than covered by the hypothesis and Justification

AE A.4

Bias that influences the prediction

 

AE A.1 Identity and characterisation of the source substance

The source substance,3-trimethoxysilylpropane-1-thiol (4420-74-0, is a member of a structural class of alkoxysilane substances containing a thiol group.3-(Triethoxysilyl)propanethiol(CAS 14814-09-6) has a single silicon atom attached to a thiol group via propane. Three methoxy groups are bound to the silicon atom. The substance hydrolyses rapidly in contact with water to produce 3-(trihydroxysilyl)propanethiol as a silanol hydrolysis product and ethanol as non-silanol hydrolysis product.

The predicted hydrolysis half-lives of the source substance, 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6), are 0.6 h at pH 4, 19 h at pH 7, 0.3 h at pH 9 and 20-25°C (QSAR). At pH 2 and 37.5 ºC (closest to the known conditions of the stomach, pH 1.5 – 3.5 and 37.5 ºC) the calculated hydrolysis half-life of the substance is 8 seconds.

The substance has Log Kow of 2.7 (QSAR), water solubility of 82 mg/l at 20°C (QSAR) and vapour pressure of 1.1 Pa at 25°C (QSAR).

AE A.2 Link of structural similarities and differences with the proposed prediction

The target and source substance have similar physicochemical properties as well as hydrolysis rates (Table 5.6.3). The target and source substances are structurally similar and are members of a structural class of alkoxysilane substances containing a thiol group. The registration substance, 3-(trimethoxysilyl)propane-1-thiol (CAS 4420-74-0), and the read-across substance, 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6), both contain one silicon atom, which is attached to a thiol group via propane.. Three ethoxy groups are bound to the silicon atom in the target substance, whereas three methoxy groups are attached to the silicon atom in the source substance. The target substance and source substance both hydrolyse rapidly to produce the same silanol hydrolysis product, 3-(trihydroxysilyl)propanethiol. The non-silanol hydrolysis products are methanol and ethanol, respectively. The alkoxysilane group can indicate the potential for toxicity by a specific mode of action. The predicted hydrolysis half life of the registered substance, 3-(trimethoxysilyl)propane-1-thiol (CAS 4420-74-0) at pH 2 and 37.5ºC (closest to the known conditions of the stomach, pH 1.5 – 3.5 and 37.5 ºC) was calculated to be approximately 5 seconds, while the predicted hydrolysis half life of the source substance, 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6), was calculated to be 8 seconds at physiological conditions.

Table 5.6.3: Physico-chemical properties

 

Target (registration substance)

Source (read-across substance)

CAS number

4420-74-0

14814-09-6

EC number

224-588-5

238-883-1

Chemical Name

3-(trimethoxysilyl)propane-1-thiol

3-(triethoxysilyl)propane-1-thiol

Chemical name of silanol hydrolysis product

3-(trihydroxysilyl)propanethiol

3-(trihydroxysilyl)propanethiol

Molecular weight
 (gmol-1)

196.34

 

238.42

 

Molecular weight
 (gmol-1) (silicon containing hydrolysis product)

154.26

 

154.26

 

log Kow(parent)

1.7 (QSAR)

2.7 (QSAR)

log Kow(silicon-containing hydrolysis product)

-1.4 (QSAR)

-1.4 (QSAR)

Water solubility (parent)

1.0E+06 mg/l at 20°C (QSAR)

82 mg/l at 20°C (QSAR)

Water solubility (silicon-containing hydrolysis product)

1.0E+06 mg/l (QSAR)

1E+06 mg/l (QSAR)

Hydrolysis at pH 2, 37.5°C

5 seconds

8 seconds

Vapour pressure (parent)

8.1 Pa at 25°C (QSAR)

1.1 Pa at 25°C (QSAR)

Vapour pressure (silicon-containing hydrolysis product)

1.1E-04 Pa at 25°C (QSAR)

1.1E-04 Pa at 25°C (QSAR)

 

AE A.3 Reliability and adequacy of the source study

The proposed 90-day repeated dose toxicity study will be conducted according to OECD Guideline 408 and in compliance with GLP. Rats will be used as test species and the test material will be administered orally.

The proposed prenatal developmental toxicity study will be conducted according to OECD Guideline 414 and in compliance with GLP. Rats will be used as test species and the test material will be administered orally.

AE A.4 Bias that influences the prediction

Data on 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6) will be read-across to the registered substance 3-(trimethoxysilyl)propane-1-thiol (CAS 4420-74-0). The source substance and the target substance have structural similarity and similar physico-chemical properties. They also share common hydrolysis products. Therefore, their toxicological properties are considered to be similar, with identical target organ toxicity effects and developmental toxicity effects. No other data for relevant substances are available.

No repeated dose toxicity data are currently available for substances in this analogue group. A 90-day sub-chronic toxicity study in rats via the oral route has been proposed for 3-(triethoxylsilyl)propanethiol (CAS 14814-09-6) as part of an Annex IX registration dossier in 2013. The need for further testing of this analogue group will be assessed when the results of that study are available. The data will be read-across to the registered substance, 3-(trimethoxysilyl)propane-1-thiol (CAS 4420-74-0).

No reproductive or developmental toxicity studies are currently available for substances in this analogue group. A pre-natal developmental toxicity study in rats via the oral route has been proposed for 3-(triethoxylsilyl)propanethiol (CAS 14814-09-6) as part of an Annex IX registration dossier in 2013. The need for further testing of this analogue group will be assessed when the results of that study are available. The data will be read-across to the registered substance, 3-(trimethoxysilyl)propane-1-thiol (CAS 4420-74-0).

AE A.2.1 Compounds the test organism is exposed to

The source substance as well as the target substance have similar rates of hydrolysis at physiological condition relevant for oral exposure. Both hydrolyse to the same silanol-containing product 3-(trihydroxysilyl)propanethiol, and methanol or ethanol, respectively.

When oral exposure takes place, it is necessary to assume that except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood takes place. Uptake from intestines can be assumed to be possible for all substances that have appreciable solubility in water or lipid. Other mechanisms by which substances can be absorbed in the gastrointestinal tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

Although the molecular weight of 3-(triethoxysilyl)propanethiol (CAS 14814-09-6) (approximately 238) and 3-(trimethoxysilyl)propane-1-thiol (CAS 4420-74-0) (approximately 196) is a little above the favourable range, the substances are water soluble so should oral exposure occur then it is reasonable to assume systemic exposure to 3-(triethoxysilyl)propanethiol will occur also.

For the hydrolysis product, 3-(trihydroxysilyl)propanethiol, oral exposure to humans following hydrolysis in the gastro-intestinal tract or via the environment may be relevant. With a significantly higher solubility and lower molecular weight than the parent, then should oral exposure to 3-(trihydroxysilyl)propanethiol occur then it is reasonable to assume systemic exposure will occur also and to a greater extent than the parent.

Information about the effects of methanol on fertility is limited (OECD, 2004b). Slight increases in sperm abnormalities were noted in a study in mice although the effect on fertility was not investigated. In a rat 2-generation study there were no effects on fertility. In a cynomolgus monkey study no effects were noted.

In rats, foetal NOAELs have been defined up to 5000 ppm after inhaled exposure. A corresponding figure of 1000 ppm has been defined for mice, which are considered to be more sensitive. At higher concentrations litter resorptions and increased incidences of foetal variations, and in some cases, malformations e. g. exencephaly and encephalocele have been noted at 20000 ppm in rats and 5000 ppm in mice (OECD, 2004b).

Ethanol is reported to have an effect on male fertility in some rat studies but not others and where noted generally involve sperm parameters (OECD, 2004a). However, where effects are noted they occur only at high doses.

Rats and mice maintained on liquid diets containing 5 – 10% ethanol for 5 weeks or longer showed some adverse physical and functional effects on the testes. Some indications of toxicity to the foetus, including deaths, growth retardation and increased malformations have been noted in rats and mice given diets in which 15-35% of the calories were derived from ethanol. However, in other studies, no effect on the foetuses were seen in mice and rabbits given drinking water containing up to 15% ethanol, or inhaling up to 20000 ppm ethanol, during pregnancy (OECD, 2004a).

AE A.2.2 and A.2.3 Common underlying mechanism, qualitative and quantitative aspects

Data on 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6) will be read-across to the registered substance 3-(trimethoxysilyl)propane-1-thiol (CAS 4420-74-0). The source substance and the target substance have structural similarity and similar physico-chemical properties. They also share common hydrolysis products. Therefore, their toxicological properties are considered to be similar, with identical target organ toxicity effects and developmental toxicity effects.No deaths were observed in an acute oral toxicity study for the structural analogous substance. The reported LD50value was >2000 mg/kg bw (RTC, 1996).

Acute oral, and dermal toxicity studies in rats are available for the two substances, 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0) and 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6). Key and supporting oral studies for these substances report LD50 values ranging from 893 mg/kg bw for males and 741 mg/kg bw for females to >2000 mg/kg bw. The available dermal studies indicate LD₅₀ values of >2000 mg/kg bw.

3-Trimethoxysilylpropane-1-thiol (CAS 4420-74-0) is classified for acute oral toxicity according to Regulation (EC) No 1272/2008 as Acute Oral Category 4; H302 Harmful if swallowed. No classification is required for acute dermal toxicity.

No classification is required for acute oral or dermal toxicity for the read-across substance, 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6).

The key acute oral toxicity study for the registered substance, 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0), reports an LD₅₀ value of 0.88 mL/kg bw (equivalent to 893 mg/kg bw) in males and 0.73 mL/kg bw (equivalent to 741 mg/kg bw) in females. The study was conducted according to a protocol similar to OECD Test Guideline, but not in compliance with GLP. Doses of 2.0, 1.0, 0.71 and 0.5 ml/kg bw for male rats and 1.0, 0.71, 0.5 and 0.25 ml/kg bw for female rats were administered orally by gavage. Animals were then observed for 14 days. Body weights were determined immediately prior to dosing and on Days 7 and 14. At the end of the observation period all animals surviving were killed and a gross pathological examination performed on each animal. Animals that died were similarly examined. Kidneys and urinary bladder from two males and two females from each exposure group were subjected to a detailed histopathology examination. For males, both of the highest dose, and 4/5 of the 1.0 ml/kg bw groups died within the first day after dosing (one died on Day 2). For females all of the highest dose, and 2/5 of the 0.71 ml/kg bw group died within the first day after dosing. Clinical signs were sluggishness, unsteady gait, lacrimation, yellow or red wetness or stains on the peri urogenital fur, blood in the urine, a red crust around the nose and eyes, and prostration (in two animals). Animals that died revealed discoloured and/or mottled lungs (pink, red or salmon-coloured), discoloured stomachs and intestines (white to yellow, red or grey), gas and liquid filled stomachs and intestines, dark red or mottled tan livers, dark red to brown kidneys, liquid-filled abdominal cavities, one bladder filled with red liquid and blood in urine. Survivors had mottled pink to red lungs. One male had small mottled testes with cream-coloured foci and red submandibular lymph nodes. Detailed histopathological examination of the kidneys and urinary bladders revealed tubular proteinosis in the kidneys of male rats from each dose. No significant lesions were found in the male rat bladders or in the female kidneys or bladders. There were no effects on body weights.

The key acute oral toxicity study for the source substance, 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6), reports an LD₅₀ value of 6.17 mL/kg bw (equivalent to 6108 mg/kg bw). The study was conducted according to a protocol similar to OECD test guideline, but it was not compliant with GLP. Doses of 16, 8 and 4 ml/kg bw were administered through an oral gavage route to male and female rats. The animals were observed for 14 days. Mortality, clinical signs of toxicity and body weight changes were noted regularly during the study period. 3/3 deaths in 16 ml/kg dose group, 4/5 deaths in 8 ml/kg group, 0/5 in 4 ml/kg group were noted during the study period. The observed clinical signs included sluggishness, deep breathing, with tremor-like muscular spasms and loss of coordination in the highest dose group. The symptoms progressed to salivation and convulsions followed by the death of all three animals. Similar clinical signs were evident in the 8 ml/kg dose group, with the death of 4/5 animals. There were no deaths in the lowest dose group, but the animals appeared sluggish. There were no remarkable changes in body weight. In victims, petechial haemorrhages or congestion in the lungs; livers mottled; kidneys speckled and slightly congested; stomachs and intestines distended and liquid or gas-filled; intestines yellow. Nothing remarkable in survivors was observed.

The key acute dermal study for the target substance, 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0), reported LD₅₀ values of 2.46 ml/kg bw (equivalent to 2497 mg/kg bw) for males and 2.14 ml/kg bw (2172 mg/kg bw) for females. The study was conducted according to a protocol similar to OECD Test Guideline but was not compliant with GLP. Undiluted test material was applied to the shaved backs of five male and five female New Zealand white rabbits, under an occlusive dressing for 24 hours. The doses given were 4.0, 2.0 and 1.0 ml/kg bw. The animals were observed regularly for mortality, clinical signs of toxicity and body weight changes during the 14-day study period. Necropsy was performed at the end of the study period or after death that occurred prior to scheduled sacrifice. All male and female animals given 4.0 ml/kg bw died within one day of dosing. One male animal died at 2.0 ml/kg bw, within one day of dosing. Two females died (Day 2 and 6) at 2.0 ml/kg bw. No animals died at 1.0 ml/kg bw. Local cutaneous effects included erythema, oedema, necrosis, desquamation, fissuring, ulceration, alopecia and scabs. A red liquid was apparent around the anus and/or the paperboard beneath the cages of several animals. Other signs of toxicity included sluggishness (two animals), unsteady gait (one animal), spasmodic movement (one animal), diarrhoea (one animal) and red discharge around nose and mouth. Affected animals recovered with two to three days. Necropsy of animals that died revealed red lungs, trachea filled with blood (two animals), the stomach of one animal had a red focal area, dark red kidneys, kidneys filled with blood (one animal) or a yellow to green gelatinous material, a dark red bladder (in one), blood in the urine of one animal and dark red enlarged lymph nodes. There were also instances of vascularisation and haemorrhages on the skin. Gross pathological examination of survivors revealed mottled red lungs (two with dark red foci), tracheas filled with blood and excoriation of the treated skin. The kidneys and bladders of two male and two female rabbits from all dose groups were subjected to detailed histological examination. At high doses of 2.0 and 4.0 ml/kg bw kidneys lesions included epithelial necrosis of the renal pelvis, tubular epithelial cell degeneration and proteinosis. There were no kidney lesions at 1.0 ml/kg bw, and no significant urinary bladder lesions ant any dose.

The key acute dermal study for the source substance, 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6), reports an LD₅₀ value of 2.52 mL/kg bw (equivalent to 2494 mg/kg bw). The study was conducted according to a protocol similar to OECD Test Guideline but was not compliant with GLP. Doses of 16, 8, 4, 2, 1 ml/kg undiluted test substance were applied onto male rabbit skin, kept under occlusive dressing for 24 hours. Mortality, clinical signs of toxicity and body weight changes were noted regularly during the 14-day study period. Necropsy of all the animals was performed at the end of the study period for survivors or after death for animals that died prior to scheduled death. 2/2 (16 ml/kg), 4/4 (8 ml/kg), 2/4 (4 ml/kg), 2/4 (2 ml/kg), 1/4 (1 ml/kg) died within 14 days after patch removal. The observed clinical signs included erythema, ecchymosis, scabs and desquamation at application site. Slight body weight losses were prevalent in test animals. In victims, livers were paled and mottled, spleens dark, kidneys congested. Nothing remarkable in survivors.

Supporting acute inhalation studies were also available and all of them report no deaths following exposure to saturated vapour of test substance. The studies did not meet current guideline requirements for acute inhalation toxicity. They do, however, add weight of evidence to this endpoint.

AE 2.4 Exposure to other compounds than to those linked to the prediction

Neither the target substance3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0), nor the source substance, 3-(triethoxysilyl)propane-1-thiol (CAS 14814-09-6), have impurities of toxicological concern.

The identification of the target substance indicates that it has purity of <98% and no impurities are present at concentrations <1%.

The identification of the source substance indicates that it has purity of <93% and no impurities are present at concentrations <1%.

AE 2.5 Occurrence of Other Effects than Covered by the Hypothesis and Justification

Not relevant


[1]European Chemicals Agency (ECHA) (2015) Read-across Assessment Framework. Appendix B, Scenario 2.

Justification for classification or non-classification

In the absence of data there is no classification for repeated dose toxicity.