3-(dimethoxymethylsilyl)propanethiol

Endpoint summary

Description of key information

There were no data for acute toxicity for the registered substance. Data are read across from the analogous substance 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0). The key study for acute oral toxicity (BRRC, 1990) was conducted according to a test protocol that is comparable to the appropriate OECD test guideline, but not in compliance with GLP. The acute oral LD₅₀ was identified as 893 mg/kg bw for males and 741 mg/kg bw for females for 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0).

The key study for acute dermal toxicity (BRRC, 1990) was conducted according to a test protocol that is comparable to the appropriate OECD test guideline, but not in compliance with GLP. The acute dermal LD₅₀ was identified to be 2497 mg/kg bw for males and 2172 mg/kg bw for females for 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0).

In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the inhalation route (required in Section 8.5.2) does not need to be conducted as reliable data via the oral and dermal routes are available.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

741 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 172 mg/kg bw

Additional information

The data for acute toxicity are read across from the analogous substance 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0).

The key study for acute oral toxicity (BRRC, 1990) reports LD₅₀ values of 893 mg/kg bw for males and 741 mg/kg bw for females. The clinical signs included sluggishness, unsteady gait, lacrimation, yellow or red wetness or stains on the periurogenital fur, blood in the urine, a red crust around the nose and eyes, and prostration. The 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.

The key study for acute dermal toxicity (BRRC, 1990) reports LD₅₀ values of 2497 mg/kg bw for males and 2172 mg/kg bw for females. The clinical signs included sluggishness, unsteady gait, spasmodic movement, diarrhoea and red discharge around nose, mouth and anus. Affected animals recovered within two to three days. Necropsy of animals that died revealed red lungs, trachea filled with blood, the stomach of one animal had a red focal area, dark red kidneys, kidneys filled with blood or a yellow to green gelatinous material, a dark red bladder, 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, tracheas filled with blood and excoriation of the treated skin.

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 acute toxicity, irritation, sensitisation and genotoxicity endpoints relevant properties are physicochemical properties, structural similarity and hydrolysis-rate. In the following paragraphs the proposed read-across for the above endpoints from 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0) to 3-[dimethoxy(methyl)silyl]propane-1-thiol (CAS 31001-77-1) is evaluated point by point. Additional information is given in a supporting report (PFA 2014ap) attached in Section 13.

Read-across hypothesis

The hypothesis is that source (read-across) and target (registration) substances have comparable toxicological properties because they contain an identical propanethiol sidechain attached to silicon and hydrolyse to analogous silicon-containing hydrolysis products. At the pH of the stomach 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0) and 3-[dimethoxy(methyl)silyl]propane-1-thiol (CAS 31001-77-1) both hydrolyse very rapidly (half-life in the order of seconds). They share the common hydrolysis product methanol, which does not contribute to any adverse effects for short term toxicity at the relevant dose levels based on publicly available information. This is discussed further below.

Read-across justification

The predicted half-lives at 20 -25^oC of the registered substance, 3-[dimethoxy(methyl)silyl]propane-1-thiol (CAS 31001-77-1), are 1.4 hours at pH 7 , 0.1 hours at pH 4, 0.03 hours at pH 9, all at 20-25°C (QSAR). 

At 37.5°C and pH 2 (relevant for conditions in the stomach following oral exposure), the worst case calculated half-life is approximately 5 seconds. The products of hydrolysis are 3-(dihydroxymethylsilyl)propanethiol and methanol.

The read-across substance, 3-trimethoxysilylpropane-1-thiol (CAS 4420-74-0), has a predicted hydrolysis half-life of 2.6 hours at pH 7,.0.2 hours at pH 4, 0.1 hours at pH 9 and at 20-25° C (QSAR).

At 37.5ºC and pH 2 (relevant for conditions in the stomach following oral exposure), the worst case calculated half-life is approximately 5 seconds. The products of hydrolysis are 3-(trihydroxysilyl)propanethiol and methanol.

 

Analogue approach justification

(a) Structural similarity

The registration and read-across substances are structurally similar and are members of an analogue group of alkoxysilane substances containing a thiol functional group. Both contain a silicon atom to which is attached to a propanethiol side chain. The propanethiol side chains of the two substances are identical. The registered substance has two methoxy groups and a methyl group bound to silicon. The only difference in the read across substance is that all three groups bound to the silicon are methoxy groups. Both hydrolyse rapidly to produce similar silicon-containing hydrolysis products, 3-(dihydroxymethylsilyl)propanethiol and 3-(trihydroxysilyl)propanethiol, and the same non-silicon hydrolysis product, methanol. The presence of an additional methyl group in the registration substance means that its silanol hydrolysis product is slightly more lipophilic than that of the read-across substance but it is not expected to significantly impact the toxicity of the substance since the chemical group likely to be associated with adverse effects is the thiol group. There are no impurities in either substance that would affect the hazard profile.

(b) Similar toxicokinetics

When oral exposure takes place it can be assumed, except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood occurs. 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).

 

The properties relevant to oral absorption include water solubility and molecular weight. As the hydrolysis of both the target and read across substance is very rapid in the low pH of the stomach, if oral exposure did occur, it would be to the hydrolysis products. 

Since the silicon-containing hydrolysis products have similar molecular weight (<200) and are both very soluble, they would both be readily absorbed via the stomach in a similar way. 

 

Dermal exposure would be to the parent compound as well as the hydrolysis products.

The fat solubility and the potential dermal penetration of a substance can be estimated by using the water solubility- and log K_ow values. Substances with log K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. The log K_ow values of the parents (>1) are similar and favourable for dermal absorption, whereas the hydrolysis products are less readily absorbed through the skin (log K_ow values <1). The water solubility of the parent and the hydrolysis products are also in the similar range.

 

Both substances therefore have similar toxicokinetics via the oral and dermal routes.

 

(c) Similar physicochemical characteristics

The key physicochemical parameters are summarised below. The similarity of the hydrolysis rates at pH relevant to oral exposure is important. Both parent substances are soluble in water, have low log K_ow and comparable vapour pressure; they are of similar molecular weight.

Table: Key physicochemical parameters

	Target (registration substance)	Source (read-across substance)
CAS Number	31001-77-1	4420-74-0
EC number	250-426-8	224-588-5
Chemical Name	3 -[dimethoxy(methy)lsilyl]propane-1-thiol	3-trimethoxysilylpropane-1-thiol
Purity	>99%	>98%
Impurities	Siloxane, alkoxysilane	Organosilane and siloxane, methanol
Molecular weight (gmol^-1)	180.34	196.34
log Kow(parent)	2.9 at 20°C (QSAR)	1.7 at 20°C (QSAR)
log Kow(silanol hydrolysis product)	0.5 at 20°C (QSAR)	-1.4 at 20°C (QSAR)
Water solubility (parent)	290 mg/l at 20°C (QSAR)	2.8E+03 mg/l at 20°C (QSAR)
Water solubility (silanol hydrolysis product)	47000 mg/l at 20°C (QSAR) (limited by condensation reactions)	1E+06 mg/l at 20°C (QSAR) (limited by condensation reactions)
Vapour pressure (parent)	23 Pa at 25°C (QSAR)	8.1 Pa at 25°C (QSAR)
Vapour pressure (silanol hydrolysis product)	0.0092 Pa at 25°C (QSAR)	1.5E-04 Pa at 25°C (QSAR)
Hydrolysis t1/2at pH 7 and 20-25°C	1.4 h	2.6 h
Hydrolysis t1/2at pH 2 and 37.5°C (relevant for oral exposure)	5 seconds	5 seconds

 

(d) Discussion of toxicity of the non-silanol hydrolysis products

 

The acute toxicity of the non-silanol hydrolysis product, methanol is well established. Ophthalmologic changes and acidosis are described as typical primary effects in humans, in which 300 - 1000 mg/kg methanol is considered to result in death (OECD 2004). At the doses of parent substance, the methanol toxicity is not expected to be relevant. Furthermore, methanol is not acutely harmful for rats and would not be expected to contribute to acute toxicity.

 

The repeated dose toxicity of the methanol, has also 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 high doses and generally effects when noted, are considered adverse only at the upper end of the dose ranges studied e. g 650 mg/m³ in monkeys, 13000 mg/m³ in rats.

References:

OECD (2004): SIDS Initial Assessment Report for SIAM 19, Berlin, Germany, 18-20 October 2004, Methanol, CAS 67-56-1.

 

Justification for classification or non-classification

Based on the available data on the read-across substance 3-trimethoxysilylpropane (CAS 4420-74-0), the registered substance 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 inhalation or dermal toxicity.