4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane

Endpoint summary

Description of key information

The key study for acute oral toxicity reports an LD50 value of greater than 2150 mg/kg bw for 4,4,13,13 -tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane ("S2"; CAS No. 56706-10-6, EC No. 260-350-7) conducted according to OECD Test Guideline 401 and in compliance with GLP (ASTA Medica AG, 1996).

 

The key read-across acute inhalation toxicity study with bis[3-(triethoxysilyl)polysulfides (“polysulfides”; CAS No. 211519-85-6, EC No. 915-673-4) was conducted according to OECD Test Guideline 403 but pre-dated GLP. In this study, a polysulfides LC50 of at least 7967 mg/m3 in rats exposed for 4 hours was identified. No deaths were reported and clinical signs were minor and transient (RCC Ltd, 1983).

 

The key study for acute dermal toxicity was conducted with low purity S2, in which an S2 LD50 value of greater than 2000 mg/kg bw was determined. The study was conducted according to OECD Test Guideline 402 and in compliance with GLP (WIL, 2000).

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 150 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 13 to 27 Jan 1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: outbred Wistar stock, (kfm:Wistar)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, 4414 Fuellinsdorf, SWITZERLAND
- Age at study initiation: 9 weeks (males), 12 weeks (females)
- Weight at study initiation: 229-268 g (males), 217-272 g (females)
- Fasting period before study: apparently none - food withheld during treatment
- Housing: 5/Macrolon type 4 cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 10
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12 h/ 12 h

IN-LIFE DATES: From: 1983-01-13 To: 1983-01-27

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: PVC nose-only tube-shaped chambers arranged radially around central chamber.
- Exposure chamber volume: 100 l
- Method of holding animals in test chamber: not stated
- Source and rate of air: dynamic, 10 l/min (operated as described in Sachsse et al 1973 & 1976).
- Method of conditioning air: -
- System of generating particulates/aerosols: test material supplied to spray nozzle by Perfusor R ED 1-300 automatic infusion pump. Air flow 600 l/hr; air pressure 3 atmospheres.
- Method of particle size determination: gravimetric (4-stage cascade impactor on Selectron filter)
- Treatment of exhaust air: -
- Temperature, humidity, pressure in air chamber: 22.5° C (SD 0.4); 57% RH (SD 9)
- Oxygen level: 20 % vol

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetric (Selectron filter pore size 0.2 microns)
- Samples taken from breathing zone: not stated

VEHICLE
none

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: 46% 1-7 microns (2 measurements)

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric

Duration of exposure:

4 h

Concentrations:

7967 mg/m3 (measured) (standard deviation 510)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: mortality and clinical observations 5 times during day 1, then daily; body weights recorded on days 1, 8, 15.
- Necropsy of survivors performed: yes.
- Other examinations performed: clinical signs, body weight.

Statistics:

None.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 7 967 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: standard deviation 510 mg/m3

Mortality:

No deaths. See table 1.

Clinical signs:

other: Minor clinical signs reported during day 1. See table 1.

Body weight:

No effect on body weight.

Gross pathology:

No treatment-related effects reported.

Other findings:

None

Table 1: Concentrations, exposure conditions and mortality or evident toxicity

Nominal Conc. (ml/h)	Analytical Conc. (mg/m3)	Mean particle size distribution µm	Mortality (males and females/total)	Number with evident toxicity (males and females/total)
60	7967 (SD 510)	46% 1-7	0/10	Day 1: slight dyspnoea, slight exophthalmos or slightly ruffled fur in all exposed animals. Days 2-15: no overt toxicity
0	0	-	no data	-

 SD: standard deviation

Interpretation of results:

GHS criteria not met

Conclusions:

In a reliable study conducted according to OECD Test Guideline 403 but without indication of compliancy to GLP, an LC50 in excess of 7967 mg/m3 in rats exposed for 4 h was identified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 7 967 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 23 Nov 1999 to 7 Dec 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was conducted according to an appropriate OECD test guideline, and in compliance with GLP. The test material was similar to the registered substance but contained a higher proportion of an S3 isomer. The original study and the read-across are considered to be reliability 2.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crl:CD(SD)IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Source: Charles River Labs, Raleigh, NC, USA

- Age at study initiation: 8 wk (m), 9 wk (f)

- Weight at study initiation: 293-315 g (m), 241-265 g (f)

- Diet (e.g. ad libitum): standard diet, ad libitum

- Water (e.g. ad libitum): drinking water, ad libitum

- Acclimation period: at least 7 days


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 71.4-72.1 deg F

- Humidity (%): 33.7-44.6

- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: 1999-11-24 To: 1999-12-07

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE

- % coverage: 18-23

- Type of wrap if used: gauze binder with non-irritating tape


REMOVAL OF TEST SUBSTANCE

- Washing (if done): wiped with moistened paper towel

- Time after start of exposure: 24 h


TEST MATERIAL

- Amount(s) applied (volume or weight with unit): 1.94 ml/kg bw (1.03 g/ml)

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 (in dose groups)

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: observations mortality twice daily, clinical changes daily, body weight days 0, 7, 14

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight

Statistics:

None given - limit test

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

None.

Clinical signs:

other: No treatment-related effects.

Gross pathology:

No treatment-related effects detected.

Other findings:

- Other observations: eschar (scabbing or sloughing) in 3/10, resolved by day 10; desquamation (shedding of skin) in 6/10, resolved by day 14. No erythema or oedema.

Table 1: Number of animals dead and with evident toxicity

Dose (mg/kg bw)	Mortality (# dead/total)			Number with evident toxicity (#/total)
	Male	Female	Combined	Male	Female	Combined
2000	0/5	0/5	0/10	No systemic toxicity only local effects reported

 

Interpretation of results:

GHS criteria not met

Conclusions:

From a reliable study conducted in compliance with the standard guideline and in accordance with GLP, no mortality or systemic effects were seen at 2000 mg/kg bw. The test substance was similar to the registered substance but contained a higher proportion of an S3 isomer.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Additional information

One key acute oral study is available for the registered substance S2 (ASTA Medica AG, 1996), conducted in a manner similar to (the now deleted) OECD Test Guideline 401 and in compliance with GLP. A single limit dose was administered to groups of male and female rats via gavage. No mortality or treatment-related effects were seen at 2150 mg/kg bw S2; the LD50 was identified as greater than this value.

A supporting study conducted according to OECD Test Guideline 401 for acute oral toxicity and in compliance with GLP was also available (WIL, 2000). The study was conducted with a low purity S2 and the results support the key findings. The LD50 was determined to be >2000 mg/kg bw.

No acute inhalation toxicity studies are available for the registered substance. The key read-across study for acute inhalation toxicity was conducted according to OECD Test Guideline 403 but pre-dated GLP (RCC, 1983). An LC50 greater than 7967 mg/m3 was determined for polysulfides in a 4-hour exposure to an aerosol of the registered substance. There were no mortalities or necroscopy findings. Minor clinical signs were reported during day 1, but these were more likely due to discomfort during the exposure procedure than indications of systemic toxicity. During the test study period there were no signs of overt toxicity. There were no effects on body weight, and gross pathology revealed no treatment related effects. Polysulfides is a multiconstituent reaction mass of the submission substance and two other polysulfide constituents (i.e., the trisulfide S3 and tetrasulfide S4). The three constituents are very similar in terms of structure and physicochemical and toxicological properties and so read-across is considered appropriate.

No acute dermal toxicity studies are available for the registered substance. A supporting read-across study for acute dermal toxicity with the related substance polysulfides was conducted largely in a manner similar to the OECD Test Guideline 402 but which pre-dated GLP. No mortality or systemic effects in rats treated at 4983 mg/kg bw was observed. Eschar was recorded in 8/10 animals, which resolved by day 13. No treatment-related abnormalities were reported at necropsy (Degussa Institute of toxicology, 1983). Thus, the dermal LD50 for polysulfides was at least 4983 mg/kg bw. The test material used in this dermal study contained a slightly higher proportion of S3 (see Section 1) than the registered material but this does not affect use of the data as no toxicological differences are expected between S2 and S3; this is discussed further in Section 7.8.

The substance in the read-across study with polysulfides contained up to 25% of the registered substance. The other constituents were the structurally similar analogue substances S3 and S4. The data included as read across, from low purity S2 contained ca. 65% of the registered substance. The other constituents were the structurally similar S1 (monosulfide) and S3. Due to their structural similarity and similar physicochemical properties, the read-across substances are considered to be representative of the registered substance. See the discussion of read across in the reproductive toxicity section endpoint summary (Section 5.9 of the CSR) for a more detailed justification for the read-across approach.

Justification for classification or non-classification

Based on the available substance-specific and read-across data, 4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane does not require classification for acute toxicity according to Regulation (EC) No. 1272/2008.