Registration Dossier

Diss Factsheets

Administrative data

Description of key information

No acute toxicity studies are available for the registered substance, therefore these endpoints are addressed by weight of evidence from reliable data on a number of related substances. Based on weight of evidence, the acute oral and dermal LD50 values for rats are >2000 mg/kg. The acute aerosol inhalation LC50 is >7967 mg/m3.  In the available acute oral toxicity studies (WIL, 2000a; ASTA Medica AG, 1996; LPT, 1977a), there were no deaths and no significant clinical or necropsy findings at doses up to and exceeding 2000 mg/kg. No acute inhalation toxicity studies are available for the registered substance. However,  a study for the related substance CAS 211519-85-6, conducted according to the standard guideline but without GLP (RCC, 1983), identified an LC50 in excess of 7967 mg/m3 in rats exposed for 4 h. No deaths were reported and clinical signs were minor and transient. No acute dermal toxicity studies are available for the registered substance. However, a guideline, GLP study is available for a related material (WIL, 2000) in which no mortality and no systemic effects were observed up to a limit dose of 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
during April and May 1977 (no further details)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
No guideline is indicated. The method described is similar to the (now deleted) OECD 401.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Sprague Dawley outbred strain
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: S. Ivanovas GmbH & Co, med. Versuchstierzuchten KG, Postfach 7, D-7964 Kißlegg/Allgäu, GERMANY
- Age at study initiation: 38 days (males), 42 days (females)
- Weight at study initiation: 100-105 g
- Fasting period before study: 15-16 h
- Housing: 1/Macrolon cage type II
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: not stated

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 0.5
- Humidity (%): 60 +/- 3
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): not stated


IN-LIFE DATES: not stated - experimental work conducted during April and May 1977
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
none

MAXIMUM DOSE VOLUME APPLIED: 15.9 ml/kg bw
Doses:
10, 12.6, 15.9 ml/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 28 days
- Frequency of observations and weighing: frequency of clinical observations and body weight measurements not stated
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
None
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 15.9 mL/kg bw
Based on:
test mat.
Mortality:
No deaths in any group (see table 1).
Clinical signs:
No overt toxicity other than minor reduction in weight gain (see table 1).
Body weight:
Minor reduction in weight gain probably associated with slightly reduced food intake (see table 1).
Gross pathology:
No significant findings.
Other findings:
None.

Table 1: Number of animals dead or with evident toxicity

 Dose


(ml/kg bw)

Mortality (dead/total)

Reduced food intake

(mean %)

Reduced body weight development

(mean %)

Male

Female

Combined

Days 1,2,7

Days 1,2,7

10

0/10

0/10

0/20

6,4,0 

2,4,4, 

12.6

0/10

0/10

0/20

10,2,0 

4,4,6 

15.9

0/10

0/10

0/20

11,4,6 

 2,0,4

 

Interpretation of results:
GHS criteria not met
Conclusions:
A reliable study conducted in a similar manner to a standard guideline but without GLP status identified an LD50 in excess of 15.9 ml/kg bw in male and female rats.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
From 28 Feb 1996 to 13 March 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: HsdCpb:WU
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Source: Harlan-Winkelmann

- Age at study initiation: 7 wk (m), 8 wk (f)

- Weight at study initiation: 166-181 g (m), 135-149 g (f)

- Fasting period before study: 16 h

- Housing: 1/cage

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

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

- Acclimation period: 5 days



ENVIRONMENTAL CONDITIONS

- Temperature (°C): 20.5 - 22.0

- Humidity (%): 48-62

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



IN-LIFE DATES:

From: 1996-02-28 To: 1996-03-13
Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
VEHICLE

- Concentration in vehicle: 215 mg/ml

- Amount of vehicle: 10 mg/kg bw

- Lot/batch no. (if required): 1545501

DOSAGE PREPARATION (if unusual):

"Aqueous solutions were prepared by shaking immediately before dosing". Presumably "aqueous" is incorrect in this statement.
Doses:
2150 mg/kg bw (male and female)
No. of animals per sex per dose:
5 (in dose groups)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: observations daily; bw days 0, 7, 14

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight.
Statistics:
Described only as limit test.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 150 mg/kg bw
Based on:
test mat.
Mortality:
None
Clinical signs:
None reported.
Body weight:
Weight gain (males and females).
Gross pathology:
No treatment-related effect detected.

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

2150

0/5

0/5

0/10

0/5

0/5

0/10

 

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 treatment-related effects were seen at 2150 mg/kg bw.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
from 24 Nov 1999 to 8 Dec 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral 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, USA

- Age at study initiation: 8wk (m), 6 wk (f)

- Weight at study initiation: 248-276 g (m), 211-221 g (f)

- Fasting period before study: 18-20 h

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

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

- Acclimation period: 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: 1999-11-25 To: 1999-12-08
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 1.94 ml/kg bw (1.03 g/ml)
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 (in dose groups)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: observations mortality 2x daily, clinical changes daily, bw 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:
Yellow deposit round anogenital and/or urogenital areas of all animals to day 3. No treatment-related observations from day 4. [Test material is a yellow liquid.]
Body weight:
Weight gain (males and females).
Gross pathology:
1 male had a dilated renal pelvis.

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

1/5

0/5

1/10

 

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 and only minor treatment-related effects were seen at 2000 mg/kg bw. The LD50 was therefore determined to be >2000 mg/kg. The test substance was similar to the registered substance but contained a higher proportion of S3 isomer.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 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 wk (males), 12 wk (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 wk

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 deg 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

-

 

Interpretation of results:
GHS criteria not met
Conclusions:
A reliable study conducted in compliance with the standard guideline but without GLP status, identified an LC50 in excess of 7967 mg/m3 in rats exposed for 4 h.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
7 967 mg/m³

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
from 23 June to 7 July 1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
See below
Principles of method if other than guideline:
No guideline stated. Study conforms largely to OECD 402 with minor deviations as stated below.
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann Versuchstierzucht GmbH, Borchen, GERMANY
- Age at study initiation: 10-14 wk (males); 10-11 wk (females)
- Weight at study initiation: 224-304 g (males); 161-180 g (females)
- Fasting period before study: 16 h
- Housing: 1/ Macrolon type II cage
- Diet: standard ad libitum
- Water: drinking water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2
- Humidity (%): 55 +/- 5
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12 h/12 h


IN-LIFE DATES: From: 1982-06-23 To: 1982-07-07
Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: no details given
- % coverage: - No data
- Type of wrap if used: no details given

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no details given

TEST MATERIAL
- Amount(s) applied: 4.64 ml/kg bw (4983 mg/kg bw)
Duration of exposure:
No details of removal of test material. Observation for 28 days following application.
Doses:
4983 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 28 days
- Frequency of observations and weighing: no details given on frequency of clinical observations. Apparently body weights were not recorded.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: no details
Statistics:
None.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 4 983 mg/kg bw
Based on:
test mat.
Mortality:
No deaths recorded during 28 days observation.
Clinical signs:
No evidence of treatment-related toxicity, however no details were given of the extent of observations.
Body weight:
No reference in this report to body weight measurements.
Gross pathology:
No treatment-related abnormalities reported.
Other findings:
Eschar, recorded in 8/10 animals, finally resolved on day 13. No further details are given.

No tabulated details of findings are given in this report.

Interpretation of results:
GHS criteria not met
Conclusions:
A reliable study, conducted largely in a manner similar to the standard guideline but without GLP status, found no mortality or systemic effects in rats treated at 4983 mg/kg bw.
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
from 23 Nov 1999 to 7 Dec 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
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:
No treatment-related effects.
Body weight:
Weight gain (males and females)
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

The registered substance is a reaction mixture comprising approximately 60% w/w of 4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane (S2 constituent) and 40% w/w of 3,15-dioxa-8,9,10-trithia-4,14-disilaheptadecane,4,4,14,14-tetraethoxy- (S3 constituent).

No acute toxicity data are available for the registered substance, therefore these endpoints are addressed using weight of evidence from reliable data for a number of related substances. The composition of these related substances includes different concentrations of both constituents present in the registration substance, and the available data indicate that there are no differences in acute toxicity for constituents with different numbers of sulfur atoms in a (poly)sulfide chain. Since the three test substances cover the composition range of the registered substance, and no acute toxicity effects were seen in any study, additional testing with the registration substance itself is not warranted.

Acute oral toxicity

A study using a pure grade of S2 (CAS 56706-10-6) (ASTA Medica AG, 1996) conducted in a manner similar to (the now deleted) OECD 401, involved gavage administration of a single limit dose to groups male and female rats. No mortality or treatment-related effects were seen at 2150 mg/kg bw, the LD50 was identified as greater than this value.

In a guideline study with a similar material (low purity S2) which contained a higher proportion of the S3 constituent than S2 but a lower proportion than the registered substance, no mortality and only minor and transient treatment-related effects were observed at a limit dose of 2000 mg/kg bw (WIL, 2000a).

A third study is available for the related substance polysulfides, bis[3-(triethoxysilyl)propyl] (CAS 211519-85-6), which is a reaction mass containing principally the S2 (15-60%), S3 (25-40%) and S4 (5-30%) constituents. This study (LPT, 1977a) was conducted according to a method that was similar to the now-deleted OECD 401. There were no mortalities and no treatment-related effects except a minor reduction in body weight gain. The LD50 for rats was reported to be >15.9 ml/kg.

Acute dermal toxicity

In a guideline study conducted in accordance with OECD 402 and GLP with low purity S2 which contained mainly the S2 and S3 constituents present in the registered substance (WIL, 2000b), no mortality, clinical signs of systemic toxicity or gross necropsy abnormalities were observed. The acute dermal LD50 for rats was therefore >2000 mg/kg. Local effects were noted (eschar and desquamation), but these had fully resolved at the end of the 14-day observation period.

A second study is available for the related substance polysulfides, bis[3-(triethoxysilyl)propyl] (CAS 211519-85-6), which is a reaction mass containing principally the S2 (15-60%), S3 (25-40%) and S4 (5-30%) constituents. This study (Degussa-Asta, 1983) was conducted according to a method that was similar to OECD 402, but was not compliant with GLP. There were no mortalities, clinical signs of systemic toxicity or gross necropsy abnormalities, and the LD50 was reported to be >4983 mg/kg. Eschar was noted, but was fully resolved by Day 13.

Acute inhalation toxicity

Only one relevant acute inhalation study is available (RCC, 1983). The study was conducted using polysulfides, bis[3-(triethoxysilyl)propyl] (CAS 211519-85-6), which is a reaction mass containing principally the S2 (15-60%), S3 (25-40%) and S4 (5-30%) constituents, in accordance with OECD 403 but without GLP. The acute aerosol LC50 was reported as >7967 mg/m3. There were no mortalities or necropsy findings. Minor clinical signs were reported on the day of exposure only, but these were more likely to be due to discomfort during the exposure procedure than indications of systemic toxicity.

See discussion in the repeated dose toxicity section (CSR Section 5.5) for a more detailed justification for read-across approach.

Justification for classification or non-classification

The available oral, inhalation and dermal data do not support classification for acute oral, inhalation or dermal toxicity according to Regulation (EC) No 1272/2008.