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Administrative data

Description of key information

In the key acute oral toxicity study, conducted according to OECD Test Guideline 420 and in compliance with GLP, a LD50 value greater than 2000 mg/kg bw was reported (Harlan Laboratories, 2010).

The key acute inhalation toxicity study for the mixture of 2,4,6,8,10-pentamethylcyclopentasiloxane (CAS 6166-86-5) and 2,4,6,8-tetramethylcyclotetrasiloxane (CAS 2370-88-9) (approximately 50/50%), conducted according OECD Test Guideline 403 and in compliance with GLP, concluded a LC50 greater than 4.9 mg/l. (Dow Corning Corporation, 2002).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010-05-04 to 2010-07-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Test animals:
Animals: Rat, RccHan: WIST(SPF)
Rationale: Recognized by international guidelines as a recommended test system.
Breeder: Harlan Laboratories B.V., Kreuzelweg 53, 5961 NM Horst / The Netherlands
Number of Animals: 6 females (nulliparous and non-pregnant)
Age (when treated): 10 - 11 weeks
Body Weight Range (when treated): 163.4 g – 194.6 g
Identification: Unique cage number and corresponding color-coded spots on the tail. The animals were marked at acclimatization start.
Randomization: Selected by hand at time of delivery. No computer generated randomization program.
Acclimatization: At least 7 days under laboratory conditions, after health examination. Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

Environmental conditions:
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with a room temperature of 22 ± 3 °C and a relative humidity between 30-70% (excepted once with a value of 72.7% during approximately 1 hour), automatically controlled light cycle of 12 hours light and 12 hours dark and music played during the daytime light period.

Accommodation: In groups of up to five by sex in Makrolon type-3 (if one animal/cage) to type-4 (if more than one animal/cage) cages with wire mesh tops and standard softwood bedding (‘Lignocel’ J. Rettenmaier&Söhne GmbH&CoKG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) including paper enrichment (Enviro-dri from Lillico, Biotechnology, Surrey, UK).

Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 83/09 (Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) ad libitum (except for the overnight fasting period prior to intubation and approximately 3-4 hours post dose). Results of analyses for contaminants are archived at Harlan Laboratories Ltd.

Water: Community tap water from Füllinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at Harlan Laboratories Ltd.

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The dose solutions were prepared shortly before each application occasion using a magnetic stirrer as homogenizer.

The test item was weighed into a tared glass beaker on a suitable precision balance. Homogeneity of the neat test item was maintained during administration using a magnetic stirrer.

The test item was administered neat as delivered by the Sponsor at a variable dose concentration: 300 mg/kg or 2000 mg/kg.

The animals received a single dose of the test item by oral gavage administration after being fasted for approximately 17 to 20 hours, but with free access to water. Food was presented approximately 3 to 4 hours after administration of neat test item.

Sighting Study: A single animal was used for each dose level investigated. The following initial dose levels were used: 300 and 2000 mg/kg. The dose level chosen was that which was expected to produce evident toxicity. In the absence of any relevant toxicity data, 300 mg/kg was used in the first instance. As no signs of toxicity were seen at the initial dose, then the next higher dose level was investigated. Since no mortality occurred at 2000 mg/kg the sighting test was complete and the main study was conducted at this dose level. Dosing was sequential, allowing approximately 72 hours before investigation of the next dose level. The animals were observed for fourteen days.

The dosing volume was 0.31 mL/kg (300 mg/kg) or 2.06 mL/kg (2000 mg/kg).

Main Study: A group of five animals was used for the highest dose level investigated (2000 mg/kg). The five animals included one animal tested at the selected dose level in the sighting study and an additional four animals in the main study. The dosing volume was 2.06 mL/kg body weight.

Rationale: Oral administration was considered to be an appropriate application method as it is a possible route of human exposure during manufacture, handling and use of the test item.
Doses:
300 mg /kg body weight (sighting study)
2000 mg/kg body weight (sighting study and main study)
No. of animals per sex per dose:
1 female at 300 mg/kg;
5 females at 2000 mg/kg
Control animals:
no
Details on study design:
Observations:
Viability / Mortality: Daily during the acclimatization. Once before the treatment and within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (in common with the clinical signs) and twice daily during days 2 – 15.

Clinical Signs: Daily during the acclimatization and treatment period. Additionally, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. Observations included changes in the skin and fur, eyes and mucous membranes, and respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Body Weights: On test days 1 (prior to administration), 8 and 15.

Necropsy:
All animals were killed at the end of the observation period by carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. An external examination and opening of the abdominal and thoracic cavities for examinations of major organs were performed. The appearance of any macroscopic abnormalities was recorded. No organs or tissues were retained.

Statistics:
No statistical analysis was performed.
Preliminary study:
The animal of the first sighting study dosed at 300 mg/kg bw survived. as did the second animal dosed at 2000 mg/kg bw

Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No intercurrent deaths occurred during the course of the study.
Clinical signs:
Slightly ruffled fur was observed in the animal dosed at 300 mg/kg bw from test day 3 to day 5, and in one animal dosed at 2000 mg/kg bw from 2 hours after administration to test day 3. No clinical signs were observed in the four additional animals dosed at 2000 mg/kg bw throughout the entire observation period of the main study.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
2,4,6,8-Tetramethylcyclotetrasiloxane did not show any evidence of toxicity at the dose level of 2000 mg/kg bw after single oral administration to five female rats, observed over a period of 14 days. The study concluded a LD50 value greater than 2000 mg/kg bw.


Executive summary:

The acute toxicity of 2,4,6,8 -tetramethylcyclotetrasiloxane when administered by a single oral gavage to rats was investigated according to OECD test guideline No. 420 and Commission Regulation (EC) No. 440/2008, B.1.

To determine the dose level investigated in the main study, a sighting study was conducted with two animals (female RccHan:WIST (SPF) rat). The test item was administered neat as delivered by the Sponsor. The two animals were separately treated with the test item at the initial dose level of 300 or 2000 mg/kg bw by single oral gavage administration. The dosing volumes were 0.31 mL/kg (300 mg/kg) or 2.06 mL/kg (2000 mg/kg), respectively. In the main study, an additional four female animals were treated with the test item at the dose level of 2000 mg/kg bw.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded within the first 30 minutes and approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

All animals survived until the end of the study period.

In the sighting study, slightly ruffled fur was observed in the animal dosed at 300 mg/kg from test day 3 to day 5, and in the animal dosed at 2000 mg/kg bw from 2 hours after administration to test day 3. No clinical signs were observed in the four additional animals dosed at 2000 mg/kg bw throughout the entire observation period of the main study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy.

2,4,6,8-Tetramethylcyclotetrasiloxane did not show any evidence of toxicity at the dose level of 2000 mg/kg bw after single oral administration to five female rats, observed over a period of 14 days.

LD50 (female rat): greater than 2000 mg/kg bw.

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:
2001-2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Only one dose, 5 mg/m3, top dose for vapours according to guideline version of 1981 but insufficient by today's gudieline version. Study does not meet the current classification cut-offs.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
modified: whole-body, 5M/5F, one dose of 5 mg/l (vapour)
Deviations:
yes
Remarks:
but not considered to have impacted the study outcome. (page containing Table with deviations missing)
GLP compliance:
yes
Remarks:
US-EPA TSCA GLP 40 CRF part 792
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
5 male, 5 female rats, strain Sprague-Dawley, Crl:CD(SD)IGS;
At strat of study: age 9 weeks;
body weights females 201.8 - 227.7 grams;
body weights males 298.1-334.5 grams;
one group only;
identification by eartags and indivudual cage labels;
individually housed in wire-meshe cages elevated above absorbent material, regularly cleaned in accordance with good animal husbandry;
environmentally controlleed animal rooms;
artificial lighting, light/dark 12/12;
temperature 22+-3 degr.C , 30-70% relative humidity, 10-15 air changes /hr;
certified rodent deit ad lib except during exposure. reverse-osmosis purified tap water at lib.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
clean air
Remarks:
source: Nash air compressor AL-574; serial filters Matheson 460/461 and Balston 100-118-DX and 100-8-BX.Dilutuion air stream: HEPA-filtered, activated carbon filtered, warmed and humidified room air.
Details on inhalation exposure:
whole- body exposure.
limit test.
target concentration 450 ppm = 5 mg/l.
measured concentrations 445 ppm= 4.9 mg/l.
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Rochester-type, Stainless steel and glass whole-body exposure chamber;
- Exposure chamber volume: 450 liters;
- Method of holding animals in test chamber: stainless steel mesh caging;
- Source and rate of air: Room air, mean chamber airflow rate 105 +- 0.8 L/min. (14 air changes /hr) dilution air stream;
- method of conditioning; HEPA-filtered, activated carbon filtered, warmed and humidified room air;
- Temperature: 24.1 +-1.2 degr C;
- humidity: 49.7 +- 3% RH;
- pressure in air chamber:
- oxygen content: 20.9 degr. C;
TEST ATMOSPHERE
- Brief description of analytical method used: Varian Gas chromatograph 3400 with GC/IFD; one sample /30 minutes. Calibrated using 5 levels of bag standards in the range of 250-650 ppm;
- Samples taken from breathing zone: No.

VEHICLE
- Composition of vehicle: compressed, filtered air:

Analytical verification of test atmosphere concentrations:
yes
Remarks:
See above for analytical method details. measured concentration showed good correlation with calculated nominal concentrations (4.3% difference)
Duration of exposure:
ca. 280 min
Remarks on duration:
20 minutes lead time to build up to min. 99% of target concentration; 20 minutes end lag time to reduce concentrations to max 1% of target concentrations.
Concentrations:
mean measured chamber concentration: 4.9 +- 0.2 mg/l (445 +- 16.6 ppm)
See table in "any other observations on results"
No. of animals per sex per dose:
5 males, 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations:Mortality twice daily, once during weekends. Clinical signs: once daily
- Frequency of weighing: day1, prior to exposure; day 8; day 15 (prior to sacrifice)
- Necropsy of survivors performed: yes (complete gross pathology examination)
Statistics:
not applicable: no mortality
Preliminary study:
not performed.
Sex:
female
Dose descriptor:
LC50
Effect level:
> 4.9 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Also incuding 20 min. lead time and 20 min. lag time
Sex:
male
Dose descriptor:
LC50
Effect level:
> 4.9 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Also incuding 20 min. lead time and 20 min. lag time
Mortality:
None
Clinical signs:
other: None
Body weight:
Body weight ranges and body weight gains were within acceptable ranges throughout duration of the study (barring one deviation) (Table individual body weight gains missing)
Gross pathology:
No gross pathology findings
Other findings:
none reported

Conditions during exposure.

Time point (30 min. intervals)

Measured conc. (ppm)

Measured conc. (mg/l)

Temperature

(°C)

Humidity (%RH)

Air flow (L/min)

1

N.A.

N.A.

21.6

53.1

106

2

414

4.5

22.7

53.2

106

3

425

4.7

23.3

51.5

105

4

444

4.9

23.9

47.4

105

5

446

4.9

24.7

44.8

105

6

446

4.9

25.0

48.4

105

7

460

5.0

25.0

53.7

105

8

444

4.9

24.8

48.8

105

9

456

5.0

24.9

48.2

105

10

467

5.1

24.8

48.0

103

Mean

445

4.9

24.1

49.7

105

SD

16.6

0.2

1.2

3.0

0.8

Interpretation of results:
GHS criteria not met
Conclusions:
The test substane is a mixture of the submission substance, 2,4,6,8-tetramethylcyclotetrasiloxane (CAS 2370-88-9) and 2,4,6,8,10-pentamethylcyclopentasiloxane (CAS 6166-86-5). These substances are structurally very closely related and, as shown in the hydrolysis test (see 5.1.2) will probably result in similar or identical hydrolysis product in contact with water. The results for the mixture are therefore considered to be applicable to both substances individually. No mortality was seen after a 4-hour exposure to a mean measured concentration of 4.9 mg/l or during a 14-day observation. The LC50 is considered to be greater than 4.9 mg/l.

The selected single dose is in the range of 2
Executive summary:

An acute inhalation study was performed with a mixture of 2,4,6,8,10-pentamethylcyclopentasiloxane (CAS 6166-86-5) and 2,4,6,8-tetramethylcyclotetrasiloxane. Five male and five female animals were exposed in a whole-body exposure chamber for 4 hours and subsequently observed for 14 days. Only one dose was tested: nominal 5 mg/l, measured 4.9 mg/l. No mortalitiy or any clinical signs were observed. The LC50 of the mixture is > 4.9 mg/l.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
4 900 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In the key acute oral toxicity study, conducted according to OECD Test Guideline 420 and in compliance with GLP, a LD50 value greater than 2000 mg/kg bw was reported (Harlan Laboratories, 2010). HD4 did not show any evidence of toxicity, barring some slightly ruffled fur, at a dose level of 2000 mg/kg bw after single oral administration to six female rats, observed over a period of 14 days.

In the key acute inhalation toxicity study for the mixture of 2,4,6,8,10-pentamethylcyclopentasiloxane (CAS 6166-86-5) and 2,4,6,8-tetramethylcyclotetrasiloxane (CAS 2370-88-9) (approximately 50/50%), conducted according to OECD Test Guideline 403 and in compliance with GLP, a LC50 value of greater than 4.9 mg/L was reported (Dow Corning Corporation, 2002a). The study was performed using a mixture of the registered substance and 2,4,6,8,10-pentamethylcyclopentasiloxane (CAS 6166-86-5). There were no mortalities, clinical signs or adverse necropsy findings following 4-hour exposure at a nominal limit dose of 5 mg/l.

See attachment to IUCLID Section 13 for justification of using data for the mixture of 2,4,6,8,10-pentamethylcyclopentasiloxane (CAS 6166-86-5) and 2,4,6,8-tetramethylcyclotetrasiloxane (CAS 2370-88-9).



Justification for classification or non-classification

Based on the available data, no classification for acute toxicity is required for 2,4,6,8-tetramethylcyclotetrasiloxane according to Regulation (EC) No 1272/2008.