Registration Dossier

Administrative data

Description of key information

In the key acute oral toxicity study (Toxikon Corporation, 1990a), which was comparable to the now deleted OECD 401, and to GLP, the LD50 value for male and female rats was >5000 mg/kg bw.  

In the key acute inhalation toxicity study (RCC, 1994), which was comparable to OECD 403, and to GLP, the LC50 value was 8670 mg/m3.  

In the key acute dermal toxicity limit test (WIL Research Laboratories, 1977), which was pre-GLP, but comparable to OECD 402, the LD50 value was >2000 mg/kg bw.  

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
The test was conducted based upon the Federal Hazardous Substances Act - Consumer Product Safety Commission, 16 CFR, Part 1500, Chapter 2, Subpart C, Section 1500.3, 1990.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS

- Source: Charles River Breeding laboratories (Wilmington, MA)

- Age at study initiation: 8-12 weeks old

- Weight at study initiation: 200-300 g bw

- Fasting period before study: overnight

- Housing: individually housed using stainless steel cages

- Diet: commercial rodent ration, ad libitum

- Water: municipal tap water, ad libitum

- Acclimation period: 3 day quarantine upon receipt



ENVIRONMENTAL CONDITIONS

- Temperature (°F): 68 +/-3

- Humidity (%): 30-70

- Air changes (per hr): min. 10-13

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

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
No data available.
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Clinical observations were conducted daily and included all toxicologic and pharmacologic signs including nature, onset, severity and duration of abnormal or unusual cardiovascular, respiratory, excretory, behavioural and other activities, as well as signs including adverse effect on the central nervous system (paralysis, lethargy, lack of coordination and staggering) and time of death. Individual body weights were determined on the fasted animals on day 0 (shortly before the test article was administered) and again on study day 7 and 14.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: A gross necropsy was performed on all animals on day 14.
Statistics:
No statistical analysis performed.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no mortalities.
Clinical signs:
There were no overt signs of toxicity noted in any test animal during the observation period.
Body weight:
All animals exhibited a gain in body weight during the post treatment period.
Gross pathology:
No unusual lesions were noted in any of the animals at necropsy.
Other findings:
None reported.
Interpretation of results:
GHS criteria not met
Conclusions:
An acute oral LD50 value of >5000 mg/kg for male and female rats was determined in a reliable study conducted according to an appropriate test protocol.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 000 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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Qualifier:
according to
Guideline:
EPA OTS 798.1150 (Acute inhalation toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS

- Source: Charles River WIGA GmbH, Sandhoferweg 7, D-97633 Sulzfeld, Germany

- Age at study initiation: 6-8 weeks

- Weight at study initiation: 126-150g males, 106-122g females

- Fasting period before study:

- Housing: Individual housing in Makrolon type 3 cages with standard softwood bedding.

- Diet: pelleted standard Kliba 343 rat maintenance diet, ad libitum.

- Water: community tap water (Geneva), ad libitum

- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 22 +/-3C

- Humidity (%): 30-70

- Air changes (per hr): 10-15

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


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: Inhalation exposure was performed according to the method of Sachsse et al. (1973, 1976). The test article stream reached the animal's nose through ports situated at different levels around the axis of the chamber. Each level has 8 ports and can be rotated, allowing close observation of all the animals without interruption of exposure. The flow-past, nose-only design of this exposure system is based upon the fluid dynamic modelling of the aerosol flow. It ensures a uniform test article distribution, provides a constant stream of "fresh" test article to each animal and precludes rebreathing the exhaled air.

- Exposure chamber volume: The internal active volume of the chamber for exposure up to 24 animals was approximately 0.7 litres.

- Method of holding animals in test chamber: The animals were confined separately in Makrolon tubes that are positioned radially around the exposure chamber.

- Source and rate of air: Airflow rate was 1.25-1.52 l air/minute per animals

- System of generating particulates/aerosols: The system consisted of a reservoir with test article for constant pressure feeding of nebulizer, a nebulizer, a glass chamber dilution system, a constant pressure airflow to nebulizer, flowmeter controlled airflow for test article dilution and an outlet to the nose-only exposure system.

- Temperature, humidity, pressure in air chamber: Samples for the measurements of the test article concentration (analytical, gravimetric), oxygen concentration, relative humidity and temperature were collected from a port of the exposure chamber, directly from the feed tube delivering 'fresh' test article to the animal's nose. Therefore, all the measurements were isoaxial and represented exactly what was delivered to the animals.


TEST ATMOSPHERE

- Brief description of analytical method used: The relative test article concentration was measured during each exposure using a RAM-1 light scattering type aerosol device from GCA Corp., Bedford Massachusetts, U.S.A. The analytical determinations of the test article were performed using test atmosphere samples collected in wash bottles connected to the exhaust of the Gelman filter holder (used for gravimetric determinations.) The volatile phase of the test atmosphere was passed into three wash-bottles placed in series containing each 80 ml of n-fexame cooled at -70C. The content of each wash bottle was transferred into 100 ml volumetric flasks made up to 100ml with the rinsing. Aliquots of each wash bottle were put into appropriate sealed vials and sent for analysis at ambient temperature.

- Samples taken from breathing zone: yes


TEST ATMOSPHERE (if not tabulated)

- Particle size distribution: The distribution of the particle size in the aerosol was not measured due to the relatively low vapour pressure of the test article. Preliminary trials performed with an impactor produced unreliable results, due to partial evaporation of the test article during the course of the technical procedure.



Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
8.10, 7.42, 10.91, and 15.87 (nominal). 4.62 mg/l, 6.73 mg/l, 9.82 mg/l, 15.37 mg/l (actual).
No. of animals per sex per dose:
5/sex/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Clinical signs and mortality were noted during and following the exposures over a 15-day observation period. Body weights were recorded once during the acclimation period, on test day 1 prior to exposure, and on test days 2, 3, 4, 5,
6, 9, 12 and 15. Food consumption was measured once during the acclimation period (over 5 days), and during 8 intervals following the exposure (from days 1-2, 2-3, 3-4, 4-5, 5-6, 6-9, 9-12 and 12-15).

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: All animals were necropsied, and all macroscopic abnormalities recorded. The lungs, trachea, larynx, nasopharyngeal tissues, liver, spleen, thymus, lymph nodes (mandibular, mesenteric, mediastinal), salivary glands, as well as other organs with macroscopic findings were collected from all animals and fixed in a buffered solution. The lungs were instilled with fixative under a hydrostatic pressure of 30 cm. The lungs, liver, spleen and thymus of all surviving animals were weighed before fixation.
Statistics:
The LOGIT-Model (LOGIT: A program for dose response analysis, Koshiver J. and Moore D., Computer Programs in Biomedicine, 10, 1979, 61-75) was used to calculate the LC50.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
8.67 mg/L air
Based on:
test mat.
95% CL:
>= 7.3 - < 10.32
Exp. duration:
4 h
Mortality:
See Table 1.
Clinical signs:
During exposure: Concentration-dependent incidence and intensity of restlessness were observed at all exposure levels, particularly among animals from the two upper exposure groups. This sign was also more intense in females than males. A few rats from groups 1 to 3 also showed tachypnea.

After exposure: Stiff gait, hunched posture, ruffled fur, restlessness and tachypnea were observed in most or all rats from both sexes which survived the exposure, starting immediately after exposure and lasting up to study day 13.
Tachypnea persisted in a few males and females from groups 1 to 3 for one to four days following exposure. Lacrimation
was observed in one female from group 2. The single female that survived exposure in group 3 showed mild serous
rhinorrhea.
Body weight:
In group 1, the mean body weight in both sexes was considered to be normal for animals of this strain and age, and to be unaffected by treatment. In group 2, the rats of both sexes showed practically no growth during the first observation week. Growth resumed during the second week, and the mean weight was considered as normal in both sexes at the time of the terminal sacrifice. In group 3, both surviving male and female rats showed a
moderate-to-marked weight loss during the first 2 or 3 days following exposure, then growth resumed. The male had not achieved a normal weight at the end of the 14-day observation period, whereas the weight of the female was considered as normal. Due to the death of all animals, no assessment was made in group 4.
Gross pathology:
No remarkable differences were observed in absolute/relative organ weights among all surviving animals. No significant findings were noted in the lungs of animals surviving the treatment period. In group 3, the lungs from the animals that died were reddish or dark red and incompletely collapsed. In group 4, the lungs from the animals that died were dark red and incompletely collapsed in one male and in 2 females. These findings were
considered to be treatment-related. The eyes of 4 males and 4 females from the high dose exposure group had a grey-white colouration, focal and general; this finding was considered to be treatment-related.
Other findings:
Food Consumption: In group 1, the mean food consumption in both sexes was considered to be normal for animals of this strain and age, and to be unaffected by treatment. In group 2, food consumption was slightly reduced in males during the first day following exposure and moderately reduced in females during the first two days following exposure. Then food consumption returned to normal values in both sexes. In group 3, no data are available for both surviving male and female rats for the first 2 days following exposure (due to technical error). In the male, food intake was low until
day 5 and then returned to normal. In the female, it was considered as normal from the first days when record was available (day 3). Due to the death of all animals, no assessment could be made in group 4.

Table 1: Concentrations, exposure conditions and mortality per animals treated

Nominal

Conc. (mg/L)

Mortality (# dead/total)

Males

Females

Combined

4.62

 0/5

 0/5

 0/10

6.73

0/5

0/5

0/10

9.82

 4/5

4/5 

 8/10

15.37 

5/5

5/5 

 10/10

 

Exposure Concentrations: Results of the nominal, gravimetric and analytical determinations 

of decamethylcyclopentasiloxane measured for the four exposure groups are summarized below.  

As gravimetric concentrations correspond to the liquid phase, and analytical concentrations 

to the vapor phase of the test article, the results were added.  Except for the lowest 

exposure concentration, good agreement was found between the sum of gravimetric and 

analytical values and nominal concentrations.  
        

Test Atmosphere Concentrations (mg/L air)
Group   Nom.(1)  Grav.(2)   Analyt.(3)   Total(4)
1       8.10     2.53       2.09         4.62
2       7.42     4.49*      2.24*        6.73*
3       10.91    7.54*      2.28*        9.82
4       15.87    13.58*     1.79*        15.37*

*Mean of two values.
Nom= nominal; Grav = gravimetric; Analyt = analytical
(1): Concentrations based upon the amount of test article used during the exposure period.
(2): Corresponds to the liquid phase of the test atmosphere collected on the Gelman filters.
(3): Corresponds to the vapor phase of the test atmosphere collected in n-hexane.
(4): Total of 2 and 3.  The values were used to calculate the LC50.



Exposure Conditions: The temperature, relative humidity and oxygen concentration ranges 

in the test atmosphere measured during the exposure periods are given below:

Groups  Temp.      RH        O2
        (degC)     (% rh)   (vol %)
1     19.8 - 20.7  3.8-5.2  20.8-20.9
2     20.4 - 21.1  5.3-7.6  20.8-21.0
3.    20.8 - 21.6  4.9-5.3  20.7-20.8
4     18.5 - 19.1  5.9-6.9  20.8-20.9         
        
RH= relative humidity; O2 = O2 concentration

Interpretation of results:
GHS criteria not met
Conclusions:
An acute inhalation LC50 value of 8.67 mg/L was determined for male and female rats in a reliable study conducted according to an appropriate test protocol, and in compliance with GLP.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
8 670 mg/m³

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS

- Source: King's wheel Rabbitry at Mt.Vernon, Ohio

- Weight at study initiation: 2.2 -2.5kg

- Acclimation period: 27 days

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE

- Area of exposure: The skin of one male and two females was abraded with a clipper head so as to penetrate the stratum corneum without causing bleeding. The skin of the remaining three rabbits was left intact. The test material was weighed separately for each rabbit and spread evenly over the clipped area with a glass stirring rod.


- Type of wrap if used: The entire test site was then covered with two layers of 4 -ply gauze, occluded with rubber dental dam and fastened with Johnson and Johnson porpur tape.

REMOVAL OF TEST SUBSTANCE

- Washing (if done): After the exposure period, each rabbit was removed from the harness, the occlusive wrap was removed and any unabsorbed test material was wiped off with a wet disposable paper towel.

- Time after start of exposure: 24 hours


Duration of exposure:
24 hours
Doses:
The animals were dosed with a single application of undiluted test material at the dose level of 2g per kg body weight.
No. of animals per sex per dose:
3M, 3F
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Necropsy of survivors performed: yes

Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during either the 24 hour exposure period or the 14 day observation period that followed.
Clinical signs:
No changes in behaviour or signs of systemic toxicity were observed at any time during the study. Incidental observation of gren mucoid faeces were noted. One rabbit did not eat for a day, but neither was dose related. On day 4, one of the rabbits had slight erythema.
Gross pathology:
None of the rabbits had any signs of skin irritation at the test site throughout the study. There were no visible lesions in any of the rabbits at gross necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
An acute dermal LD50 value of >2000mg/kg was determined for male and female rabbits in a reliable study conducted according to an appropriate test protocol. Not conducted according to GLP.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

The key acute oral toxicity study (Toxikon Corporation, 1990a) was conducted according to the now deleted OECD test guideline 401. Sprague-Dawley rats (5 animals/sex) were given D5 as an oral gavage dose of 5000 mg/kg bw. The animals were then observed for mortality and clinical signs of toxicity for 14 days. A necropsy examination was conducted on each animal following the 14 day observation period. There were no deaths, no signs of toxicity, and growth and necropsy findings were normal. The LD50 for male and female animals was therefore >5000 mg/kg bw. Two reliable supporting studies (Carpenter, 1974; Springborn Institute for Bioresearch, Inc, 1977) confirm the finding of the key study that the acute oral LD50 (rat) for D5 is greater than 5000 mg/kg.

The key acute inhalation toxicity study (RCC, 1994) was conducted to OECD test guideline 403. Fischer 344 rats (5 animals/sex/group) were exposed, nose-only, to an aerosol of D5 at concentrations of 4620 (group 1), 6730 (group 2), 9820 (group 3) and 15370 (group 4) mg/m3 (actual concentrations) for 4 hours.

The animals were then observed for mortality and clinical signs of toxicity for 14 days. A necropsy examination was conducted on each animal following the 14 day observation period or at death. There were 8/10 and 10/10 deaths in the 9820 and 15370 mg/m3 groups, respectively. During exposure there was a concentration-dependent incidence and intensity of restlessness were observed at all exposure levels, particularly among animals from the two upper exposure groups. This sign was also more intense in females than males. A few rats from groups 1 to 3 also showed tachypnea. Following exposure stiff gait, hunched posture, ruffled fur, restlessness and tachypnea were observed in most or all rats from both sexes which survived the exposure, starting immediately after exposure and lasting up to study day 13. Tachypnea persisted in a few males and females from groups 1 to 3 for one to four days following exposure. Lacrimation was observed in one female from group 2. The single female that survived exposure in group 3 showed mild serous rhinorrhea. Animals in groups 2, 3 and 4 had reduced body weight gain following treatment. No significant findings were noted at necropsy in the lungs of animals surviving the treatment period. In group 3, the lungs from the animals that died were reddish or dark red and incompletely collapsed. In group 4, the lungs from the animals that died were dark red and incompletely collapsed in one male and in 2 females. These findings were considered to be treatment-related.

This study gave an LC50of 8670 mg/m3. In this study no deaths were observed at concentrations at or below the saturated vapour concentration. In a reliable supporting study (Bayer AG, 1984) no deaths were observed up to the highest achievable vapour concentration of 6720 mg/m3.The NOAEC for acute effects was 4620 mg/m3based on general toxicity and effects on body weight.

The key acute dermal toxicity study (WIL Research Laboratory, 1977) was conducted according to OECD test guideline 402. New Zealand white rabbits (3 animals/sex) were dermally exposed to undiluted D5 at a dose of 2000 mg/kg bw under an occlusive dressing for 24 hours. Following the 24 hours exposure the animals were observed for mortality and clinical signs of toxicity for a further 14 days. A necropsy examination was conducted on all of the animals following the 14 day observation period. There were no deaths, or signs of toxicity or dermal irritation, and no abnormal findings at necropsy. The acute dermal LD50 for D5 is greater than 2000 mg/kg. A reliable supporting study (Carpenter et al, 1974) reported that the acute dermal LD50 is >15,360 mg/kg in rabbits.




Justification for classification or non-classification

Based on the available data D5 does not require classification for acute toxicity according to Regulation (EC) No. 1272/2008.