Registration Dossier

Administrative data

Description of key information

In the key oral acute toxicity study (Bushy Run Research Center, 1982) in rats the LD50 was determined to be > 16.0 ml/kg (12.16 g/kg bw) for males and females. 

The key inhalation study (Dow Corning Corporation, 1997) in rats gave an LC50 of 15956 ppm (ca. 106 mg/l). 

In the key acute dermal toxicity study (Institut Francais de Recherches et Essais Biologiques, 1982), the LD50 for male and female rats was determiend to be >2000 mg/kg.  

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
not in compliance with GLP.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Hilltop-Wistar albino rats, weighing between 200 and 300 g, received the test material by stomach intubation with a ball-end stainless steel needle.  The sample was injected through the needle by means of a syringe and doses were varied by adjusting the volume of the test material.  The rats were fasted overnight before dosing.  Five males and 5 females were included on each level (16.0 and 8.0 ml/kg). 
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Hilltop-Wistar albino
Sex:
male/female
Details on test animals and environmental conditions:
weighing between 200 and 300 g
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE: Not applicable

MAXIMUM DOSE VOLUME APPLIED: Not stated
Doses:
8.0 and 16.0 ml/kg
No. of animals per sex per dose:
5/sex/group
Control animals:
no
Details on study design:
Hilltop-Wistar albino rats, weighing between 200 and 300 g, received the test material by stomach intubation with a ball-end stainless steel needle.  The sample was injected through the needle by means of a syringe and doses were varied by adjusting the volume of the test material.  The rats were fasted overnight before dosing.  Five males and 5 females were included on each level (16.0 and 8.0 ml/kg).  The animals were maintained on appropriate commercial diet and municipal water.  Both were available ad libitum except during period of fasting, manipulation or restraint.   Animal weights were recorded at 0 days (before dose), 7 days and 14 days (just prior to sacrifice).  At death or sacrifice, each animal was subjected to gross pathologic evaluation.
Statistics:
 LD50s were calculated by the moving average method (Thompson, 1947) and were based on a 14-day observation period.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 16 mL/kg bw
Based on:
test mat.
Remarks on result:
other: corresponding to 12.16 g/kg
Mortality:
MALES:
 16.0 ml/kg Dead/Dosed: 0/5
8.0 ml/kg Dead/dosed: 1/5

FEMALES:
 16.0 ml/kg Dead/Dosed: 0/5
8.0 ml/kg Dead/Dosed: 0/5
Clinical signs:
MALES:
16.0 ml/kg  None noted.
 8.0 ml/kg: In the animal that died, sluggishness, unsteady gait at 4 min; death at 15 min.  In survivors, none noted.

FEMALES:
 16.0 ml/kg None noted.
8.0 ml/kg  None noted.
Body weight:
MALES:
16.0 ml/kg Weight change (g) at 7 days: 64 to 60 (mean = 67); Weight change (g) at 14 days: 101 to 121 (mean = 113)
8.0 ml/kg Weight change (g) at 7 days: 72 to 81 (mean = 76); Weight change (g) at 14 days: 96 to 107 (mean = 102)

FEMALES:
 16.0 ml/kg Weight change (g) at 7 days: 30 to 42 (mean = 36) Weight change (g) at 14 days: 35 to 59 (mean = 49)
8.0 ml/kg Weight change (g) at 7 days: 24 to 39 (mean = 33) Weight change (g) at 14 days: 33 to 43 (mean = 38)
Gross pathology:
MALES:
 16.0 ml/kg : Nothing remarkable.
 8.0 ml/kg  In animal that died, lungs with dark spots; liver dark; stomach liquid-filled, injected; intestines and kidneys red.  In survivors, nothing remarkable.

FEMALES:
 16.0 ml/kg : Nothing remarkable.
8.0 ml/kg  Nothing remarkable.
Other findings:
No other findings reported.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral LD50 was determined to be > 16.0 ml/kg, dosed as received, in both male and female rats.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
12 160 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:
1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Principles of method if other than guideline:
The mean actual exposure concentrations were significantly higher than OECD limit test guideline of 5 mg/l.
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 Laboratories, Raleigh, NC

- Age at study initiation:Males approximately 8 weeks and females approximately 10 weeks old when exposed.

- Weight at study initiation: 126 - 150 g

- Housing: Individually in stainless steel, wire mesh-bottom cages

- Diet: Purina rodent chow ad libitum except during exposure

- Water: Ad libitum

- Acclimation period: One week

ENVIRONMENTAL CONDITIONS

- Temperature (°C): 22 ± 2

- Humidity (%): 30 - 70

- Air changes (per hr): Not stated

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

IN-LIFE DATES: From: 15th February 1994 To: 3rd March 1994
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: Stainless steel and glass exposure chambers

- Exposure chamber volume: 120 litre

- Method of holding animals in test chamber:

- Source and rate of air: Ambient air; 10-15 air changes per hour (20.4 - 20.5 litres per minute)

- Method of conditioning air: HEPA and charcoal filters

- System of generating particulates/aerosols: Not applicable

- Method of particle size determination: Not applicable

- Treatment of exhaust air: HEPA and charcoal filters then passed through water scrubber

- Temperature, humidity in chamber: 22.9 - 23.9 °C; 52.0 - 61.2% humidity

TEST ATMOSPHERE

- Brief description of analytical method used: Gas chromatography

- Samples taken from breathing zone: Yes

VEHICLE

Not applicable

TEST ATMOSPHERE
- Particle size distribution: Not applicable

- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Not applicable
Analytical verification of test atmosphere concentrations:
yes
Remarks:
GC
Duration of exposure:
4 h
Concentrations:
11,000; 14,000 and 18,000 (nominal); 10,067; 14,050 and 16,659 ppm (as measured by gas chromatography)
No. of animals per sex per dose:
5/sex/dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight, organ weights, gross pathology
Statistics:
No statistical analysis included.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
15 956 ppm
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: 95% CL = 14,024-34,045
Sex:
male/female
Dose descriptor:
other: NOEL
Effect level:
10 067 ppm
Based on:
test mat.
Exp. duration:
4 h
Mortality:
See Table 1.

One animal in the mid-dose group was sacrificed for human reasons on Day 2. This was not included in the statistical analysis.
Clinical signs:
other: During the 4-hour exposure, some of the animals exposed to concentrations of 14,050 and 16,659 ppm test material experienced prostration and convulsions. Ataxia was also observed in the high exposure group. The primary clinical sign after the exposure was
Body weight:
No apparent effects on body weight gains were observed.
Gross pathology:
In animals that died, congestion and/or haemorrhage of various lobes of the lung were observed in males and females. Congestion of the lungs was also noted in one female from each of the two higher exposure groups at the final sacrifice of the animals that survived exposure.
Other findings:
- Potential target organs: Lung

- Other observations: Response was generally consistent between males and females.

Table 1: Concentrations, exposure conditions and number of evident toxicity per animals treated

Nominal

Conc. (ppm)

Analytical Conc. (ppm)

Number dead/Number exposed

Males

Females

Combined

11000

10067 

 0/5

0/5 

0/10

 14000

14050

 1/5

 1/5

 2/10

18000

 16659

3/5

3/5

 6/10

 

Interpretation of results:
GHS criteria not met
Conclusions:
An acute inhalation LC50 of 15,956 ppm with (95% confidence limits of 14,024-34,045) was determined for male and female rats in an reliable study conducted according to an appropriate test protocol, and in compliance with GLP. This is equivalent to ca. 106 mg/l.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
106 000 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
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
It was not compliant with GLP.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
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: IFFA CREDO

- Weight at study initiation: 180-200g

- Housing: in individual cages (37.5x17x15 cm)

- Diet: IFFARAT feed, ad libitum

- Water: ad libitum



ENVIRONMENTAL CONDITIONS

- Temperature (°C): 22 +/- 1C

- Humidity (%): 50 +/- 10

- Air changes (per hr): 8



IN-LIFE DATES: From: To:
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE

- Area of exposure: shaved dorsal skin

- Type of wrap if used: an aluminium sheet, held in place with adhesive tape


REMOVAL OF TEST SUBSTANCE

- Washing (if done): not rinsed



TEST MATERIAL

- Amount(s) applied (volume or weight with unit): 2.62 ml/kg



Duration of exposure:
Single application, not rinsed
Doses:
2000 mg/kg
No. of animals per sex per dose:
5M, 5F
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days


Statistics:
No statistical analysis reported in the study report.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals died during the study.
Clinical signs:
No skin reactions were noted during the exposure or over the 14 day observation period.
Body weight:
No test substance adverse effects on body weight were reported.
Gross pathology:
Not reported.
Other findings:
Not reported.
Interpretation of results:
GHS criteria not met
Conclusions:
An acute dermal LD50 value of >2000 mg/kg was determined for male and female rats 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
Value:
2 000 mg/kg bw

Additional information

Other results from supporting studies in rats are in agreement with the conclusion that D4 is not harmful via the oral route.]

In the key acute oral study (Bushy Run Research Center, 1982) Hilltop-Wistar rats (5 animals/sex/dose) were administered 8 or 16 ml/kg bw of HMDS by oral gavage then observed for 14 days. Animal weights were recorded at 0 days (before dosing), 7 days and 14 days (just prior to sacrifice). At death or sacrifice, each animal was subjected to gross pathologic evaluation. The only death was a male in the low dose group, which showed sluggishness and unsteady gait at 4 minutes and death at 15 minutes. Necropsy revealed lungs with dark spots, dark liver, liquid-filled, injected stomach, and red intestines and kidneys. There were no adverse findings in the animals that survived. The LD50 was >16 ml/kg bw (equivalent to 12160 mg/kg bw). A number of supporting studies (Reliability 2 or 4) confirm that the acute oral LD50 for HMDS in rats is well in excess of the dosing limit of current guidelines and it is therefore not harmful for acute exposures via the oral route.

In the key acute inhalation study (Dow Corning Corporation, 1997) Sprague-Dawley rats (5 animals/sex/dose) were exposed to HMDS at concentrations of 10067; 14050 and 16659 ppm for 4 hours then observed for 14 days.

At death or sacrifice, each animal was subjected to gross pathologic evaluation

Animals exposed to concentrations of 14050 and 16659 ppm experienced prostration and convulsions. Ataxia was also observed in the high exposure group. The primary clinical sign after the exposure was porphyrin staining of the eyes and face; this was evident in some of the animals of the two higher exposure groups for the entire observation period. In animals that died, congestion and/or hemorrhage of various lobes of the lung were observed in males and females. Congestion of the lungs was also noted in one female from each of the two higher exposure groups at the final sacrifice of the animals that survived exposure. The LC50 was 15,956 ppm with (95% confidence limits of 14,024-34,045). There are no reliable supporting studies for the acute inhalation route for HMDS.

In the key acute dermal study (Institut Francais de Recherches et Essais Biologiques, 1982) Sprague-Dawley rats (5 animals/sex) had HDMS applied to their skin under occlusive conditions at a dose of 2000 mg/kg bw, the skin was not rinsed and the animals were then observed for 14 days. There were no mortalities, clinical signs of toxicity, adverse necropsy findings or indications of local skin irritation. There are an additional two studies that support the conclusion that HMDS is not harmful for acute exposures via the dermal route.


Justification for classification or non-classification

Based on the available oral, dermal and inhalation toxicity data, HMDS does not meet the criteria for classification for acute toxicity

according to Regulation (EC) 1272/2008.