Registration Dossier

Administrative data

Description of key information

No mortality was observed after oral, dermal, inhalatory or intraperitoneal application of a single dose of 5000 mg/kg body weight, 3160 mg/kg body weight, 1951 mg/m³ and 1000 mg/kg body weight, respectively. All studies were performed prior to GLP requirements but are adequately reported for evaluation. Minor deviations include the recording of body weight or autopsy findings for some studies. Transient clinical signs resolved within the post-treatment observation period. There were no findings indicative of target organ toxicity. Acute oral, intraperitoneal and inhalation toxicity was studied on rats. Acute dermal toxicity was investigated on rabbits. Acute oral toxicity was also studied in mice.

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:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
purity not indicated, body weighs not given, no data for individual animals
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
no data for single animals, body weight not recorded.
Principles of method if other than guideline:
20 young adult rats were used in this study to determine the range of toxicity. The material was administered to ether-sedated fasted animals as a suspension in DMSO/corn oil (50/50) heated to 50 °C. Controls were given DMSO/corn oil (50/50) only. The dose was given intragastrically with a ball-tipped needle and syringe. After treatment, all animals were observed daily for 30 days for aberrant physiological and behavioral responses
GLP compliance:
no
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
- Storage condition of test material: 25 °C in a glass container sealed inside a polyethylene bag
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 67 days
- Weight at study initiation: 250 - 270 g
- Fasting period before study: Yes
Route of administration:
oral: gavage
Vehicle:
other: DMSO/corn oil (50/50)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 500 mg/mL
- Justification for choice of vehicle: Insoluble in water

DOSAGE PREPARATION (if unusual): 5 g of test material were dissolved in 5 mL of DMS0 at 50 °C. This solution was diluted with 5 mL of corn oil, which formed a suspension of the test substance in the liquid medium. This suspension was kept at 50 °C until administration was completed.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Preliminary study
Doses:
5 g/kg
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 30 days
- Frequency of observations and weighing: No data
- Necropsy of survivors performed: No data
- Other examinations performed: aberrant physiological and behavioral responses
Preliminary study:
Because the LD50 was greater than 5 g/kg, the material was considered to be nontoxic.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Sex:
male
Dose descriptor:
LD0
Effect level:
>= 5 000 mg/kg bw
Mortality:
none
Clinical signs:
The report gives a general assessment that all behavioural and physiological responses were normal.
Body weight:
not recorded
Gross pathology:
not mentioned
Other findings:
none
Interpretation of results:
GHS criteria not met
Conclusions:
Because the LD50 was greater than 5 g/kg, the material was considered to be nontoxic.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
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
Study period:
1980-10-23, 1980-11-13
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
10 h light instead of 12. 2 doses only.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
Species:
rat
Strain:
other: Tif: RAIf (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Bred and raised on the premises
- Age at study initiation:
- Weight at study initiation: 197 - 252 g
- Fasting period before study:
- Housing: 10 animals per cage in Macrolon cages, Type 4 (Ehret, 783 Emmendingen/Germany)
- Diet (e.g. ad libitum): Ad libitum (NAFAG, Gossau/SG, Switzerland)
- Water (e.g. ad libitum): Ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 10
- Photoperiod (hrs dark / hrs light): 14/10
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: Plexiglass exposure chamber
- Exposure chamber volume: 100 L
- Method of holding animals in test chamber: The rats were placed in separate PVC-tubes such that the snout and nostrils of the animals only
were exposed to the aerosol
- Source and rate of air: Air stream discharged into the exposure chamber at a rate of 10 L/min
- Method of conditioning air: Injection into an air stream
- System of generating particulates/aerosols: By introducing the solid test material with the aid of a Grafix Exaktomat Injector (Cerutti AG, Bern, Switzerland) into an air stream
- Method of particle size determination: 4 stage Cascade Impactor (C.F. Casella and Co., Ltd., Regent House, Britannia Walk, London) with Selectron filters (Schleicher and Schull AG, Feldbach, Switzerland) of 25 mm diameter and a pore size of 0.2 μm at an air flow rate of 17.5 L/min
-Pressure in air chamber: negative
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetrically by sampling the test atmosphere through a Selectron filter of 50 mm diameter and a 0.2 μm pore size
Duration of exposure:
4 h
Concentrations:
762 ± 41 and 1951 ± 68 mg/m3 (measured)
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 1, 2 and 4 h as well as at 2 hours post-exposure and daily. Body weights were recorded immediately prior
to exposure and at day 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross examination
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1 951 mg/m³ air (analytical)
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
LC0
Effect level:
>= 1 951 mg/m³ air (analytical)
Exp. duration:
4 h
Mortality:
None
Clinical signs:
other: AlI animals exposed to the test material recovered within 6 days. Slight dyspnoea and ruffled fur were noted in both treatment groups
Body weight:
not affected
Gross pathology:
No gross pathological changes were observed.
Other findings:
The particle size distribution analysis of the chamber airborne particles showed that at least 82 % were smaller than 7 µm in diameter for all exposures.

TABLE 2. PHARMACOTOXIC SIGNS

Exposure level (mg/m3) Pharmacotoxic sign Observation period
Hours Day
Exposure
1 2 4 24 2 3 4 5 6 7 8 9 10 11 12 13 14
762 ± 41 Exophthalmus

+
+ +










Ruffled fur

+
+ + +









1951 ± 68 Exophthalmus

+
+ + +









Ruffled fur

+
+ + + +








Mild = +; Moderate = ++; Severe = +++

TABLE 3. MEAN BODY WEIGHT  ± SD (GRAMS)

Day Sex Concentration (mg/m3)
0 (control) 762 ± 41 1951 ± 68
1 Male 241 ± 9 252 ± 8 202 ± 12
Female 223 ± 6 224 ± 7 197 ± 9
7 Male 291 ± 8 286 ± 13 258 ± 13
Female 232 ± 9 231 ± 7 211 ± 9
14 Male 332 ± 13 330 ± 17 300 ± 15
Female 254 ± 10 250 ± 6 227 ± 10
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
1 951 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:
1964
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups rabbits of either sex were used. A single application of the test material was made at different dose levels. The material was applied to the closely clipped abdominal skin. The test material was moistened with corn oil and spread evenly on a non-absorbent paper backing which was then applied to the skin. The trunks of the animals were wrapped securely with gauze and adhesive tape. After an exposure period of 24 hours, the binders were removed and the area of exposure was washed. The animals were observed for toxic effects and mortality. Throughout the observation period the rabbits were individually housed in elevated metal cages and food and water were freely available at all times. At the end of the observation period each animal was weighed, sacrificed, and examined grossly.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.2 - 2.5 kg
- Housing: Individually in elevated metal cages
- Diet (e.g. ad libitum): Ad libitum (Purina Rabbit Chow)
- Water (e.g. ad libitum): Ad libitum
Type of coverage:
occlusive
Vehicle:
corn oil
Details on dermal exposure:
TEST SITE
- Area of exposure: Abdomen
- Type of wrap if used: Gauze and adhesive tape
- The areas of exposure of two animals at each level were abraded and the other two remained intact.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Sponged with warm tap water to remove any sample residue
- Time after start of exposure: 24 h

TEST MATERIAL
- Constant volume or concentration used: no
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): Enough to moisten the test substance
Duration of exposure:
24 h
Doses:
100, 316, 1000, and 3160 mg/kg bw
No. of animals per sex per dose:
2
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 1, 4, 24 h, and once daily thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: gross examination
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 3 160 mg/kg bw
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 3 160 mg/kg bw
Mortality:
None
Clinical signs:
Normal appearance and behavior
Body weight:
Normal
Gross pathology:
None
Other findings:
Following the removal of the binders at the endo of the exposure period, most or all of the material was still present on the abdomen and the binders of all animals. At the end of the 24h-exposure period, slight erythema was seen in all animals; however, this dermal response completely subsided between the second and the fifth day. For three to seven days during the observation period, slight desquamation was noted on the area of exposure of two animals (one at each level). At termination, there were no signs of dermal irritation in any animal.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal LD50 for albino rabbits is greater than 3160 mg/kg of body weight and there was no evidence of systemic toxicity from percutaneous absorption of the test material.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 160 mg/kg bw

Additional information

The test substance has been investigated in six acute oral toxicity studies, two acute inhalation studies, one acute dermal study and one acute intraperitoneal study and all studies consistently show absence of mortality and target organ toxicity. All studies were performed prior to the introduction of GLP and OECD guidelines. However, they were reported in sufficient detail to conclude that the procedures are sufficiently similar to the OECD guidelines, especially in regard to dose levels, treatment duration and endpoints.

Acute oral toxicity

For acute oral toxicity, three studies are available that were all performed with doses of up to 5000 mg/kg bw. Two studies used male rats whereas the third study used female mice. Sufficient details are reported to allow evaluation of the studies. For all studies, a single dose was given by gavage, and the procedures are comparable to OECD testing guidelines for acute oral toxicity. For the studies by Drake, a post-observation period of 30 days was applied, but necropsy was not included. No mortality and no treatment-related clinical signs were recorded in any of the three studies. Two additional studies are available testing two different batch materials of the test item. In these studies, dose levels of up to 10000 mg/kg in were administered by gavage to both male and female rats. Mortalities occurred among the male test animals (one male of the control group, one male of the low dose and one male of the high dose) probably unrelated to treatment. All female animals survived. Diarrhea, slight hypoactivity and rough coat were recorded until day 3 after administration. Body weight gains were within the expected range. The LD50 values derived in both studies were greater than 10000 mg/kg. In conclusion, the acute oral toxicity of the test article is very low with LD50 values above the regulatory testing limits.

Acute dermal toxicity

The acute dermal toxicity study was performed with 4 female and 4 male rabbits, each two having abraded skin. The test item was identified with a code without further information. It was applied with an occlusive wrapping in corn oil at doses of 100, 316, 1000 and 3160 mg/kg body weight for 24h. There was no mortality, no clinical signs and no effect on body weight gain. Dermal effects were observed at 100 and 3160 mg/kg only: After 24 h exposure, slight erythema was observed in all animals until 1-4 days after exposure. Slight desquamation was noted on the area of exposure in two animals (one from each level) for 3-7 days, which had subsided at the end of the observation period. No information is given whether this was observed for rats with the abraded or intact skin. At termination, there were no signs of dermal irritation in any animal. There were findings upon necropsy. With the limitation in reporting details, the study is adequate for hazard assessment.

Acute inhalation toxicity

The key study for acute inhalation toxicity was performed with a commercial product with a nose-only set-up. Its design and reporting details are adequate for hazard assessment. Rats were exposed to aerosols with concentrations of 0, 762 and 1951 mg/m³ for 4h. At least 82% of the particles had a diameter of less than 7 µm. Concentrations were determined gravimetrically. Exophthalmus and ruffled fur were observed until 2-5 days after exposure. No mortality occurred. There were no effects on body weight gain and no findings upon necropsy.

Acute toxicity by other routes

Upon intraperitoneal injection of 1000 mg/kg body weight, both male and female rats showed dyspnoea, exophthalmus, ruffled fur and curved body posture from which they recovered within 9 days. Body weight gain was not affected during the 14-day observation period. Necropsy findings included peritoneal adhesions or pseudomembranes around the spleen in all animals; one female had also adhesions around the kidney. The study is adequately reported for evaluation.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for acute toxicity under Regulation (EC) No. 1272/2008.