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Description of key information

The acute oral and dermal toxicity of the test substance was evaluated in three different studies in rats. One male animal died by day 9 of the dermal toxicity study. The death is not considered as treatment-releated mortality. Gross pathology was without any findings. Diarrhoea was observed in one oral toxicity study and is considered as high dose phenomenom. LD50 in acute oral and dermal test was estimated to be greater than 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
Study period:
2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1987
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
1998
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 Hsd: Sprague Dawley® SD® rats
- Source: Harlan Sprague Dawley, Inc.
- Age at study initiation: not mentioned
- Weight at study initiation: not mentioned
- Fasting period before study: over night
- Housing: suspended stainless steel cages. All housing and care were based on the standards recommended by the Guide for the Care and Use of Laboratory Animals
- Diet (e.g. ad libitum): PMI Certified Rodent Meal ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 5d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 37-51
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES: From: 16.03.2000 To: 30.03.2000
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
VEHICLE PEG 400
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg bw
- 2000 mg/kg bw single oral dose (gavage)
Doses:
2000 mg/kg bw, 10 ml/kg, 200 mg/ml
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Clinical Observations
Limit test animals were observed for clinical abnormalities at approximately 1, 2, 4, 8 and 24 hours (post-dose) and daily thereafter (days 1-14). A general health/mortality check was performed twice daily (in the morning and in the afternoon).

Body Weights
Individual body weights were obtained for the limit test animals prior to fasting (day -1), prior to dosing on day 0 and on days 7 and 14.

Food Consumption
Individual food consumption was recorded for all animals on days 0, 7 and 14.

Scheduled Euthanasia
All limit test animals were euthanized by carbon dioxide inhalation at study termination (day 14) and necropsied. Body cavities (cranial, thoracic, abdominal and pelvic) were opened and examined. No tissues were retained.
Statistics:
means and standard deviations
Sex:
male/female
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Remarks on result:
other: no mortality occurred
Mortality:
No mortality occurred during the limit test.
Clinical signs:
The most notable clinical abnormalities observed during the study included fecal/urine stain, mucoid/soft stools, diarrhea, congested breathing and dark
material around the nose/eyes.
Body weight:
Body weight gain was noted for all animals during the test period.
Gross pathology:
No gross internal findings were observed at necropsy on study day 14.
Other findings:
A slight decrease in food consumption was noted from day 7-14; however, adequate food consumption was noted for all animals during the test period.

Table 2: Mean body weights

Day

Males

Females

Mean [g]

SD [g]

N

Mean [g]

SD [g]

N

-1

291

9.6

5

214

11.1

5

0

264

8.3

5

193

8.0

5

7

320

10.9

5

217

8.5

5

14

347

16.4

5

224

9.8

5

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this test, the acute oral LD50 was estimated to be greater than 2000 mg/kg in the rat.
Executive summary:

The single-dose oral toxicity was evaluated in Sprague-Dawley rats. A limit test was performed in which one group of five male and five female rats received a single oral administration of the test article at a dose of 2000 mg/kg body weight. Following dosing, the limit test rats were observed at 1,2,4, 8 and 24 hours post-dose and daily thereafter and weighed weekly. Individual food consumption was recorded weekly. A gross necropsy examination was performed on all limit test animals at the time of scheduled euthanasia (day 14). No mortality occurred during the limit test. The most notable clinical abnormalities observed during the study included fecal/urine stain, mucoid/soft stools, diarrhea, congested breathing and dark material around the nose/eyes. Body weight gain and adequate food consumption were noted for all animals during the test period. No gross internal findings were observed at necropsy on study day 14.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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:
2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1987
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
1998
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: SLI from Harlan Sprague Dawley, Inc.
- Age at study initiation: 9-11 weeks
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 36-56
- Air changes (per hr): 10/15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
On the following day (day 0), the test article was administered dermally to approximately 10% of the body surface area. The four corners of this area were delineated in the clipped area with an indelible marker. The appropriate amount of test article was moistened with an appropriate amount of deionized water to form a paste and was then spread evenly over the delineated area and held in contact with the skin with an appropriately sized 4-ply porous gauze dressing backed with a plastic wrap which was placed over the gauze dressing (occlusive binding). Removal and ingestion of the test article was prevented by placing an elastic wrap over the trunk and test area. The elastic wrap was further secured with a tape harness on the cranial end of the trunk and then secured with adhesive tape around the trunk at the caudal end. Individual doses were calculated based on the animal's day 0 body weight. After an approximate 24-hour exposure period, the gauze dressing, plastic and elastic wrap were removed and the corners of the test site re-delineated using a marker. Residual test article was removed using gauze moistened with deionized water followed by dry gauze.
Duration of exposure:
24h
Doses:
2000 mg/kg, 100%
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Clinical Observations
Limit test animals were observed for clinical abnormalities at approximately 1, 2, 4, 8 and 24 hours (post-dose) and daily thereafter (days 1-14). A general health/mortality check was performed twice daily (in the morning and in the afternoon).

Body Weights
Individual body weights were obtained for the limit test animals prior to dosing on day 0 and for all surviving animals on days 7 and 14. The animal found dead after day 9 was also weighed.

Food Consumption
Individual food consumption was recorded for all animals on days 0, 7 and 14. Food was weighed back for the animal found dead.

Gross Necropsy
All limit test animals that died spontaneously during the study or were euthanized by carbon dioxide inhalation at study termination (day 14) were
necropsied. Body cavities (cranial, thoracic, abdominal and pelvic) were opened and examined. Tissues were retained from the animal that died and were preserved in 10% neutral buffered formalin for possible future histopathology.

Dermal Observations
Limit test animals were examined for erythema and edema following patch removal on study day 1 and daily thereafter (days 2-14) according to the
Macroscopic Dermal Grading System which is based on Draize [2]. The dermal test sites were reclipped as necessary to allow clear visualization of the skin.
Statistics:
mean and standard deviation
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
One male was found dead on day 9
Clinical signs:
The most notable clinical abnormalities observed during the study included dark material around the facial area, urine stain and ocular discharge. No dermal irritation was noted at the site of test article application.
Body weight:
Body weight loss was noted for one female during the study day 0-7 body weight interval and for two females during the study day 7-14 body weight interval. Body weight gain was noted for all other surviving animals during the test period.
Gross pathology:
In the animal that died, gross internal findings included abnormal contents in the small intestine, mottled lungs, enlarged spleen, distended urinary bladder and fluid contents in the thoracic cavity. No gross internal findings were observed at necropsy on study day 14.
Other findings:
Although there was a slight increase in males and a slight decrease in females during the second interval, the food consumption was considered to be
comparable between day 0-7 and day 7-14 for both males and females.

Table 1: Mean body weights

Day

Males

Females

Mean [g]

SD [g]

N

Mean [g]

SD [g]

N

0

274

7.1

5

225

11.4

5

7

292

8.0

5

227

13.4

5

14

310

9.4

4

230

9.8

5

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Under the conditions of this test, the acute dermal LD50 of the test substance was estimated to be greater than 2000 mg/kg in the rat.
Executive summary:

The single-dose dermal toxicity of the test substance was evaluated on Sprague-Dawley rats. A limit test was performed in which one group of five male and five female rats received a single dermal administration of the test article at a dose of 2000 mg/kg body weight. Following dosing, the limit test rats were observed daily and weighed weekly. Individual food consumption was recorded weekly. A gross necropsy examination was performed on all limit test animals at the time of death or scheduled euthanasia (day 14).

Mortality during the limit test occurred at 2000 mg/kg bw, 1/5 male, 0/5 female.

The one mortality occurred by study day 9. The most notable clinical abnormalities observed during the study included dark material around the facial area, urine stain and ocular discharge. No dermal irritation was noted at the site of test article application. Body weight loss was noted for one female during the study day 0-7 body weight interval and for two females during the study day 7-14 body weight interval. Body weight gain was noted for all other surviving animals during the test period. Although there was a slight increase in males and a slight decrease in females during the second interval, the food consumption was considered to be comparable between day 0-7 and day 7-14 for both males and females. In the animal that died, gross internal findings included abnormal contents in the small intestine, mottled lungs, enlarged spleen, distended urinary bladder and fluid contents in the thoracic cavity. No gross internal findings were observed at necropsy on study day 14.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Oral acute toxicity

The acute oral toxicity of the test substance was evaluated in two studies. In the key study, a limit test was performed in which one group of five male and five female Sprague-Dawley rats received a single oral administration of the test article at a dose of 2000 mg/kg body weight. Following dosing, the limit test rats were observed at 1, 2, 4, 8 and 24 hours post-dose and daily thereafter and weighed weekly. No mortality occurred during the limit test. The most notable clinical abnormalities observed during the study included faecal/urine stain, mucoid/soft stools, diarrhoea, congested breathing and dark material around the nose/eyes. No gross internal findings were observed at necropsy on study day 14.

In a second, supporting study, acute oral toxicity was evaluated in male and female rats when administered as a single gavage dose at a level of 2000 mg/kg of body weight. No mortality was observed during the study. All animals appeared normal and exhibited body weight gain during the study. The macroscopic necropsy examinations conducted at termination did not reveal any visible lesions.

Dermal acute toxicity

Dermal toxicity of the test substance was evaluated in Sprague-Dawley rats. A limit test was performed in which one group of five male and five female rats received a single dermal administration of the test article at a dose of 2000 mg/kg body weight. Mortality during the limit test occurred at 2000 mg/kg bw in one male rat by study day 9. In the animal that died, gross internal findings included abnormal contents in the small intestine, mottled lungs, enlarged spleen, distended urinary bladder and fluid contents in the thoracic cavity. No gross internal findings were observed at necropsy on study day 14. The most notable clinical abnormalities observed during the study included dark material around the facial area, urine stain and ocular discharge. No dermal irritation was noted at the site of test article application.

Justification for classification or non-classification

Classification, Labelling, 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.