Registration Dossier

Administrative data

Description of key information

Repeated inhalation toxicity: The repeated inhalation toxicity of the test item to rats was determined. he animals were exposed to doses of 150, 500 and 1500 ppm equivalent to doses of 0.54, 1.8 and 5.4 mg/L. No NOAEL value was determined. Minor effects were observed. Animals exposed to the highest concentration exhibited motor incoordination after the first two exposures but not after seven exposures, suggesting that some tolerance may have occurred. 
Repeated dermal toxicity: The repeated dermal toxicity of the test item to rabbits was determined. The NOAEL value was determined to be 344 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: only secondary literature (handbook)
Qualifier:
no guideline followed
Principles of method if other than guideline:
Method: other: Repeated inhalation toxicity
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
7 days
Frequency of treatment:
6 hour/day
Remarks:
Doses / Concentrations:
150, 500 or 1500 ppm (0.54; 1.8; 5.4 mg/L)
Basis:
no data
No. of animals per sex per dose:
8 animals/dose and control.
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes



Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Other examinations:
Organ weights: Yes
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Critical effects observed:
not specified

Animals exposed to the highest concentration exhibited motor incoordination after the first two exposures but not after seven exposures, suggesting that some tolerance may have occurred. They appeared lethargic for 3 to 4 hours after exposure. There was an increase in both absolute and relative liver and kidney weights and a decrease in blood glucose level; gross pathologic examination did not reveal any consistent changes attributable to exposure

Conclusions:
The repeated dose toxicity (inhalation) of the test item on rats was examined. Minor effects were observed. Animals exposed to the highest concentration exhibited for example motor incoordination after the first two exposures but not after seven exposures, suggesting that some tolerance may have occurred. No NOAEC was determined.
Executive summary:

The repeated dose toxicity (inhalation) of the test item was examined. Rats were exposed to the test item over a period of 7 days with a frequency of 6 hours per day. 8 animals per dose and control were used. The animals were exposed to doses of 150, 500 and 1500 ppm equivalent to doses of 0.54, 1.8 and 5.4 mg/L. Control animals were not treated. As a result animals exposed to the highest concentration exhibited motor incoordination after the first two exposures but not after seven exposures, suggesting that some tolerance may have occurred. They appeared lethargic for 3 to 4 hours after exposure. There was an increase in both absolute and relative liver and kidney weights and a decrease in blood glucose level; gross pathologic examination did not reveal any consistent changes attributable to exposure. No further information are available.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat
Quality of whole database:
only secondary literature (handbook), no NOAEL identified

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: only secondary literature (handbook)
Qualifier:
no guideline followed
Principles of method if other than guideline:
Repeated dermal toxicity
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Sex:
male/female
Details on exposure:
Route of Administration: dermal, half of the dose was applied to the clipped backs of the rabbits twice a day.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
5 days/week
Remarks:
Doses / Concentrations:
0.344 or 3440 mg/kg bw/day
Basis:
no data
No. of animals per sex per dose:
5 males and 5 females
Control animals:
yes, concurrent vehicle
Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEL
Effect level:
344 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic toxicity
Dose descriptor:
LOAEL
Effect level:
344 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effects
Critical effects observed:
not specified

No adverse effects were detected in those animals that received the low dose other than the expected local effects to the skin at the site of application. These included erythema, drying, thickening, cracking and induration. The high dose caused similar but more extensive injury to the skin and caused serious systemic effects. Three animals of each sex became comatose and died or were sacrified in a moribund condition after a few applications. Gross and histopathologic examinations failed to reveal morphologic lesions that would account for the condition of these animals. With the exception of decreases in body size, adipose reserves, and glycogen of hepatocytes, all other parameters were within the normal range.

Conclusions:
The repeated dermal toxicity of the test item to rats was tested in a subacute study. The NOEAL was determined to be 344 mg/kg bw/day.
Executive summary:

The repeated dermal toxicity of the test item to rabbits was tested in a subacute study. The animals were exposed over a period of 4 weeks with a frequency of 5 days per week. The test item was administrated by applying half of the doses to the clipped backs of the rabbits twice a day. 5 males and 5 females were exposed to a dose of 3440 mg/kg bw/day. Control animals were used, treated with the concurrent vehicle. The NOAEL (basis for effect level systemic toxicity) was determined to be 344 mg/kg bw/day. The LOAEL (basis for effect level local effects) was determined to be 344 mg/kg bw/day. No adverse effects were detected in those animals that received the low dose other than the expected local effects to the skin at the site of application. These included erythema, drying, thickening, cracking and induration. The high dose caused similar but more extensive injury to the skin and caused serious systemic effects. Three animals of each sex became comatose and died or were sacrified in a moribund condition after a few applications. Gross and histopathologic examinations failed to reveal morphologic lesions that would account for the condition of these animals. With the exception of decreases in body size, adipose reserves, and glycogen of hepatocytes, all other parameters were within the normal range.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
344 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
only secondary literature (handbook)

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: only secondary literature (handbook)
Qualifier:
no guideline followed
Principles of method if other than guideline:
Repeated dermal toxicity
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Sex:
male/female
Details on exposure:
Route of Administration: dermal, half of the dose was applied to the clipped backs of the rabbits twice a day.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
5 days/week
Remarks:
Doses / Concentrations:
0.344 or 3440 mg/kg bw/day
Basis:
no data
No. of animals per sex per dose:
5 males and 5 females
Control animals:
yes, concurrent vehicle
Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEL
Effect level:
344 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic toxicity
Dose descriptor:
LOAEL
Effect level:
344 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effects
Critical effects observed:
not specified

No adverse effects were detected in those animals that received the low dose other than the expected local effects to the skin at the site of application. These included erythema, drying, thickening, cracking and induration. The high dose caused similar but more extensive injury to the skin and caused serious systemic effects. Three animals of each sex became comatose and died or were sacrified in a moribund condition after a few applications. Gross and histopathologic examinations failed to reveal morphologic lesions that would account for the condition of these animals. With the exception of decreases in body size, adipose reserves, and glycogen of hepatocytes, all other parameters were within the normal range.

Conclusions:
The repeated dermal toxicity of the test item to rats was tested in a subacute study. The NOEAL was determined to be 344 mg/kg bw/day.
Executive summary:

The repeated dermal toxicity of the test item to rabbits was tested in a subacute study. The animals were exposed over a period of 4 weeks with a frequency of 5 days per week. The test item was administrated by applying half of the doses to the clipped backs of the rabbits twice a day. 5 males and 5 females were exposed to a dose of 3440 mg/kg bw/day. Control animals were used, treated with the concurrent vehicle. The NOAEL (basis for effect level systemic toxicity) was determined to be 344 mg/kg bw/day. The LOAEL (basis for effect level local effects) was determined to be 344 mg/kg bw/day. No adverse effects were detected in those animals that received the low dose other than the expected local effects to the skin at the site of application. These included erythema, drying, thickening, cracking and induration. The high dose caused similar but more extensive injury to the skin and caused serious systemic effects. Three animals of each sex became comatose and died or were sacrified in a moribund condition after a few applications. Gross and histopathologic examinations failed to reveal morphologic lesions that would account for the condition of these animals. With the exception of decreases in body size, adipose reserves, and glycogen of hepatocytes, all other parameters were within the normal range.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
344
Study duration:
subacute
Species:
rabbit
Quality of whole database:
only secondary literature (handbook)

Additional information

Repeated dose toxicity (inhalation)

The repeated dose toxicity (inhalation) of the test item was examined. Rats were exposed to the test item over a period of 7 days with a frequency of 6 hours per day. 8 animals per dose and control were used. The animals were exposed to doses of 150, 500 and 1500 ppm equivalent to doses of 0.54, 1.8 and 5.4 mg/L. Control animals were not treated. As a result animals exposed to the highest concentration exhibited motor incoordination after the first two exposures but not after seven exposures, suggesting that some tolerance may have occurred. They appeared lethargic for 3 to 4 hours after exposure. There was an increase in both absolute and relative liver and kidney weights and a decrease in blood glucose level; gross pathologic examination did not reveal any consistent changes attributable to exposure. No further information are available.

Repeated dermal toxicity

The repeated dermal toxicity of the test item to rabbits was tested in a subacute study. The animals were exposed over a period of 4 weeks with a frequency of 5 days per week. The test item was administrated by applying half of the doses to the clipped backs of the rabbits twice a day. 5 males and 5 females were exposed to a dose of 3440 mg/kg bw/day. Control animals were used, treated with the concurrent vehicle. The NOAEL (basis for effect level systemic toxicity) was determined to be 344 mg/kg bw/day. The LOAEL (basis for effect level local effects) was determined to be 344 mg/kg bw/day. No adverse effects were detected in those animals that received the low dose other than the expected local effects to the skin at the site of application. These included erythema, drying, thickening, cracking and induration. The high dose caused similar but more extensive injury to the skin and caused serious systemic effects. Three animals of each sex became comatose and died or were sacrified in a moribund condition after a few applications. Gross and histopathologic examinations failed to reveal morphologic lesions that would account for the condition of these animals. With the exception of decreases in body size, adipose reserves, and glycogen of hepatocytes, all other parameters were within the normal range.


Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Only study available

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Only study available

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Only study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation according to Annex VI of Regulation (EC) 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result and according to the harmonised Annex VI classification the substance is considered not to be classified for repeated dose toxicity under Regulation (EC) No 1272/2008.

Self-Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data is reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on the results the substance is considered not to be classified for repeated dose toxicity under Regulation (EC) No 1272/2008.