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Description of key information

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg bodyweight.
The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

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:
Study performed between 11 August 2011 and 15 September 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Female Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd.
- Age at study initiation: Eight to twelve weeks of age
- Weight at study initiation: 171 - 187g. The bodyweights fell within an interval of ±20% of the mean initial bodyweight of the first treated group.
- Fasting period before study: Overnight fast immediately before dosing and for approximately three to four hours after dosing
- Housing: The animals were housed in groups of three in suspended solid floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): Food (2014C Teklad Global Rodent diet) was allowed throughout the study.
- Water (e.g. ad libitum): Free access to mains drinking water was allowed throughout the study.
- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Set to achieve limits of 19 to 25°C
- Humidity (%): Set to achieve limits of 30 to 70%
- Air changes (per hr): At least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.
Route of administration:
oral: gavage
Vehicle:
arachis oil
Remarks:
Used for the 300 mg/kg dose level only.
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 mg/ml for 300 mg/kg dose level

MAXIMUM DOSE VOLUME APPLIED:
10 ml/kg for 300 mg/kg dose level. 2.11 ml/kg for 2000 mg/kg dose level.

DOSAGE PREPARATION:
For the purpose of the 2000 mg/kg dose level, the test item was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level. For the purpose of the 300 mg/kg dose level, the test item was freshly prepared, as required, as a solution at the appropriate concentration in arachis oil BP.

The test item was formulated within approximately two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose.
Doses:
300 mg/kg and 2000 mg/kg
No. of animals per sex per dose:
3 females at 300 mg/kg
9 females at 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for up to fourteen days. Due to a technician error, the second group of animals treated at a dose level of 2000 mg/kg were killed on Day 7. A third group of animals was therefore treated at a dose level of 2000 mg/kg.

Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment or at death.

- Necropsy of survivors performed: yes; At the end of the observation period the surviving animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Statistics:
None recorded.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 500 mg/kg bw
Based on:
test mat.
Mortality:
Individual mortality data are given in Table 1 (attached background material).
There were no deaths.
Clinical signs:
Individual clinical observations are given in Table 2 and Table 3 (attached background material).
There were no signs of systemic toxicity.
Body weight:
Individual bodyweights and weekly bodyweight changes are given in Table 4 and Table 5 (attached background material).
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
Individual necropsy findings are given in Table 6 and Table 7 (attached background material).
A cavity in the right kidney was noted at necropsy of one animal treated at a dose level of 2000 mg/kg. This was considered to be a genetic defect and not test item related. No abnormalities were noted at necropsy of the remaining animals.
Other findings:
None
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg bodyweight (Globally Harmonised Classification System – Unclassified).
Executive summary:

Introduction.

The study was performed to assess the acute oral toxicity of the test item following a single oral administration in the Wistar strain rat. The method was designed to be compatible with the following

- OECD Guidelines for the Testing of Chemicals No. 423 “Acute Oral Toxicity – Acute Toxic Class Method” (adopted 17 December 2001)

- Method B1 tris Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008

- United States Environmental Protection Agency Health Effects Test Guidelines OPPTS 870.1100 Acute Oral Toxicity, 2002

- Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 2000

Method.

A group of three fasted females was treated with the test item at a dose level of 300 mg/kg bodyweight. Based on the results from this dose level further groups of fasted females were treated at a dose level of 2000 mg/kg bodyweight. Dosing was performed sequentially.

The test item was administered orally undiluted or as a solution in arachis oil BP. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. 

There were no deaths.

Clinical Observations. 

There were no signs of systemic toxicity.

Bodyweight. 

All animals showed expected gains in bodyweight over the study period.

Necropsy. 

A cavity in the right kidney was noted at necropsy of one animal treated at a dose level of 2000 mg/kg. This was considered to be a genetic defect and not test item related  No abnormalities were noted at necropsy of the remaining animals.

Conclusion.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg bodyweight (Globally Harmonised Classification System – Unclassified).

The test item does not meet the criteria for classification according to the Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Dangerous Substances.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 500 mg/kg bw
Quality of whole database:
The study has been conducted according to OECD Guideline 423 and GLP and is adequately reported. The study has been assigned a reliability of 1.

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:
Study performed between 21 November 2012 and 05 December 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 10 December 2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Health and Welfare, 1992
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Five male and five femake Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd.
- Age at study initiation: Eight to twelve weeks of age
- Weight at study initiation: At least 200 g. The weight variation did not exceed ±20% of the mean weight for each sex.
- Fasting period before study: None.
- Housing: The animals were housed in suspended solid-floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24-Hour exposure period and in groups of five, by sex, for the remainder of the study.
- Diet (e.g. ad libitum): Free access to food (2014C Teklad Global Rodent diet) was allowed throughout the study.
- Water (e.g. ad libitum): Free access to mains drinking water was allowed throughout the study.
- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Set to achieve limits of 19 to 25°C
- Humidity (%): Set to achieve limits of 30 to 70%
- Air changes (per hr): At least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
PROCEDURE:
On the day before treatment the back and flanks of each animal were clipped free of hair.

Using available information on the toxicity of the test item, a single group of animals was treated as follows:
Dose Level: 2000 mg/kg
Specific gravity: 0.942
Dose volume: 2.12 ml/kg
Number of rats: 5 male and 5 female

The calculated volume of test item, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area) using a graduated syringe. A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. The animals were caged individually for the 24-Hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.

REMOVAL OF TEST SUBSTANCE:
After the 24-Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item. The animals were returned to group housing for the remainder of the study period.




Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5 male and 5 female at 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing:
The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.

After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the Draize scale (see evaluation of skin reactions).

Any other skin reactions, if present were also recorded.

Individual bodyweights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.

- Necropsy of survivors performed: yes
At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Individual mortality data are given in Table 1 (attached background material).
There were no deaths.
Clinical signs:
Individual clinical observations are given in Table 1 (attached background material).
There were no signs of systemic toxicity
Body weight:
Individual bodyweights and weekly bodyweight changes are given in Table 4 (attached background material).
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
Individual necropsy findings are given in Table 5 (attached background material).
No abnormalities were noted at necropsy.
Other findings:
Dermal Reactions:
Individual dermal reactions are given in Table 2 and Table 3 (attached background material).
Very slight erythema was noted at the test sites of three females. There were no signs of dermal irritation noted in the remaining animals.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.
Executive summary:

Introduction.

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat. The method was designed to be compatible with the following:

• OECD Guidelines for the Testing of Chemicals No. 402 "Acute Dermal Toxicity" (adopted 24 February 1987)

• Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008

• United States Environmental Protection Agency Health Effects Test Guidelines OPPTS 870.1200 Acute Dermal Toxicity, 2002

• Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 10 December

• Japanese Ministry of Health and Welfare, 1992

Method.

A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality.

There were no deaths.

Clinical Observations.

There were no signs of systemic toxicity.

Dermal Irritation.

Very slight erythema was noted at the test sites of three females. There were no signs of dermal irritation noted in the remaining animals.

Bodyweight.

All animals showed expected gains in bodyweight over the study period.

Necropsy.

No abnormalities were noted at necropsy.

Conclusion.

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

The test item did not meet the criteria for classification according to the Classification, Labelling and Packaging Regulation or the Globally Harmonised Classification System.

The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Dangerous Substances.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study has been conducted according to OECD Guideline 402 and GLP and is adequately reported. The study has been assigned a reliability of 1.

Additional information

Acute Oral Toxicity

Introduction.

The study was performed to assess the acute oral toxicity of the test item following a single oral administration in the Wistar strain rat. The method was designed to be compatible with the following

- OECD Guidelines for the Testing of Chemicals No. 423 “Acute Oral Toxicity – Acute Toxic Class Method” (adopted 17 December 2001)

- Method B1 tris Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008

- United States Environmental Protection Agency Health Effects Test Guidelines OPPTS 870.1100 Acute Oral Toxicity, 2002

- Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 2000

Method.

A group of three fasted females was treated with the test item at a dose level of 300 mg/kg bodyweight. Based on the results from this dose level further groups of fasted females were treated at a dose level of 2000 mg/kg bodyweight. Dosing was performed sequentially.

The test item was administered orally undiluted or as a solution in arachis oil BP. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. 

There were no deaths.

Clinical Observations. 

There were no signs of systemic toxicity.

Bodyweight. 

All animals showed expected gains in bodyweight over the study period.

Necropsy. 

A cavity in the right kidney was noted at necropsy of one animal treated at a dose level of 2000 mg/kg. This was considered to be a genetic defect and not test item related  No abnormalities were noted at necropsy of the remaining animals.

Conclusion.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg bodyweight.

Acute Dermal Toxicity

Introduction.

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat. The method was designed to be compatible with the following:

- OECD Guidelines for the Testing of Chemicals No. 402 "Acute Dermal Toxicity" (adopted 24 February 1987)

- Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008

- United States Environmental Protection Agency Health Effects Test Guidelines OPPTS 870.1200 Acute Dermal Toxicity, 2002

- Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 10 December

- Japanese Ministry of Health and Welfare, 1992

Method.

A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality.

There were no deaths.

Clinical Observations.

There were no signs of systemic toxicity.

Dermal Irritation.

Very slight erythema was noted at the test sites of three females. There were no signs of dermal irritation noted in the remaining animals.

Bodyweight.

All animals showed expected gains in bodyweight over the study period.

Necropsy.

No abnormalities were noted at necropsy.

Conclusion.

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.


Justification for selection of acute toxicity – oral endpoint
The available acute oral toxicity study is assigned a reliability of 1 and is the only acute oral toxicity study available for the dataset.

Justification for selection of acute toxicity – inhalation endpoint
Refer to acute toxicity inhalation data waiver.

Justification for selection of acute toxicity – dermal endpoint
The available acute dermal toxicity study is assigned a reliability of 1 and is the only acute dermal toxicity study available for the dataset.

Justification for classification or non-classification

The substance does not meet the criteria for classification, under the CLP regulations, for acute toxicity via the oral route based on the result of an acute oral toxicity study conducted to OECD Guideline 423, giving an estimated LD50 of greater than 2500 mg/kg bodyweight.

The substance does not meet the criteria for classification, under the CLP regulations, for acute toxicity via the dermal route based on the results of an acute dermal toxicity study conducted to OECD Guideline 402, which gave an LD50 of greater than 2000 mg/kg bodyweight.

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