Registration Dossier

Administrative data

Description of key information

Acute Toxicity Oral: LD50 = > 2000 mg/kg bw; OECD 423; Sanders (2011)

Acute Toxicity Inhalation: Waiver - exposure considerations (vapour pressure)

Acute Toxicity:; Dermal: LD50 = > 2000 mg/kg bw; OECD 402; Sanders (2011)

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:
The study was performed between 28 June 2011 and 26 July 2011.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
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:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 2000
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Female Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: Eight to twelve weeks of age.
- Weight at study initiation: 150 - 186 g (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): 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.
The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of 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%.
Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study.
- 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:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 31.4 mg/ml and 209.0 mg/ml

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusual):
For the purpose of the study the test item formulations were adjusted for the water content (4.3%) of the test item. The test item was freshly prepared, as required, as a solution at the appropriate concentration in distilled water.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
In the absence of data regarding the toxicity of the test item, 314 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight) was chosen as the starting dose.






Doses:
314 (equivalent to 300 mg active ingredient/kg bodyweight) and 2090 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight).
No. of animals per sex per dose:
3 females at 314 mg/kg
6 females at 2090 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.
Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment.

- Necropsy of survivors performed: yes; At the end of the observation period the 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.

Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Individual mortality data are given in Table 1 (see attached background material).
There were no deaths.
Clinical signs:
Individual clinical observations are given in Table 2 and Table 3 (see 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 (see attached background material).
Animals showed expected gains in bodyweight over the study period, except for one animal treated at a dose level of 314 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight) which showed expected gain in bodyweight during the first week but no gain in bodyweight during the second week.
Gross pathology:
Individual necropsy findings are given in Table 6 and Table 7 (see attached background material).
No abnormalities were noted at necropsy.
Interpretation of results:
GHS criteria not met
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 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight) (Globally Harmonised Classification System - Unclassified).
Executive summary:

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

A group of three fasted females was treated with the test item at a dose level of 314 mg/kg bodyweight (equivalent to 300 mg active ingredient/kg bodyweight). Based on the results from this dose level further groups of fasted females were treated at a dose level of 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight). Dosing was performed sequentially.

The test item was administered orally as a solution in distilled water. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

There were no deaths. There were no signs of systemic toxicity. Animals showed expected gains in bodyweight over the study period, except for one animal treated at a dose level of 314 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight) which showed expected gain in bodyweight during the first week but no gain in bodyweight during the second week. No abnormalities were noted at necropsy.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight) (Globally Harmonised Classification System - Unclassified).

The test item did not meet the criteria for classification according to the Classification, Labelling and Packaging Regulation (CLP).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
All studies required for this tonnage band have been submitted and were Klimisch 1 (key studies).

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to REACH Annex VIII, 8.5.2. Column 2, testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. The substance has a low measured vapour pressure of 7.9 x 10-6 Pa at 25°C and inhalation exposure is not considered a significant route of exposure. No acute toxicity study via the inhalation reoute was therefore conducted.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
No acute toxicity study was required, based on exposure considerations - the low vapour pressure precludes inhalation as a significant route of exposure.

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:
The study was performed between 27 July 2011 and 10 August 2011.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
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:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (MAFF), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 26 June 2001
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Health and Welfare, 1992
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Five male and five female Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: Eight to twelve weeks of age.
- Weight at study initiation: At the start of the study the animals weighed 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 Tekland Global Rodent diet) was allowed throughout the study.
- Water (e.g. ad libitum): Free access to mains drinking water was allowed throughout the study.
The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of 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%
Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study.
- Air changes (per hr): At least fifteen 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:
PREPARATION OF TEST ITEM
For the purpose of the study the dose was adjusted for the water content (4.3%) of the test item.
The test item was weighed out according to each animal’s individual bodyweight and moistened with distilled water prior to application.


TEST SITE
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 group of five male and five female rats was treated with the test item at a dose level of 2090 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight).

The appropriate amount of test item, moistened with distilled water, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area). 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 distilled water to remove any residual test item. The animals were returned to group housing for the remainder of the study period.






Duration of exposure:
24 hour contact period.
Doses:
Dose level of 2090 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight).
No. of animals per sex per dose:
Five males and five females at 2090 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.

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.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
Individual clinical observations and mortality data are given in Table 1 (see attached background material).
There were no signs of systemic toxicity.
Body weight:
Individual bodyweights and weekly bodyweight changes are given in Table 4 (see attached background material).
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
Individual necropsy findings are given in Table 5 (see attached background material).
No abnormalities were noted at necropsy.
Other findings:
Dermal Reactions:
Individual dermal reactions are given in Table 2 and Table 3 (see attached background material).
There were no signs of dermal irritation.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight).
The test item does not meet the criteria for classification according to the Classification, Labelling and Packaging Regulation or the Globally Harmonised Classification System.
Executive summary:

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 August 1998

- Japanese Ministry of Agriculture, Forestry and Fisheries (MAFF), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 26 June 2001

- Japanese Ministry of Health and Welfare, 1992

A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the test item to intact skin at a dose level of 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight).

Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

There were no deaths. There were no signs of systemic toxicity. There were no signs of dermal irritation. All animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight).

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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
All studies required for this tonnage band have been submitted and were Klimisch 1 (key studies).

Additional information

Acute Toxicity: Oral

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

A group of three fasted females was treated with the test item at a dose level of 314 mg/kg bodyweight (equivalent to 300 mg active ingredient/kg bodyweight). Based on the results from this dose level further groups of fasted females were treated at a dose level of 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight). Dosing was performed sequentially.

The test item was administered orally as a solution in distilled water. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

There were no deaths. There were no signs of systemic toxicity. Animals showed expected gains in bodyweight over the study period, except for one animal treated at a dose level of 314 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight) which showed expected gain in bodyweight during the first week but no gain in bodyweight during the second week. No abnormalities were noted at necropsy.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight) (Globally Harmonised Classification System - Unclassified).

The test item did not meet the criteria for classification according to the Classification, Labelling and Packaging Regulation (CLP).

Acute Toxicity: Inhalation

According to REACH Annex VIII, 8.5.2. Column 2, testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.  The substance has a low measured vapour pressure of 7.9 x 10-6 Pa at 25°C and inhalation exposure is not considered a significant route of exposure.  No acute toxicity study via the inhalation reoute was therefore conducted.

Acute Toxicity: Inhalation

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 August 1998

- Japanese Ministry of Agriculture, Forestry and Fisheries (MAFF), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 26 June 2001

- Japanese Ministry of Health and Welfare, 1992

A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the test item to intact skin at a dose level of 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight).

Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

There were no deaths. There were no signs of systemic toxicity. There were no signs of dermal irritation. All animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2090 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight).

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

Justification for classification or non-classification

Based on the available data, the substance does not meet the criteria for acute toxicity classification in accordance with Regulation (EC) 1272/2008 (CLP).