Registration Dossier

Administrative data

Description of key information

ORAL
LD50 >2500 mg/kg (rat); OECD 423 and EU method B.1 tris
DERMAL
LD50 >2000 mg/kg (rat); OECD 402 and EU method B.3

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:
14 March 2001 to 6 April 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: Males: 225 - 238 g; Females: 201 - 205 g
- Fasting period before study: Overnight fast immediately before dosing
- Housing: solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

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.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): at least 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark, 12 hours light


IN-LIFE DATES: NDA
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
- Justification for choice of vehicle: NDA
- Lot/batch no. (if required): NDA
- Purity: NDA


MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg


DOSAGE PREPARATION (if unusual): The test material was freshly prepared, as required, as a suspension at the appropriate concentration in arachis oil BP.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: NDA - although it is reasonable to assume the testing laboratory had prior information leading to the selection of the inital dose level of 2000 mg/kg.
Doses:
2000 mg/kg bodyweight
No. of animals per sex per dose:
2000 mg/kg: 3 male, 3 female
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 0.5, 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
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: NDA
Statistics:
NDA
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 500 mg/kg bw
Mortality:
Male: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 0
Clinical signs:
Signs of toxicity related to dose levels: there were no signs of systemic toxicity
Body weight:
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
Effects on organs: no abnormalities were noted at necropsy.
Other findings:
- Organ weights: NDA
- Histopathology: NDA
- Potential target organs: NDA
- Other observations: NDA
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 material in the Sprague-Dawley CD (Crl: CD® (SD) IGS BR) strain rat was estimated from the attached flow chart (Test Procedure with a Starting Dose of 2000 mg per kg bodyweight.pdf) as being greater than 2500 mg/kg bodyweight.
No mortalities were noted in animals treated with 2000 mg/kg bodyweight.
Executive summary:

In an acute oral toxicity study (656/089), a group of 6 fasted eight week old Sprague Dawley strain rats (three male and three female) were given a single oral dose of Experimental 11214-70 in arachis oil at a dose level of  2000  mg/kg bw and observed for 15 days.

Combined Oral LD50(estimated):>2500 mg/kg bw

No mortality occurred. No signs of systemic toxicity were noted during the study, and no abnormalities were noted at necropsy.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 500 mg/kg bw
Quality of whole database:
The study was conducted in accordance with standardised guidelines under GLP conditions and was awarded reliability score of 1. The quality of the database is therefore considered to be high.

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:
25 February 2008 to 10 March 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
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: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: at least 200g. The weight variation did not exceed ± 20% of the mean weight for each sex, except for one male animal which was slightly outside this range. This deviation was considered not to affect the purpose or integrity of the study.
- Fasting period before study: None
- Housing:suspended solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

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. The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): at least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light


IN-LIFE DATES: From: 25 February 2008 To: 10 March 2008
Type of coverage:
semiocclusive
Vehicle:
arachis oil
Details on dermal exposure:
TEST SITE
- Area of exposure: NDA
- % coverage: approximately 10 % of total body surface area
- Type of wrap if used: a piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage


REMOVAL OF TEST SUBSTANCE
- Washing (if done): 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 material
- Time after start of exposure: after 24-hour contact


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Concentration (if solution): N/A
- Constant volume or concentration used: yes
- For solids, paste formed: NDA


VEHICLE
- Amount(s) applied (volume or weight with unit): the appropriate amount of test material, moistened with arachis oil BP, was applied as evenly as possible to an area of shorn skin
- Concentration (if solution): N/A
- Lot/batch no. (if required): NDA
- Purity: NDA
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
2000 mg/kg: 5 male, 5 female
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 0.5, 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 following scale from Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31:

EVALUATION OF SKIN REACTIONS

Erythema and Eschar Formation Value
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beef redness) to slight eschar formation (injuries in depth) 4

Oedema Formation Value
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) 4

Any other skin reactions, if present were also recorded.

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

- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: None
Statistics:
No data available.
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
There were no signs of systemic toxicity.
Body weight:
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
- Organ weights: NDA
- Histopathology: NDA
- Potential target organs: NDA
- Other observations: there were no signs of dermal irritation
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 material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.
Executive summary:

In an acute dermal toxicity study (0656/0379), a group of ten 8-12 week old Sprague-Dawley strain rats (five male and five female) were dermally exposed to Experimental 11591-54 in arachis oil for 24 hours to approximately 10 % of total body surface area at a dose level of  2000  mg/kg bw.  Animals then were observed for 14 days.

 

Combined Dermal LD50: >2000 mg/kg bw

 

No mortality occurred. No signs of systemic toxicity were noted during the study, and no abnormalities were noted at necropsy. No signs of irritation exhibited in any animals.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study was conducted in accordance with standardised guidelines under GLP conditions and was awarded reliability score of 1. The quality of the database is therefore considered to be high.

Additional information

Oral

The acute oral toxicity of the test material to the rat was investigated using the acute toxic class method in accordance with the standardised guidelines OECD 423 and EU Method B.1 tris under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria for assessing data quality set forth by Klimisch et al. (1997).

Three male and three female fasted Sprague-Dawley rats were exposed to a 2000 mg/kg limit dose of the test material in arachis oil via gavage. The rats were observed for 14 days.

No mortality occurred. No signs of systemic toxicity were noted during the study, and no abnormalities were noted at necropsy.

Under the conditions of this study the Combined Oral LD50(estimated) was >2500 mg/kg bw.

Inhalation

In accordance with section 8.5.2 of Column 2 of REACH Annex VIII, the acute toxicity by inhalation study does not need to be conducted as exposure of humans via inhalation is unlikely given the low vapour pressure and low proportion of particles of an inhalable size.

 

Dermal

The acute dermal toxicity of the test material to the rat was investigated using the standard acute method in accordance with the standardised guidelines OECD 402 and EU Method B.3 under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria for assessing data quality set forth by Klimisch et al. (1997).

Five male and five female Sprague-Dawley rats were exposed to a 2000 mg/kg limit dose of the test material in arachis oil in a semi-occlusive fashion for 24 hours. The rats were observed for 14 days.

No mortality occurred. No signs of systemic toxicity were noted during the study, and no abnormalities were noted at necropsy. No signs of irritation were exhibited in any animals.

Under the conditions of this study the Combined Dermal LD50 was >2000 mg/kg bw.


Justification for selection of acute toxicity – oral endpoint
Only one study available.

Justification for selection of acute toxicity – dermal endpoint
Only one study available.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to acute toxicity via the oral or dermal route.