Registration Dossier

Administrative data

Description of key information

In accordance with a study conducted according to Guideline OECD 423, the oral LD50 of the test substance can be considered > 5000 mg/kg bw in rats.

In accordance with a study conducted according to Guideline OECD 402, the dermal LD50 of the test substance is > 5000 mg/kg bw in rabbit.

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:
04-25 April 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study performed according to OECD Guideline 423 with minor deviations: temperature and relative humidity were occasionally lower than the minimum optimum values
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
dated 17 December, 2001
Deviations:
yes
Remarks:
temperature and relative humidity were occasionally lower than the minimum optimum values
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
temperature and relative humidity were occasionally lower than the minimum optimum values
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
23 October 2015
Test type:
acute toxic class method
Limit test:
yes
Test material information:
Composition 1
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Batch No.of test material: 171893
- Date received: 22 April 2016
- Manufacturing date: 10 December 2015
- Expiry date: 09 December 2017
- Purity test date: 10 December 2015

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Fridge (6 ± 3°C), darkness

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Used as supplied
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Elevage JANVIER LABS, France
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 8 or 9 weeks
- Weight at study initiation: 180-219 g
- Fasting period before study: Food was removed on Day 1 and then redistributed 4 hours after the test item administration.
- Housing: Animals were housed by group of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid.
- Diet (e.g. ad libitum): Foodstuff (ENVIGO - 2016), ad libitum
- Water (e.g. ad libitum): Drinking water (tap-water from public distribution system), ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 18-25°C
- Humidity: 17-70%
- Air changes: At least 10/hour
- Photoperiod: 12 hours dark / 12 hours light
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DOSAGE PREPARATION: In the first and the second step of the study, the test item was administered by gavage under a volume of 2.20 mL/kg bw (corresponding to 2000 mg/kg bw, according to the density of 0.911 g/mL supplied by the Sponsor) using a suitable graduated syringe fitted with an oesophageal metal canula.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 female rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality were recorded at 30 minutes, 1 hour, 3 hours, 4 hours, and then once daily for 14 days. Animals were weighed on Day 0 (just before administering the test item) and then on Day 2, Day 7 and Day 14.
- Necropsy of survivors performed: Yes; animals were euthanized with sodium pentobarbital on Day 14 and macroscopic observations were noted.
Statistics:
No data
Preliminary study:
Not applicable
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study.
Clinical signs:
A decrease in spontaneous activity (2/6), Preyer’s reflex (1/6) and muscle tone (3/6) was noted in the first hours of the test. The animal recovered a normal activity at 24-hour post-dose.
Body weight:
The body weight evolution of the animals remained normal throughout the study.
Gross pathology:
The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the oral LD50 of the test substance is > 2000 mg/kg bw in rats. In accordance with OECD Guideline 423, the LD50 cut-off of the test substance may be considered to be > 5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to Regulation (EC) No 1272/2008 and according to the Globally Harmonised System on classification and labelling of chemicals (GHS). No signal word or hazard statement is required.
Executive summary:

In an acute oral toxicity study performed according to Guideline OECD 423 and in compliance with GLP, a single dose of 2000 mg/kg bw of the test substance was given by oral gavage to a group of 6 female Wistar rats. Animals were then observed for mortality and clinical signs of toxicity for 14 days.

No mortality occurred during the study. A decrease in spontaneous activity (2/6), Preyer’s reflex (1/6) and muscle tone (3/6) was noted in the first hours of the test. The animals recovered a normal activity at 24-hour post-dose. The body weight evolution of the animals remained normal during the study. The macroscopic examination of the animals at the end of the study did not reveal any treatment related changes.

Rat Oral LD50 > 2000 mg/kg bw.

Therefore, the oral LD50 of the test substance is > 2000 mg/kg bw in rats. In accordance with Guideline OECD 423, the LD50 cut-off of the test substance may be considered to be > 5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to Regulation (EC) No 1272/2008 and according to the Globally Harmonised System for classification and labelling of chemicals (GHS). No signal word or hazard statement is required.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
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:
1972
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Reference:
Composition 0
Principles of method if other than guideline:
Standard acute method: Test substance at three dose levels was applied to the clipped intact and abraded skin on the back of 12 albino rabbits (4/dose) for 24 hours. Animals were then observed for dermal reactions, food consumption, body weights and general behaviour for 14 days.
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Label on test material: RIFM 71-10-56 1-13-72
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2-3 kg
- Housing: Individually housed in metabolism cages
- Diet (e.g. ad libitum): Rabbit pellets, ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: At least 2 weeks
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Prior to placing the animals on test their backs were clipped free of all hair with small animal clippers. The backs were further prepared by making epidermal abrasions every two to three centimeters, longitudinally, over the clipped area of exposure. The abrasions were sufficiently deep so that they penetrated the stratum corneum bot not the dermis, so that no bleeding occurred.
- Type of wrap if used: Application areas were covered with a rubber sleeve or dam which fit snuggly around each animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Application sites were thoroughly wiped down.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.0, 3.9 and 6.0 mL/kg bw
Duration of exposure:
24 hours
Doses:
2.0, 3.9 and 6.0 mL/kg bw
No. of animals per sex per dose:
4 rabbits/dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Examinations performed: During the observation period each animal's food consumption, body weights and general behavior were recorded. Before beginning of the test and at the end of the observation period, haematology and urinalysis were performed on all surviving animals.
- Necropsy of survivors performed: No
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 6 mL/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Mortality:
No mortality occurred during the study.
Clinical signs:
All animals remained normal throughout the study.
Body weight:
All animals gained normal weight throughout the study.
Gross pathology:
Not applicable
Other findings:
- Dermal reactions: Application sites on the back did not show any erythema or oedema and remained normal throughout the study.
- Food consumption: All animals consumed their daily ration and behaved normal throughout the study.
- Haematology: A comparison of the initial and final haematogram values of each animal did not reveal any significant changes.

None

Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 of the test substance is > 5000 mg/kg bw in rabbits therefore it is not classified according to Regulation (EC) No 1272/2008 and according to the GHS.
Executive summary:

In an acute dermal toxicity study, 2.0, 3.9 or 6.0 mL/kg bw of the test substance was applied to the clipped intact and abraded skin on the back of 12 albino rabbits (4/dose) for 24 hours. Animals were then observed for dermal reactions, food consumption, body weights and general behaviour for 14 days.

All animals consumed their daily ration, gained weight and behaved as normal laboratory acclimatized animals. Application sites on the back did not show any erythema or oedema and remained normal throughout the study. A comparison of the initial and final haematogram values of each animal did not reveal any significant changes.

Rabbit dermal LD50 > 6 mL/kg bw (equivalent to 5466 mg/kg bw, considering 0.911 g/mL as the density of the test substance).

 

Therefore, the dermal LD50 of the test substance is > 5000 mg/kg bw in rabbits and it is not classified according to Regulation (EC) No 1272/2008 and according to the GHS.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 000 mg/kg bw

Additional information

In an acute oral toxicity study performed according to Guideline OECD 423 and in compliance with GLP, a single dose of 2000 mg/kg bw of the test substance was given by oral gavage to a group of 6 female Wistar rats. Animals were then observed for mortality and clinical signs of toxicity for 14 days.

No mortality occurred during the study. A decrease in spontaneous activity (2/6), Preyer’s reflex (1/6) and muscle tone (3/6) was noted in the first hours of the test. The animals recovered a normal activity at 24-hour post-dose. The body weight evolution of the animals remained normal during the study. The macroscopic examination of the animals at the end of the study did not reveal any treatment related changes.

In an acute dermal toxicity study, 2.0, 3.9 or 6.0 mL/kg bw of the test substance was applied to the clipped intact and abraded skin on the back of 12 albino rabbits (4/dose) for 24 hours. Animals were then observed for dermal reactions, food consumption, body weights and general behaviour for 14 days. All animals consumed their daily ration, gained weight and behaved as normal laboratory acclimatized animals. Application sites on the back did not show any erythema or oedema and remained normal throughout the study. A comparison of the initial and final haematogram values of each animal did not reveal any significant changes. Rabbit dermal LD50 > 6 mL/kg bw (equivalent to 5466 mg/kg bw, considering 0.911 g/mL as the density of the test substance).

 

Justification for classification or non-classification

The oral LD50 of the test substance is > 2000 mg/kg bw in rats and the dermal LD50 of the test substance is > 5000 mg/kg bw in rabbits. In accordance with Guidelines OECD 423 and OECD 402, the LD50 cut-off of the test substance may be considered to be > 5000 mg/kg bw by oral route in the rat and by derma route in the rabbit. Therefore it is not classified according to Regulation (EC) No 1272/2008 and according to the Globally Harmonised System for classification and labelling of chemicals (GHS). No signal word or hazard statement is required.