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Registration Dossier

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Administrative data

Description of key information

Oral: LD50=1600 - 3200 mg/kg, rat, Jones 1970
Oral: LD50=3850 ± 355 mg/kg, rat, gavage, Sapegin 1985
Oral: LD50=2400 mg/kg, rat, RTECS, 1990
Dermal: LD50 > 2000 mg/kg, rat, Zelenák, 2014

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:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: The original document was not available and the values were extracted from a secondary source. The results were presented without method description.
Qualifier:
no guideline available
Principles of method if other than guideline:
No data: Unpublished Data, Laboratory of Industrial Medicine, Eastman Kodak Company, Rochester, New York.
GLP compliance:
no
Test type:
other: no data
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
oral: unspecified
Vehicle:
not specified
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LD50
Effect level:
1 600 - 3 200 mg/kg bw
Based on:
not specified
Other findings:
Reduction in hemoglobin and red blood cell (RBC) value, with a rise in white blood cell (WBC) values followed oral administration. Test item is not a methemoglobin former.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral toxicity on rat is reported as LD50 = 1600 - 3200 mg/Kg bw.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 600 mg/kg bw
Quality of whole database:
The quality of the database was rather low, with one original document available, and a second summary document.

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:
2014-01-15 until 2014-01-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: RccHan:(WIST)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adult
- Weight at study initiation: 205-245 g
- Fasting period before study: None
- Housing: Individually in Type II. polypropylene/polycarbonate cages.
- Diet: ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" ad libitum
- Water: Tap water ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 24 - 51
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 15 January 2014 To: 29 january 2014
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Back (shaved 24 hours prior to application).
- % coverage: Approximately 10% total body surface.
- Type of wrap if used: Gauze pads kept in contact with the skin with adhesive hypoallergenic plaster. The entire trunk of the animal was then wrapped with semi occlusive plastic wrap.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test item was removed, using body temperature water.
- Time after start of exposure: 24 hours.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw .
- Constant volume or concentration used: yes
- For solids, paste formed: Yes (moistened with water and distributed as uniformly as possible onto the skin).
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 1, 5 hours after application and once daily thereafter (observations); Day 0 (before the experiment) and on Days 7 and 14 (body weights).
- Necropsy of survivors performed: Yes.
Statistics:
Not applicable (limit test, no mortalities).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities.
Clinical signs:
other: No treatment-related clinical signs or signs of skin irritation.
Gross pathology:
No treatment related effects.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median lethal dose after a single dermal administration (acute dermal LD50) was greater than 2000 mg/kg bw in male and female RccHan:WIST rats.
Executive summary:

Five male and five female RccHan:(WIST) rats were treated with a single, semi occlusive dermal application of the test substance at a dose of 2000 mg/kg bw. The test item was applied as supplied. The application period was 24 hours, followed by a 14-day observation period. Clinical observations along with a check of viability and mortality were performed on all animals at 1 and 5 hours after dosing and daily for 14 days thereafter. Body weight was measured prior to dosing on Day 0 and on Days 7 and 14. Rats were killed and given a gross macroscopic examination at the end of the 2-week observation period (Day 14).

There were no mortalities. No adverse clinical signs were observed after treatment with the test item. There were no treatment related effects on body weight or body weight gain during the observation period. There were no treatment-related effects at necropsy.

The median lethal dose after a single dermal administration (acute dermal LD50) was greater than 2000 mg/kg bw in male and female RccHan:WIST rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Oral acute toxicity

Oral toxicity to mice:

Three studies have been published measuring the acute oral toxicity on mice. For 2 of them, the original document was not available. Sapegin (1985) reported 2 values for the LD50 in mice using 2 different statistical methods. All values are in good agreement. The results of these tests were not used, as the standard species for the purposes of classification is the rat.

Oral toxicity to rats:

The study by Sapegin (1985) reported for acute oral toxicity LD50=3850 ± 355 mg/kg bw. Mortality occurred within 1 day post application for the largest part of the animals. Clinical signs of toxicity included depression of the central nervous system, hypoxia, shortness of breath, sluggish behaviour. In the brain, myocardum, liver and kidney were found signs of focal hemorrhage, thrombosis and dystrophic changes.

Two other studies reported acute oral toxicity on rats. Jones (1970) obtained an LD50 = 1600 - 3200 mg/Kg bw and RTECS (1990) gives the LD50 = 2400 mg/Kg bw, however no details on the study designs were reported.

The available data for acute oral toxicity in the rat is reasonably consistent, and thus the lowest value LD50 = 1600 mg/Kg is selected as the most conservative, and is carried forward for risk assessment and classification and labelling. In accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.2, the available data is considered adequate for the purposes of risk assessment, and classification and labelling, based on a weight of evidence.

Dermal acute toxicity

Zelenák (2014) performed a study carried out in compliance with GLP and according to OECD guideline. The animals were exposed 24 hours to the substance, after which they were kept in observation for 14 days. There were no adverse clinical signs noted in any animals throughout the study. Thus, The median lethal dose of the test item after single dermal administration was found to be greater than 2000 mg/kg bw.

The study is considered complete, reliable and adequate. The acute dermal toxicity value LD50 > 2000 mg/kg bw is carried forward for the purposes of risk assessment, and classification and labelling.


Justification for selection of acute toxicity – oral endpoint
For the purpose of classification and labelling, the most conservative value has been selected.

Justification for selection of acute toxicity – dermal endpoint
Only one study was available, which was carried out according to guideline and under GLP.

Justification for classification or non-classification

Acute Oral Toxicity

The key value selected for the acute oral toxicity, LD50= 1600 mg/kg bw, is the worst-case of the available data for the standard species. This leads to the classification of the substance as Category 4, H302, Harmful if swallowed, according to the criteria in Regulation (EC) No. 1272/2008, Annex I, Part 3, 3.1.2.

Acute Dermal Toxicity

The key value selected for the acute dermal toxicity LD50 > 2000 mg/kg bw. There were no adverse clinical signs noted in any animals throughout the study. The substance does not meet the criteria for classification and labelling for acute dermal toxicity as set out in Regulation (EC) No. 1272/2008, Annex I, Part 2, Table 3.1.1.

Harmonised classification

The above classification is overwritten by the group entry classification for chloroanilines according to Table 3.1 to Annex VI of CLP Regulation (EC) No 1272/2008. The legally-binding classification is the following: Acutely toxic by the oral, dermal and inhalation route Category 3 (minimum classification).

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