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Description of key information

An acute oral study in rats is available and is considered the key study but reliable with restrictions. The test article was not toxic at the approximate limit dose of 2150 mg/kg.

An acute dermal LD50 study on the analog substance is considered the key study.  The analog substance was not toxic at the limit dose of 2000 mg/kg.

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:
09 June 2011 - 20 August 2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study does not conform to current guidlines but rather to an older OECD guideline. The study was not conducted in a GLP certified lab. However, the study was audited by the QA unit and appears to be conducted in the "spirit" of GLP.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
The study has several deviations from the current guideline.
- The study was performed according to OECD401, a test method that has been banned by OECD in 2002 due to animals welfare reasons. However, this devaiton would not impact the outcome of the study.
- Multiple doses were given. The highest dose given in the study is 10,000 mg/kg bw, the limit dose in 2,000 mg/kg bw. A limit study should have been performed.
- The laboratory has no GLP accreditation. However, it was audited by the QA unit and appears to have been conducted in the "spirit" of GLP.
- The LD50 was calculated using the Horn's method which is not a standard method, and not one of the recommended methods in the guideline. However, no toxicity was noted at the dose of 2150 mg/kg which is approximately the limit dose. Therefore, the LD50 can be stated as being > 2000 mg/kg without the need of statistics.
- It is not mentioned if water/diet is analyzed for contaminants.
GLP compliance:
no
Remarks:
The study was conducted in China for a Chinese registration. The study was not conducted in a GLP certified lab. However, the study was audited by the QA unit and appears to be conducted in the "spirit" of GLP.
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Animals were kept in animal room, National Institute of Occupational Health and Poison Control, China CDC (barrier environment, Certificate No.: SYXK(Jing) 2009- 0032). Environmental conditions for animal husbandry are maintained with the 12-h light/dark cycle, the temperature of 20-23℃, and the relative humidity of 40-70%. All animals had free access to sterilized drinking water and irradiation sterilized commercial pellet diets except during exposure (Beijing Keao Xieli Laboratory Diet Co., Ltd. Certificate No.: SCXK(Jing) 2009- 0012). Animals were acclimatized to the laboratory conditions for at least 3d prior to the test.
Route of administration:
oral: gavage
Vehicle:
corn oil
Doses:
1000, 2150, 4640 and 10000 mg/kg bw for female, and 2150, 4640, 10000 and 21500 mg/kg bw for male, respectively.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Forty rats, 20 of each sex, were divided randomly into 4 groups. The exposed dosages were 1000, 2150, 4640 and 10000 mg/kg bw for female, and 2150, 4640, 10000 and 21500 mg/kg bw for male, respectively. The animals were fasted 12h before exposure and were given test substance by gavage with a feeding needle.
The cage side observation has been given. During a 14-day post-exposure period, animals were observed daily, including the onset of signs, recovery and mortality. Individual body weight were measured and recorded on day 3, 7 and 14. Necropsy was performed for the dead rats. On the day 14 of the observation period, all surviving animals were sacrificed and were necThe LD50 and 95% confidence were determined by Horn's method.
Statistics:
The LD50 and 95% confidence were determined by Horn's method.
Sex:
female
Dose descriptor:
LD50
Effect level:
4 300 mg/kg bw
Based on:
test mat.
95% CL:
2 950 - 6 260
Sex:
male
Dose descriptor:
LD50
Effect level:
5 010 mg/kg bw
Based on:
test mat.
95% CL:
3 440 - 7 300
Mortality:
See table below.
Clinical signs:
Clinical observation: The signs such as, activity decreased, limb weakness, side position, dyspnea, issued open mouth berathing were observed in the higher dose groups (21500 and 10000 mg/kg) animals about 10 minutes after treatment. Death occurred within 4 hour after exposure. The rats in the 4640 mg/kg dose group showed slighter signs and the number of deaths was less than the higher dose groups above. No toxic signs and death occurred in the 2150 and 1000 mg/kg dose groups. The survival animals recovered within 24 hours after exposure. No gross pathological changes were observed at necropsy.
Body weight:
The weight of rats was increasing during the test period.
Gross pathology:
Such gross pathological findings as pulmonary hemorrhage and congestion of livers were observed in the died rats. No gross pathological changes were observed in the survival animals at necropsy.

Sex

Dose

(mg/kg)

 Number of

tested animals

Number

of death

Mortality (%)

Female

10000

5

5

100

 

4640

5

3

60

 

2150

5

0

0

 

1000

5

0

0

Male

21500

5

5

100

 

10000

5

5

100

 

4640

5

2

40

 

2150

5

0

0

Interpretation of results:
not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 (95% confidence limits): The oral LD50 (95% confidence limits) of the test substance is 4300 (2950-6260) mg/kg for female rats and 5010 (3440-7300) mg/kg for male rats, respectively.
Executive summary:

The objective is to evaluate the acute oral median lethal dose (LD50) of the substance, and research the gross systemic toxicity after oral administration. The acute oral LD50 (95% confidence limits): The oral LD50 (95% confidence limits) of the test substance is 4300 (2950-6260) mg/kg for female rats and 5010 (3440-7300) mg/kg for male rats, respectively.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 150 mg/kg bw
Quality of whole database:
An acute oral study in rats is available and is considered the key study but reliable with restrictions. The test article was not toxic at the approximate limit dose of 2150 mg/kg.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
No valid 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:
01 June 2012 - 05 July 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Compliant to GLP and testing guidelines; adequate consistence between data, comments and conclusions.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: breeder: Janvier, Le Genest-Saint-Isle, France.
- Age at study initiation: approximately 8 weeks old on the day of treatment
- Mean body weight at study initiation: the males had a mean body weight of 350 g (range: 336 g to 359 g) and the females had a mean body weight of 238 g (range: 231 g to 245 g).
- Fasting period before study: yes, during the night before treatment
- Housing: the animals were housed by five from the same sex and group in polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 or 8 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h.

IN-LIFE DATES: 12 June 2012 to 29 June 2012.
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 10% of body surface, dorsal site
- Type of wrap if used: hydrophilic gauze pad + adhesive hypoallergenic aerated semi-occlusive dressing + restraining bandage

REMOVAL OF TEST SUBSTANCE
- Removal of dressing: 24h post-exposure
- Washing: at 24h post-exposure, with a moistened cotton pad

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume: no
- For solids, paste formed: no
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 anmals per sex.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No unscheduled deaths occurred during the study.
Clinical signs:
No clinical signs indicative of systemic toxicity were observed in any animals.
No cutaneous reactions were observed in any animals.
Body weight:
When compared to CiToxLAB France historical control data, a lower body weight gain was noted in all females (+4 to +16 g vs. 36 ± 12 g in control data base) between day 1 and day 8. Their body weight gain returned to normal thereafter.
Despite a slight lower body weight gain noted in two males (+37 g vs. 45 ± 4 g in control data base) between day 1 and day 8 when compared to CiToxLAB France historical control data, the mean body weight gain of males was unaffected by the test item treatment.
Gross pathology:
No gross findings were observed.

see Executive summary

Interpretation of results:
not classified
Remarks:
Migrated information CLP Criteria used for interpretation of results: other:
Conclusions:
The dermal LD50 of the test item was higher than 2000 mg/kg in rats.

Therefore, the test item is not classified as toxic by dermal route according to the criteria of CLP Regulation.
Executive summary:

The objective of this study was to evaluate the potential toxicity of the test item following a single dermal application to rats.

This study was conducted in compliance with the principles of Good Laboratory Practice.

 

Methods

The test item was applied in its original form to the skin of five female then five male Sprague‑Dawley rats at the dose-level of 2000 mg/kg. The application site was covered by a semi‑occlusive dressing for 24 hours.

Each animal was observed at least once a day for mortality and clinical signs for 15 days. From day 2, any local reactions at the treatment site were also noted. Body weight was recorded on day 1 and then on days 8 and 15.

On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. No tissues were preserved.

 

Results

No unscheduled deaths and no clinical signs indicative of systemic toxicity were observed in any animals.

No cutaneous reactions were observed in any animals.

When compared to CiToxLAB historical control data, a lower body weight gain was noted in all females between day 1 and day 8. Their body weight gain returned to normal thereafter. Body weight of males was unaffected by the test item treatment.

There were no macroscopic findings in any animals.

Conclusion

The dermal LD50of the test item was higher than 2000 mg/kg in rats.

Therefore, the test item is not classified as toxic by dermal route according to the criteria of CLP Regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
A valid study is not available on the registered substance CAS# 1999-85-5. However an apparently well conducted GLP study is available on the analogous meta/para mixture. The acute dermal LD50 of the analog substance was > 2000 mg/kg. The acute dermal LD50 of the registered substance was determined to be > 2150 mg/kg and is considered supporting data due to deficiencies in the report.

Additional information

An acute oral study in rats is available but reliable with restrictions. The test article was not toxic at the approximate limit dose of 2150 mg/kg.

An acute oral study in dd mice is available.

The oral LD50 was 584 mg/kg in males and female 608 mg/kg in females. However, the report lacks adequate details on the conduct of the study and has major deviations from current guidelines (see section below on other information and study details). Lack of knowledge of the initial health of the animals, the strain, the age and fasting time may have influenced the outcome of the study.

As the mouse has major deiviations, the rat study was considered the key study for hazard assessment.

An acute dermal study in rats in available on the analog substance. The analog substance was not toxic at a limit dose of 2000 mg/kg.

Justification for selection of acute toxicity – dermal endpoint

An apparently well conducted GLP study which is considered valid without restrictions.

Justification for classification or non-classification

Based on the available data, the substance is not considered toxic via acute oral or dermal administration.