Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Compliant with current guidelines and GLP compliant

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): EC 202-228-8
- Physical state: Solid
- Analytical purity: 98.5%
- Composition of test material, percentage of components: 2-(2-naphthoxy)ethanol >98.5%; Ethylene Carbonate < 0.5%; 2-Naphthol <0.5%; Ethylene Glycol < 0.5%
- Lot/batch No.: E00173-186
- Expiration date of the lot/batch: Jul 2013
- Storage condition of test material: Room Temperature

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: The female rats were approximately 66 days of age at arrival at the Testing Facility.
- Weight at study initiation: The body weight range was 202 g to 226 g on the day after arrival at the Testing Facility.
- Fasting period before study: Rats were fasted overnight prior to dose administration through 3 to 4 hours postdose administration.
- Housing: The rats were individually housed in stainless steel, wire-bottomed cages.
- Diet (e.g. ad libitum): Ad libitum (except prior to dose administration)
- Water (e.g. ad libitum) Ad libitum:
- Acclimation period: The rats were acclimated for 5 days prior to assignment to study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Room temperature was targeted at 66°F to 77°F (19°C to 25°C).
- Humidity (%): The relative humidity was targeted at 30% to 70%.
- Air changes (per hr): The study rooms were maintained under conditions of positive airflow relative to a hallway and independently supplied with a minimum of 10 changes per hour of 100% fresh air that had been passed through 99.97% HEPA filters.
- Photoperiod (hrs dark / hrs light): An automatically controlled 12-hours light: 12-hours dark fluorescent light cycle was maintained.

IN-LIFE DATES: From: To: Dosing was initiated on 29 Aug 2011 and the in-life phase of the study was completed on 26 Sep 2011

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 60 and 400 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg
- Justification for choice of vehicle: This is a common vehicle for this type of substance.
- Lot/batch no. (if required): M-631
- Purity: 100%

DOSAGE PREPARATION (if unusual): A standard procedure was used to prepare the test material.

CLASS METHOD (if applicable) Annex 2c
- Rationale for the selection of the starting dose: It was presumed that test material of this type would not be extremely toxic.
Doses:
The doses used on study were 300 and 2000 mg/kg.
No. of animals per sex per dose:
Six female rats were used at the 300 mg/kg dose level and six female rats were used at the 2000 mg/kg dose level.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The female rats were observed and a body weight was recorded on a daily basis.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, food consumption and necropsy observations
Statistics:
Averages and percentages were calculated for this study.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All female rats assigned to study survived until scheduled euthanasia.
Clinical signs:
Clinical observations observed considered test substance-related included: hunched posture was observed in one rat at 300 mg/kg; decreased motor activity, bradypnea, slight excess salivation, ptosis, ataxia and lacrimation were observed at 300 and 2000 mg/kg; and impaired righting reflex, low carriage and coldness to the touch were observed at 300 mg/kg. The adverse clinical observations were first observed at approximately 30 minutes postdose. These clinical observations persisted for approximately two hours in the 300 mg/kg dose groups and until the end of day post-checks in the 2000 mg/kg dose groups. All rats appeared normal on DS 2 and continued to be normal for the remainder of the study except one rat at 2000 mg/kg that was observed with mild dehydration on DS 4.
Body weight:
Body weight gains were reduced in the 2000 mg/kg dose groups, as compared with values for the rats in the 300 mg/kg dose groups on DSs 1 to 2. A body weight loss was observed in the 2000 mg/kg dose groups on DSs 2 to 3. A comparable rebound in body weight gain was observed in both 2000 mg/kg dose groups on DSs 4 to 5. The mean value for the body weight change for rats in the 2000 mg/kg dose groups (averages of Groups 1 and 2) were reduced by 25% for the first week after dose administration (calculated as DSs 1 to 8), as compared with the mean value for the rats in the 300 mg/kg dose groups (average of Groups 3 and 4). Body weight gains were comparable between the 300 and 2000 mg/kg dose groups during the second week of the study (calculated as DSs 8 to 14).
Gross pathology:
No gross lesions were identified at necropsy.

Any other information on results incl. tables

Absolute (g/day) and relative (mg/kg/day) food consumption values were reduced in the 2000 mg/kg dose groups, as compared with values for the rats in the 300 mg/kg dose groups on DSs 1 to 2, 2 to 3 and 3 to 4. A comparable rebound in absolute food consumption values was observed in both 2000 mg/kg dose groups on DSs 4 to 5 and the absolute and relative food consumption values remained generally comparable for the remainder of the study including the entire study period (calculated as DSs 1 to 14). The mean absolute food consumption value for the rats in the 2000 mg/kg dose groups (averages of Groups 1 and 2) were reduced by 12% for the first week after dose administration (calculated as DSs 1 to 8), as compared with the mean value for the rats in the 300 mg/kg dose groups (average of Groups 3 and 4). 

The mean relative food consumption value for the rats in the 2000 mg/kg dose groups (averages of Groups 1 and 2) were reduced by 19% for the first week after dose administration (calculated as DSs 1 to 8), as compared with the mean value for the rats in the 300 mg/kg dose groups (average of Groups 3 and 4). Absolute and relative food consumption values were generally comparable between the 300 and 2000 mg/kg dose groups during the second week of the study (calculated as DSs 8 to 14).  

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information No mortality was caused at 2000 mg/kg; however, there were adverse clinical signs, body weight loss and decreased food consumption at this dose. Criteria used for interpretation of results: EU
Conclusions:
CONCLUSION

In conclusion, administration of a single dose of 300 or 2000 mg/kg of test substance did not cause mortality. Doses of 300 and 2000 mg/kg produced adverse clinical signs that were apparent at the 30 minute postdose observation but were no longer apparent by the end of the day postdose observation. The 2000 mg/kg dose reduced body weight and food consumption the first several days after dose administration.
Executive summary:

Executive Summary

    

The objectives of this study were to determine the acute toxicity resulting from exposure to EC 202-228-8 (test substance) in Crl:CD(SD) rats, and to estimate the defined exposure ranges where lethality is expected, since death of a proportion of the animals was a major endpoint of this study.

The study design was as follows:

Text Table1
Experimental Design

Exposure Group No.

No. of Female Rats

Test Material

Dose Level

(mg/kg)a,b

Concentration

(mg/mL)

Dose Volume

(mL/kg)

1

3

Test Substance

300

60

5

2

3

Test Substance

300

60

5

3

3

Test Substance

2000

400

5

4

3

Test Substance

2000

400

5

a  Subsequent dose levels were established by the Study Director based on the results of the initial 300 mg/kg dose.

b  Rats were fasted overnight prior to dose administration through 3 to 4 hours after dose administration.

Female rats were administered the test substance once by oral gavage. The rats were fasted overnight prior to dose administration through 3 to 4 hours postdose administration. Doses were adjusted for fasted body weights taken before administration. The first day of dose administration was designated as Day 1 of study (DS 1) for each rat.

The 300 mg/kg dose level was administered to 3 female rats. No mortality and body weight gain were observed; therefore, an additional 3 female rats were dosed once with 300 mg/kg of test substance. No mortality and body weight gain were observed following dose administration; therefore, an additional 3 female rats were dosed once with 2000 mg/kg of test substance. No mortality was observed following dose administration; therefore, an additional 3 female rats were dosed once with 2000 mg/kg of test substance. All doses were based on a 5 mL/kg dose volume.  

The following parameters and end points were evaluated in this study: clinical signs, body weights, body weight changes, food consumption, and gross necropsy findings.

Clinical observations observed considered test substance-related included hunched posture, decreased motor activity, bradypnea, slight excess salivation, ptosis, ataxia, lacrimation, impaired righting reflex, low carriage and coldness to the touch. The adverse clinical observations were first observed at approximately 30 minutes postdose. These clinical observations persisted for approximately two hours in the 300 mg/kg dose groups and until the end of day post-checks in the 2000 mg/kg dose groups. All rats appeared normal on DS 2 and continued to be normal for the remainder of the study. 

Body weight gains were reduced in the 2000 mg/kg dose groups, as compared with values for the rats in the 300 mg/kg dose groups on DSs 1 to 2. A body weight loss was observed in the 2000 mg/kg dose groups on DSs 2 to 3. A comparable rebound in body weight gain was observed in both 2000 mg/kg dose groups on DSs 4 to 5. 

Absolute and relative food consumption values were reduced in the 2000 mg/kg dose groups, as compared with values for the rats in the 300 mg/kg dose groups on DSs 1 to 2, 2 to 3 and 3 to 4. A comparable rebound in absolute food consumption values was observed in both 2000 mg/kg dose groups on DSs 4 to 5 and the absolute and relative food consumption values remained generally comparable for the remainder of the study.  

No gross lesions were identified at necropsy.

In conclusion, administration of a single dose of 300 or 2000 mg/kg of test substance did not cause mortality. Doses of 300 and 2000 mg/kg produced adverse clinical signs that were apparent at the 30 minute postdose observation, but were no longer apparent by the end of the day postdose observation. The 2000 mg/kg dose reduced body weight and food consumption the first several days after dose administration.