Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: 100% as a reaction product

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 174-197 grams
- Fasting period before study: overnight
- Housing: Singly housed in suspended stainless steel caging with mesh floors. Enrichment (e.g. nylabone) was placed in each cage. Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet (e.g. ad libitum): Purina Rodent Chow, timing - not specified
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8-16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23ºC
- Humidity (%): 56-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 25% w/w mixture in corn oil
- Amount of vehicle (if gavage): no data
- Justification for choice of vehicle: no data

DOSAGE PREPARATION (if unusual): Due to the high volume of the test substance to be administered at the 5,000 mg/kg dose level (20.47 mL/kg), each animal's dose was divided into three equal portions and administered approximately two hours apart.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Based on a limit dose of 5000 mg/kg, at the request of the Sponsor, a Main Test was conducted using a default starting dose level of 175 mg/kg administered to one female rat by oral gavage, then the Up and Down procedure was followed.
Doses:
175, 550, 1750 and 5000 mg/kg
No. of animals per sex per dose:
1 at 175 mg/kg
1 at 550 mg/kg
1 at 1750 mg/kg
3 at 5000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: At least once during first hour* after dosing and daily thereafter for 14 days
*The protocol states that the first observation will be made within 30 minutes following test substance administration. Due to a technician error, the first observation for animals of the three lowest doses was made approximately one hour following test substance administration. All animals were observed to be active and healthy approximately one hour after test substance administration and throughout the entire observation period. It is likely that the animals were also active and healthy within 30 minutes of administration. This deviation did not adversely impact the outcome of this study.
-Frequency of weighing: prior to test substance administration (initial) and again on Days 7 and 14 (termination) following dosing
- Necropsy of survivors performed: yes
- Other examinations performed: Tissues and organs of the thoracic and abdominal cavities were examined.
Statistics:
The Acute Oral Toxicity (Guideline 425) Statistical Program (Weststat, version 1.0, May 2001) was used for all data analyses including: dose progression selections, stopping criteria determinations and/or LD50 and confidence limit calculations.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
No deaths occurred.
Clinical signs:
All animals from each dose level survived, appeared active and healthy during the study. There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior.
Body weight:
All animals from each dose level gained body weight during the study.
Gross pathology:
No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.
Other findings:
- Organ weights: Not completed
- Histopathology: Not completed
- Potential target organs: no abnormalities from the tissues and organs of the thoracic and abdominal cavities

Any other information on results incl. tables

Individual Body Weights (g)

Animal No.  Dose (mg/kg) Initial  Day 7  Day 14  Dose (mL)
3101 175 196 226 254 0.14
3102 550 197 240 267 0.44
3103 1750 185 201 248 1.3
3104 5000 176 201 240 3.6
3105 5000 174 191 240 3.6
3106 5000 181 204 243 3.7

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the acute oral LD50 is greater than 5000 mg/kg of body weight in female rats.
Executive summary:

An acute oral toxicity test (Up and Down Procedure) was conducted with rats to determine the potential for the test substance to produce toxicity from a single dose via the oral route. Based on a limit dose of 5000 mg/kg, at the request of the Sponsor, a Main Test was conducted using a default starting dose level of 175 mg/kg administered to one female rat by oral gavage. Following the Up and Down procedure, one female was dosed at 550 and 1750 mg/kg and 3 females were dosed at 5000 mg/kg. Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males. All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing. Body weights were recorded prior to administration and again on Days 7 and 14 (termination) following dosing. Necropsies were performed on all animals at terminal sacrifice.

All animals survived, gained body weight, and appeared active and healthy during the study. There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period. Under the conditions of this study, the acute oral LD50 of the test substance is greater than 5000 mg/kg of body weight in female rats.