Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01/2009-03/2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study according to OECD guideline 423

Data source

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

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The test substance, identified as Dowanol™ TPnB-H Glycol Ether, Lot #WK191920K1, was received on January 13, 2009 and was further identified with EPSL Reference Number 090113-1D. The test substance was stored at room temperature. The sample was administered as received.
The following information related to the characterization of the test substance was provided by the Sponsor:
Physical Description: Brown liquid
Solubility: Estimated solubility in water <5%
Stability: Test substance was expected to be stable for the duration of testing.
Expiration Date: December 19, 2010

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Received from Harlan, Indianapolis, IN on January 6, 2009.
- Age at study initiation: young adult (12 weeks)
- Weight at study initiation: 132-144 grams at experimental start.
- Fasting period before study: overnight
- Housing: The animals were singly housed in suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals DHEW (NIH). Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 27-31 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21ºC
- Humidity (%): 15-44%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Individual doses were calculated based on the initial body weights, taking into account the specific gravity (determined by EPSL) of the test substance.
The test substance was administered to the stomach using a stainless steel ball-tipped gavage needle attached to an appropriate syringe. Following administration, each animal was returned to its designated cage. Feed was replaced immediately after dosing.
Doses:
An initial dose of 2,000 mg/kg was administered to three healthy female rats by oral gavage. Due to the death of two of these animals, the study proceeded to the next lower dose level. Three females simultaneously received a dose of 300 mg/kg. Since these animals survived, three additional females
received a 300 mg/kg dose, simultaneously. Since these animals survived, no additional animals were tested.
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
Individual body weights of the animals were recorded prior to test substance administration (initial) and again on Days 7 and 14 (termination) following dosing.

The animals were observed for mortality, signs of gross toxicity, and behavioral changes for the first several hours post-dosing and at least once daily thereafter for 14 days after dosing or until death occurred. Observations included gross evaluation of skin and fur, eyes and mucous membranes,
respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, and coma.

Surviving animals were euthanized via CO2 inhalation at the end of the 14-day observation period. Gross necropsies were performed on the decedents and all euthanized animals. The external surface of the body and all orifices, tissues, and organs of the thoracic and abdominal cavities were examined.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Mortality:
300 mg/kg bw: 0/6
2000 mg/kg bw: 2/3
Clinical signs:
300 mg/kg bw: There were no signs of gross toxicity, adverse clinical signs, or abnormal behavior.
2000 mg/kg bw: Prior to death, the animals were hypoactive and exhibited abnormal posture and/or abnormal gait. Following test substance administration, the surviving female exhibited similar clinical signs as noted above as well as piloerection and reduced fecal volume.
Body weight:
300 mg/kg bw: no abnormalities
2000 mg/kg bw: surviving animal body weight over the entire 14-day observation period
Gross pathology:
300 mg/kg bw: No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.
2000 mg/kg bw: Gross necropsy of the decedents revealed discoloration of the intestines and lungs, and one decedent had a fluid-filled stomach. No gross abnormalities were noted for the euthanized animal when necropsied at the conclusion of the 14-day observation period.
Other findings:
none

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study, the acute oral LD50 of Dowanol™ TPnB-H Glycol Ether is estimated to be between 300 and 2,000 mg/kg of body weight in female rats.
Executive summary:

An acute oral toxicity test (Acute Toxic Class Method) was conducted with Fischer 344 rats to determine the potential for Dowanol™ TPnB-H Glycol Ether to produce toxicity from a single dose via the oral route. Under the conditions of this study, the acute oral LD50 of Dowanol™ TPnB-H Glycol Ether is estimated to be between 300 and 2,000 mg/kg of body weight in female rats. An initial dose of 2,000 mg/kg was administered to three healthy female rats by oral gavage. Due to the death of two of these animals, the study proceeded to the next lower dose level. Three females simultaneously received a dose of 300 mg/kg. Since these animals survived, three additional females received a 300 mg/kg dose, simultaneously. Since these animals survived, no additional animals were tested. All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing or until death occurred. Body weights were recorded prior to administration, and on Days 7 and 14 (termination) following dosing. Necropsies were performed on all animals at sacrifice.