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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to OECD TG 425, EPA OPPTS 870.1100 and in accordance with the Principles of Good Laboratory Practices (GLP).
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
Remarks:
GLP characterization of 1,4-Cyclohexanedimethanol, reaction products with epichlorohydrin was carried out concurrently along with the conduct of the study, which did not have any impact on the study.
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Remarks:
same as above
Principles of method if other than guideline:
not applicable
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
other: yellow liquid
Details on test material:
- Name of test material (as cited in study report): 1,4 Cyclohexanedimethanol Reaction Products with Epichlorohydrin
- Analytical purity: The purity of the test material was determined to be 9.5 area % 1,4-Cyclohexanedimethanol monoglycidiyl ether, 45.0 area %, 1,4-Cyclohexanedimethanol diglycidyl ether, and 25.0 area % of the reaction product of 1,4-cyclohexanedimethanol with 3 equivalents of epichlorohydrin by gas chromatography/flame ionization detector with tentative identification of the major components by nuclear magnetic resonance and gas chromatography mass spectrometry
- Impurities (identity and concentrations): no information available
- Lot number : Lot # 1H1050NZP1
- Expiration date of the lot/batch: March 05, 2015

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan, Frederick, MD
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 124-135 grams
- Fasting period before study: yes
- Housing: The animals were singly housed in suspended stainless steel caging with mesh floors
- Diet (e.g. ad libitum): Harlan Teklad Certified Global 16% Protein Rodent Diet® #2016C. The diet was available ad libitum, except during fasting.
- Water (e.g. ad libitum): Filtered tap water was supplied ad libitum.
- Acclimation period: 6-34 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22ºC
- Humidity (%):30-49%,
- Air changes (per hr): 13 - 14.
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
not applicable
Doses:
Limit dose - 2000 mg/kg
Main test - 175, 550 and 2000 mg/kg
No. of animals per sex per dose:
Limit test - 1 female rat
Main test - 7 additional female rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for mortality, signs of gross toxicity, and behavioral changes during 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. Individual body weights of the animals were recorded prior to test substance administration (initial) and again on Days 7 and 14 (termination) following dosing or after death.
- Necropsy of survivors performed: yes - Surviving rats were euthanized via CO2 inhalation at the end of the 14-day observation period. Gross necropsies were performed on all decedents and euthanized animals. The external surface of the body and all orifices, tissues, and organs of the thoracic and abdominal cavities were examined.
Statistics:
The Acute Oral Toxicity (Guideline 425) Statistical Program (Westat, 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

Preliminary study:
An initial limit dose of 2,000 mg/kg was administered (undiluted, as received) to one healthy female rat by oral gavage. Due to mortality in this animal, the study proceeded to the Main Test. Using the default starting level of 175 mg/kg and following the Up and Down procedure, seven additional females were dosed at levels of 175, 550 or 2,000 mg/kg.
Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
1 098 mg/kg bw
Based on:
test mat.
95% CL:
550 - 2 000
Mortality:
175 mg/kg (1 rat) - no mortality
550 mg/kg (3 rats) - no mortality
2000 mg/kg (4 rats) - 100% mortality
Clinical signs:
175 mg/kg and 550 mg/kg -Apart from soft feces and reduced fecal volume noted for one rat from the 550 mg/kg dose group at 3 hours or one day post-dosing, all animals from both dose levels appeared active and healthy over the 14-day observation period. There were no other signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior in either dose groups.

2000 mg/kg - All animals died within one day of test substance administration. Toxic signs noted in the decedents prior to death included irregular respiration, hypoactivity and/or hunched posture.
Body weight:
175 mg/kg and 550 mg/kg - All animals gained body weight during the study.

Gross pathology:
175 mg/kg and 550 mg/kg - No gross abnormalities were noted for any of these animals when necropsied at the conclusion of the 14-day observation period.

2000 mg/kg - Gross necropsy of the decedents revealed red discoloration of the lungs or stomach and intestines and/or slight distention of the stomach.
Other findings:
none

Any other information on results incl. tables

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 1,4-Cyclohexanedimethanol, reaction products with epichlorohydrin (1,4-CHDM DGE) is estimated to be 1098 milligrams per kilogram of body weight (based on an assumed sigma of 0.5) in female rats with an approximate 95% confidence interval of 550 mg/kg bw (lower) to 2,000 mg/kg bw (upper). As per Guidance to Regulation (EC) No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures (2012), 1,4-Cyclohexanedimethanol, reaction products with epichlorohydrin (1,4-CHDM DGE) will be classified as acutely toxic (oral), Category 4
Executive summary:

An acute oral toxicity test (Up and Down Procedure) was conducted with female Fischer 344 rats to determine the potential for 1,4-Cyclohexanedimethanol, reaction products with epichlorohydrin, to produce toxicity from a single dose via the oral route. Under the conditions of this study, the acute oral LD50 of the test substance is estimated to be 1,098 mg/kg of body weight (based on an assumed sigma of 0.5) in female rats with an approximate 95% confidence interval of 550 mg/kg (lower) to 2,000 mg/kg (upper). As per Guidance to Regulation (EC) No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures (2012), 1,4-Cyclohexanedimethanol, reaction products with epichlorohydrin (1,4-CHDM DGE) will be classified as acutely toxic (oral), Category 4.

An initial limit dose of 2,000 mg/kg was administered (undiluted, as received) to one healthy female rat by oral gavage. Due to mortality in this animal, the study proceeded to the Main Test. Using the default starting level of 175 mg/kg and following the Up and Down procedure, seven additional females were dosed at levels of 175, 550 or 2,000 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 or until death occurred. Body weights were recorded prior to administration and again on Days 7 and 14 (termination) following dosing or after death. Necropsies were performed on all animals.