Registration Dossier

Administrative data

Description of key information

 Two current guideline, reliability 1 studies for acute oral toxicity and inhlation toxicity of CHDM DGE.  The available oral and dermal LD50 values and the inhalation LC50 values are all above the classification cut-offs. In the rat, an inhalation 4-hour LC50 value of 12000 ppm and oral LD50 values of 5400 to 7200 mg/kg bw are reported. For the dermal route there are no human data and little animal data; in rabbits the dermal LD50 exceeds 2000 mg/kg bw.
The main toxic effect associated with acute inhalation exposure (humans and animals) is CNS depression.
Based on the available data, at a concentration of 30 ppm (161 mg/m3) for 15 minutes no adverse health effects are to be expected in humans.

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:
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).
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
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
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
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.
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.
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

None

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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 098 mg/kg bw
Quality of whole database:
Good

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
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 403, EEC Part B2 and EPA OCSPP 870.1300 and in accordance with the Principles of Good Laboratory Practices (GLP)
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: F344/DuCrl rats
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (Kingston, New York)
- Age at study initiation: Animals were seven weeks at arrival and nine weeks at the time of exposure.
- Housing: After assignment, animals were housed two to three per cage in stainless steel solid bottom cages with corncob and aspen bedding
- Diet and water: Feed and municipal water was provided ad libitum except during the 2-hour acclimation period the day prior to exposure and during the 4-hour exposure period
- Acclimation period: Animals were acclimated to the laboratory for at least one week prior to the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1°C (and a maximum permissible excursion of ± 3°C)
- Humidity (%): 40-70%
- Air changes (per hr): 10-15 times/hour (average)
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
A 42-liter, Dow-modified ADG nose-only chamber [30 centimeters (cm) in diameter by 60 cm high] was used for the study. Compressed filtered air supplied tothe chamber was at ambient temperature. Airflow through the chamber was determined with a manometer which measured the pressure drop across a calibrated orifice plate and was maintained at approximately 22 liters per minute, which was sufficient to provide the normal concentration of oxygen to the animals and approximately 31 air changes per hour. The manometer was calibrated with a gas meter (Model DTM-115, Singer Aluminum Diaphragm Meter, American Meter Division, Philadelphia, Pennsylvania) prior to the start of the study. The chamber was operated at a slightly negative pressure relative to the surrounding area and was contained within a secondary vented area. Chamber and exposure room temperatures were recorded from two thermocouples attached to an electronic digital thermometer (Control Company, Friendswood, Texas), one thermocouple extended into the exposure chamber and the second was stationed next to the chamber. Chamber relative humidity was monitored by a hygrometer (VWR, West Chester, Pennsylvania) stationed in the interior of the chamber. Low relative humidity values were expected for exposures of this type, since dry, compressed air was the only source of air supplied to the chamber. Therefore, the chamber air was passed through a Model 5-60 DRI-STEEM humidifier filled with distilled water to humidify the air to a level more suitable for the animals.
Based on the 22 liter per minute flow rate, the theoretical equilibrium time to 99% (T99) of the target concentration was 8.8 minutes. The animals were placed on the chamber after the T99 had elapsed and were removed after 240 minutes of exposure.

A liquid aerosol of 1,4-CHDM DGE was generated by metering the test material with a FMI pump (Fluid Metering, Inc., Oyster Bay, New York) into a stainless steel ¼-J spray nozzle (Spraying Systems Co., Wheaton, Illinois). The test material was mixed with compressed air in the spray nozzle and aerosol was sprayed into the chamber. Since the formulation contained materials of varying vapor pressures, the test material was not recycled.

Exposure room temperature, chamber temperature, humidity, and airflow were monitored continuously and recorded approximately every 30 minutes during the exposure period.

The mass concentration of aerosol present in the chamber was determined gravimetrically 4 times during the exposure period. Samples were taken by drawing air, at 1 L/minute, through a sample probe located in the breathing zone of the animals. Aerosol particles were collected on preweighed glass fiber 47 mm filters (PALL Corporation, Ann Arbor, Michigan). Since a substantial portion of the exposure atmosphere consisted of inert vapors and water, vapor samples were collected using a charcoal and a silica-gel sorbent tube, in-line with and down-stream of the glass fiber filter to collect all components of the formulation. Background measurements of vapor in the chamber were taken prior to starting the exposure. After each atmosphere sampling, the filter and tubes were reweighed and the average background measurement was then subtracted to obtain the net weight of the particles and vapors collected. The time-weighted average (TWA) exposure concentration was calculated from the gravimetric measurements, after subtraction of the background measurements.
The nominal concentration was calculated based on the amount of test material fed into the generation system divided by the total chamber airflow.

The aerodynamic particle size was determined twice during the exposure period by drawing samples from within the animal breathing zone at a set rate, using a constant flow air sampling pump through a multi-stage mercer-style cascade impactor. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined for each sample as well as for the average of the samples.
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
4 h
Concentrations:
The resulting time-weighted average concentration was 5.19 mg/L; the nominal concentration was 63.1 mg/L. The differences between the gravimetric and the nominal concentration were due to the loss of test material coating the walls of the generation apparatus and exposure chamber, and the inefficiency of the generation system employed.
No. of animals per sex per dose:
5 male + 5 female
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
Frequency of observations and weighing: A cage-side examination was conducted at least once a day, at approximately the same time each day (usually in the morning). This examination was typically performed with the animals in their cages and was designed to detect significant clinical abnormalities that were clearly visible upon a limited examination, and to monitor the general health of the animals. The animals were not hand-held for these observations unless deemed necessary. Significant abnormalities that would be observed include, but were not limited to: decreased/increased activity, repetitive behavior, vocalization,
incoordination/limping, injury, neuromuscular function (convulsion, fasciculation, tremor, twitches), altered respiration, blue/pale skin and mucous membranes, severe eye injury (rupture), alterations in fecal consistency, and fecal/urinary quantity. In addition, all animals were observed for morbidity, mortality, and the availability of feed and water.
Animals were weighed and examined prior to exposure to the test material and observed at least every 30 minutes during the exposure period. All rats were weighed on test days 2, 4, 8, 11, and 15 during the two-week post-exposure period.at least twice daily.
- Necropsy of survivors performed: yes
- Other examinations performed: Detailed clinical observations (DCO) were conducted pre-exposure, twice following the exposure (test day 1) and daily thereafter. The DCO were conducted on all animals, at approximately the same time each day according to an established format. The examination included cage-side, hand-held and open-field observations that were recorded categorically or using explicitly defined scales (ranked).
Statistics:
Means and standard deviations were calculated for descriptive purposes for chamber concentration (mean only), animal body weights, exposure room temperature and chamber temperature, humidity, and airflow. No statistical analysis was performed as no mortality was observed.
Preliminary study:
not applicable
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.19 other: time weighted average concentration
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: 95% CL not calculated
Mortality:
All animals survived the four-hour exposure to the test material as well as the two-week post-exposure period.
Clinical signs:
other: Clinical effects noted during the four-hour exposure period were limited to soiling of the haircoat in 2/5 female rats, and labored breathing in 3/5 male rats and 5/5 female rats. In-life observations noted post-exposure included combinations of perineal
Body weight:
Mean body weight losses of 6.6% and 6.4% were noted for male and female rats, respectively, by test day 2. Pre-exposure mean body weight values were exceeded on test day 8.
Gross pathology:
There were no treatment-related visible lesions noted in any of the rats exposed to 1,4-CHDM DGE at the test day 15-scheduled necropsy
Other findings:
The average chamber temperature and relative humidity were 20.0 ± 0.0°C and 17.0 ± 1.3%, respectively. The average exposure room temperature was 20.6± 0.5°C.
The chamber O2 level was determined to be 19.9% and the CO2 level was determined to be 470 ppm. Airflow was maintained at 22 liters per minute.
Based on two determinations during the 4-h exposure, the mean MMAD of the particles was 3.54 microns with an average geometric standard deviation of 2.14 microns. Approximately 7% of the particle mass was contained in a size fraction with an aerodynamic diameter less than 1 micron. Approximately 71% of the particulate mass was present in size fractions with an aerodynamic diameter less than 6 microns.

None

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the data, the four-hour LC50 of inhaled 1,4-CHDM DGE aerosol is greater than 5.19 mg/L for male and female F344/DuCrl rats and as per Guidance to Regulation (EC) No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, 1,4-CHDM DGE will not be classified for acute inhalation toxicity.
Executive summary:

This study was conducted to determine the acute inhalation toxicological properties of 1,4-cyclohexanedimethanol, reaction products with epichlorohydrin (1,4-CHDM DGE).

Groups of five rats/sex were exposed for four hours, using a nose-only inhalation exposure system, to a time-weighted average chamber concentration of 5.19 mg 1,4 -CHDM DGE per liter of air. The mass median aerodynamic diameter (MMAD) of particulate 1,4-CHDM DGE present in the exposure chamber test atmosphere averaged 3.54 microns with an average geometric standard deviation of 2.14 microns.

All animals survived the four-hour exposure to the test material as well as the two-week post-exposure period. Clinical effects noted during the four-hour exposure period were limited to soiling of the haircoat in 2/5 female rats, and labored breathing in 3/5 male and 5/5 female rats. In-life observations noted post-exposure included combinations of perineal, perioral, perinasal, and abdominal soiling in 3/5 male and 5/5 female rats. All rats appeared normal by test day 7. Mean body weight losses of 6.6 and 6.4% were noted for male and female rats, respectively, on test day 2. Pre-exposure mean body weight values were exceeded by test day 8. There were no visible treatment-related lesions noted in any of the rats exposed to 1,4-CHDM DGE at the test day 15-scheduled necropsy.

Based on this data, the four-hour LC50 of inhaled 1,4-CHDM DGE aerosol is greater than 5.19 mg/L for male and female F344/DuCrl rats and as per Guidance to Regulation (EC) No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, 1,4-CHDM DGE will not be classified for acute inhalation toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Good

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Reliable with restrictions

Additional information

The acute toxicity potential of CHDM DGE has been sufficiently investigated with oral, inhalation, and dermal acute studies. These studies are explained below but the key findings result in acute toxicity classifications for oral (Category 4) and no classification for the inhalation or dermal routes. 

           Oral

An acute oral toxicity test (Up and Down Procedure) was conducted with female Fischer 344 rats and included a initial limit dose of 2000 mg/kg CHDM DGE in one rat followed by administration of 175, 550 or 2000 mg/kg CHDM DGE in seven additional rats (Durando, 2013). All animals in the 175 and 550 mg/kg dose levels survived exposure to the test substance and gained body weight during the study and were without significant clinical observations 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. In the 2000 mg/kg dose level, 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. Gross necropsy of the decedents revealed red discoloration of the lungs or stomach and intestines and/or slight distention of the stomach. 

Under the conditions of this study, the acute oral LD50 of CHDM DGE was estimated to be 1,098 mg/kg of body weight with an approximate 95% confidence interval of 550 mg/kg (lower) to 2,000 mg/kg (upper). 

An additional oral toxicity study was reported in 1982 (Lockwood and Taylor, 1982). The study report for this study does not contain sufficient information about the test material composition to permit a meaningful evaluation of the study results. Importantly, the test material in this study differs from that in current use, is not relevant, and the study was disregarded.

           Inhalation

An acute liquid aerosol inhalation toxicity study (OECD 403, OPPTS 870.1300) was conducted by the nose-only route in male and female Fischer 344 rats (Hotchkiss et al., 2013). Groups rats were exposed for four hours, using a nose-only inhalation exposure system, to a time-weighted average chamber concentration of 5.19 mg CHDM DGE per liter of air. All animals survived the four-hour exposure to the test material as well as the two-week post-exposure period. Clinical effects noted during the exposure period were limited to soiling of the haircoat in 2/5 female rats, and labored breathing in 3/5 male and 5/5 female rats. Post-exposure in-life observations included combinations of perineal, perioral, perinasal, and abdominal soiling in 3/5 male and 5/5 female rats. All rats appeared normal by test day 7. Mean body weight losses of 6.6 and 6.4% were noted for male and female rats, respectively, on test day 2. Pre-exposure mean body weight values were exceeded by test day 8. There were no visible treatment-related lesions noted in any of the rats exposed to CHDM DGE at the test day 15-scheduled necropsy.

Under the conditions of this study, the four hour acute inhalation LD50 for CHDM DGE aerosol is greater than 5.19 mg/L in male and female F344/DuCrl rats. 

An additional inhalation toxicity study was reported in 1982 (Lockwood and Taylor, 1982). While the results in this study were generally consistent with the key inhalation study, the study report for this study does not contain sufficient information about the test material composition to permit a meaningful evaluation of the study results. Importantly, the test material in this study differs from that in current use, is not relevant, and the study was disregarded.

           Dermal

Two reliable studies are available that evaluate the acute dermal toxicity potential of CHDM DGE. These studies were identical in their design and differed only with the test material administered, either CHDM DGE (ECLIPSE) or CHDM DGE (DER 737). 

The acute semi-occluded dermal toxicity study conducted with CHDM DGE (ECLIPSE) included two groups of 5 female New Zealand White rabbits dermally exposed to CHDM DGE (ECLIPSE) at a dose of 1000 mg/kg body weight or 2000 mg/kg body weight, respectively (Dalal, 2014). The test item was held in contact with the skin throughout the 24-hour exposure period. There was no mortality observed during the study. Erythema and scale formation were observed in all rabbits treated with CHDM DGE (ECLIPSE) at various time points during the study. All animals were active and healthy during the study and all animals gained body weight by the end of the study. External examination of the rabbits at the time of sacrifice revealed scale formation at the site of test item application on four rabbits. Visceral examination of terminally sacrificed animals did not reveal any lesions of pathological significance.

The acute dermal median lethal dose (LD50) of CHDM DGE (ECLIPSE) in female rabbits was found to be greater than 2000 mg/kg body weight. 

The acute semi-occluded dermal toxicity study conducted with CHDM DGE (D.E.R.TM 737) included two groups of 5 female New Zealand White rabbits dermally exposed to CHDM DGE (D.E.R.TM 737) at a dose of 1000 mg/kg body weight or 2000 mg/kg body weight, respectively (Dalal, 2014). The test item was held in contact with the skin throughout the 24-hour exposure period. There was no mortality observed during the study and erythema and scale formation were observed in all rabbits treated with CHDM DGE (D.E.R.TM737) at various time points during the study. All animals were active and healthy during the study. All animals gained body weight by the end of the study. External examination of the rabbits at the time of sacrifice revealed scale formation at the site of test item application on two rabbits. Visceral examination of terminally sacrificed animals did not reveal any lesions of pathological significance.

The acute dermal median lethal dose (LD50) of CHDM DGE (D.E.R.TM737) in female rabbits was found to be greater than 2000 mg/kg body weight.

Additional dermal studies reported in 1982 with test materials differing compositions that are not entirely clear. Importantly, the test material in these studies differ from that in current use, is not relevant, and the studies were disregarded.


Justification for selection of acute toxicity – oral endpoint
Reliability 1 OECD guideline study

Justification for selection of acute toxicity – inhalation endpoint
Reliability 1 OECD guideline study

Justification for classification or non-classification

Oral

An acute oral toxicity test (Up and Down Procedure) was conducted with female Fischer 344 rats and included a initial limit dose of 2000 mg/kg CHDM DGE in one rat followed by administration of 175, 550 or 2000 mg/kg CHDM DGE in seven additional rats (Durando, 2013). 

Under the conditions of this study, the acute oral LD50 of CHDM DGE was estimated to be 1,098 mg/kg of body weight 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), this study led to CHDM classified as acutely toxic (oral), Category 4.

Inhalation

An acute liquid aerosol inhalation toxicity study (OECD 403, OPPTS 870.1300) was conducted by the nose-only route in male and female Fischer 344 rats (Hotchkiss et al., 2013). Groups rats were exposed for four hours, using a nose-only inhalation exposure system, to a time-weighted average chamber concentration of 5.19 mg CHDM DGE per liter of air. 

Under the conditions of this study, the four hour acute inhalation LD50 for CHDM DGE aerosol is greater than 5.19 mg/L in male and female F344/DuCrl rats. As per Guidance to Regulation (EC) No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, CHDM DGE will not be classified for acute inhalation toxicity.

Dermal

Two reliable studies are available that evaluate the acute dermal toxicity potential of CHDM DGE. These studies were identical in their design and differed only with the test material administered, either CHDM DGE (ECLIPSE) or CHDM DGE (DER 737). Theacute semi-occluded dermal toxicity study conducted with CHDM DGE (ECLIPSE) included two groups of 5 female New Zealand White rabbits dermally exposed to CHDM DGE (ECLIPSE) at a dose of 1000 mg/kg body weight or 2000 mg/kg body weight, respectively (Dalal, 2014).  The acute semi-occluded dermal toxicity study conducted with CHDM DGE (D.E.R.TM 737) included two groups of 5 female New Zealand White rabbits dermally exposed to CHDM DGE (D.E.R.TM 737) at a dose of 1000 mg/kg body weight or 2000 mg/kg body weight, respectively (Dalal, 2014). 

The acute dermal median lethal dose (LD50) of both CHDM DGE (ECLIPSE) and CHDM DGE (D.E.R.TM737) in female rabbits was found to be greater than 2000 mg/kg body weight. As per Guidance to Regulation (EC) No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, 1,4-CHDM DGE will not be classified for acute dermal toxicity.