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Toxicological information

Acute Toxicity: inhalation

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Administrative data

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)
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 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

Test material

Reference
Name:
Unnamed
Type:
Constituent
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:
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

Administration / exposure

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.

Results and discussion

Preliminary study:
not applicable
Effect levels
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.

Any other information on results incl. tables

None

Applicant's summary and conclusion

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.