Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP/Guideline Study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

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
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
aerosol dispenser: not specified
Remarks:
migrated information: aerosol
Details on test material:
- Name of test material (as cited in study report): 1,3 and 1,4-Cyclohexanecarboxaldehyde
- Composition of test material, percentage of components: A mixture of 1,3-Cyclohexanedicarboxaldehyde and 1,4-Cyclohexanedicarboxaldehyde
- Lot/batch No.: Lot# 201001644 2nd pass Bottle # 1 and Bottle # 3

Test animals

Species:
rat
Strain:
other: F344/DuCrl
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc. (Kingston, New York)
- Age at study initiation: eight weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: animals were housed two-three per cage in stainless steel cages. Cages had solid bottom floors
- Diet (e.g. ad libitum): LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in pelleted form ad libitum except during the
2-hour acclimation period the day prior to exposure and during the 4-hour exposure period
- Water (e.g. ad libitum): 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. Animals were acclimated to the nose
cones for at least two hours on the day preceding exposure to the test material.

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 (on at 6:00 a.m. and off at 6:00 p.m.)

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
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 to the
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 30 liters per minute, which was sufficient to provide the
normal concentration of oxygen to the animals and approximately 43 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 positive pressure
relative to the surrounding area and was contained within a secondary vented area.
Chamber and exposure room temperature were recorded from two thermocouples
attached to an electronic digital thermometer (Omega Engineering, Inc., Bridgeport, New
Jersey), 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 make-up 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 30 liter per minute flow rate, the theoretical equilibrium time to 99% (T99)
of the target concentration was 6.4 minutes. The animals were placed on the chamber
after the T99 had elapsed and were removed after 240 minutes of exposure.

VEHICLE
The mass concentration of aerosol present in the chamber was determined gravimetrically
three times during the exposure period. Samples were taken by drawing air, at
1 L/minute, through a sampling probe located in the breathing zone of the animals.
Aerosol particles were collected on pre-weighed glass fiber filters (PALL
Corporation, Ann Arbor, Michigan) and charcoal sorbent tubes (SKC, Eighty Four,
Pennsylvania). Background measurements of the chamber were taken after placing
animals on the chamber and prior to starting the exposure. After each atmosphere
sampling, the filter and tubes were re-weighted to obtain the total weight of the particles.
The time-weighted average (TWA) exposure concentration was calculated from the
gravimetric measurements after the 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.

TEST ATMOSPHERE (if not tabulated)
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 MMAD and geometric standard deviation (GSD) were determined for each sample
as well as the average of the samples.
A sorbent tube was placed in-line following the cascade impactor to trap vapors to
prevent contamination of the pump used to draw the samples.

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5.22 mg/l
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 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.
- Necropsy of survivors performed: yes
- Other examinations performed: Detailed clinical observations (DCO) were conducted pre-exposure, twice on test day 1 vfollowing the exposure and daily
thereafter.
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.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC0
Effect level:
> 5.22 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
All animals survived the four-hour exposure to the test material as well as the two-week
post-exposure period.
Clinical signs:
Clinical effects noted during the four-hour exposure period were limited to soiling of the
haircoat in one male and three female rats.
In-life observations noted post-exposure included perineal, perinasal and/or extensive
body soiling in four males and three females, noisy respiration in one male and a partially
closed eye in one female
Body weight:
Mean body weight losses of 11.4% and 6.7% were noted for male and female rats,
respectively, on 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 1,3-
and 1,4-cyclohexanecarboxaldehyde at the test day 15-scheduled necropsy

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on these data, the four-hour LC50 of inhaled 1,3- and 1,4- cyclohexanecarboxaldehyde is greater than 5.22 mg/L for male and female F344/DuCrl rats.
Executive summary:

This study was conducted to determine the acute inhalation toxicological properties of 1,3- and 1,4-cyclohexanecarboxaldehyde. 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 5.22 mg 1,3- and 1,4-cyclohexanecarboxaldehyde per liter of air. The mass median aerodynamic diameter (MMAD) of particulate 1,3- and 1,4- cyclohexanecarboxaldehyde present in the exposure chamber test atmosphere averaged 3.71 microns with an average geometric standard deviation of 2.11 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 one male and three female rats. In-life observations noted post-exposure included perineal, perinasal and/or extensive body soiling in four males and three females, noisy respiration in one male and a partially closed eye in one female. All rats appeared normal by test day 6. Mean body weight losses of 11.4 and 6.7% were noted for male and female rats, respectively, on test day 2. Pre-exposure mean body weight values were exceeded on test day 8. There were no visible treatment related lesions noted in any of the rats exposed to 1,3- and 1,4 -cyclohexanecarboxaldehyde at the test day 15-scheduled necropsy. Based on these data, the four-hour LC50 of inhaled particulate 1,3- and 1,4- cyclohexanecarboxaldehyde is greater than 5.22 mg/L for male and female F344/DuCrl rats.