Registration Dossier

Administrative data

Description of key information

Acute toxicity studies are available for all three routes of exposure.

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:
2000-08-30 to 2001-06-21
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP/Guideline Study
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
other: Annex V (LD50 test)
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Qualifier:
according to
Guideline:
other: MAFF 11 Nousan 6283
Principles of method if other than guideline:
Similar to Guideline study
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Raleigh, NC
- Age at study initiation: Eight to 10 weeks old (males) and nine to 12 weeks old (females)
- Weight at study initiation: 221 to 288 grams (males) and 187 to 231 grams (females)
- Fasting period before study: Food was withheld during the 18- to 20-hour period immediately prior to dosing and returned approximately four hours after dosing.
- Housing: Individual suspended wire-mesh cages.
- Diet (e.g. ad libitum): PMI Nutrition International, Inc. Certified Rodent LabDiet® 5002
- Water (e.g. ad libitum): municipal water
- Acclimation period: The animals were acclimated to laboratory conditions for a minimum of seven days prior to initiation of dosing.

ENVIRONMENTAL CONDITIONS
- Temperature: 68-71°F
- Humidity (%): (32-70%
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

IN-LIFE DATES: From: 2001-02-23 To: 2001-03-23
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Remarks:
None
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 5000 mg/kg

DOSAGE PREPARATION (if unusual): The test article was dosed undiluted based on its specific gravity.

The dose volumes were determined by dividing the dose levels of 613, 1751 and 5000 mg/kg, expressed as g/kg, by the specific gravity (1.0572
g/ml, as determined by WIL Research Laboratories, Inc. pharmacy personnel). Individual doses were calculated based on body weights taken just
prior to dosing and dose volumes of 0.58, 1.7 and 4.7 ml/kg for the 613, 1751 and 5000 mg/kg groups, respectively.
Doses:
613 mg/kg
1751 mg/kg
5000 mg/kg
No. of animals per sex per dose:
15
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed at approximately 1, 3 and 4 hours post-dosing on study day 0 and once daily thereafter
for 14 days. Body weights were obtained and recorded on study days -1, 0 (initiation), 7 and 14 (termination). In addition, animals found dead were weighed as soon as they were found in that condition.
- Necropsy of survivors performed: yes
Statistics:
none
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 678 mg/kg bw
Based on:
test mat.
95% CL:
1 448 - 1 943
Mortality:
Male: 613 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 1751 mg/kg bw; Number of animals: 5; Number of deaths: 2
Male: 5000 mg/kg bw; Number of animals: 5; Number of deaths: 5
Female: 613 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 1751 mg/kg bw; Number of animals: 5; Number of deaths: 4
Female: 5000 mg/kg bw; Number of animals: 5; Number of deaths: 5
Clinical signs:
Signs of toxicity related to dose levels:
Various discolored areas due to discharges and excretions
were observed for all male and two female animals at 5000
mg/kg, for three male and all female animals at 1751 mg/kg
and for two male animals at 613 mg/kg.

All male and one female animal at 5000 mg/kg showed
prostration and labored respiration. Hypoactivity was
observed for all female animals and two male animals at 1751
mg/kg.

Mucoid/soft feces was observed for three male animals at
5000 mg/kg and one male and one female animal at 613 mg/kg.

Rales were observed for 2 female animals at 1751 mg/kg and
one female at 613 mg/kg.

One female at 5000 mg/kg and one male at 1751 mg/kg showed
impaired muscle coordination and one male at 5000 mg/kg was
observed with twitching.

All animals noted with neurological findings died.

One male animal at 613 mg/kg was observed with hair loss at
ventral trunk.

No other clinical findings were observed during the study.
All surviving animals appeared normal by study day 3 and
through the remainder of the study.
Body weight:
One female lost 1 gram (0.4%) of body weight from study days 7 to 14, but remained
above initial (study day 0) body weight at study termination. There were no other
remarkable body weight changes noted during the study.
Gross pathology:
Effects on organs:
Five found dead animals (three females and one male at 5000
mg/kg and one female at 1751 mg/kg) were noted with
gastrointestinal findings, including red fluid contents of
the intestine, thick white or clear fluid contents of the
stomach and/or distension of the stomach.

Two male animals at 1751 mg/kg were noted with scabbing of
urogenital area.

One female at 5000 mg/kg showed opacity of the right eye.

Three females and two males at 1751 mg/kg and one male at
613 mg/kg were noted with various external mattings.

There were no other gross necropsy findings for animals
found dead.

For surviving animals at terminal necropsy, one male animal
at 613 mg/kg was noted with red nasal matting.

There were no other gross necropsy findings for any examined
tissues.

TABLE 1. GROSS NECROPSY OBSERVATIONS INCIDENCE SUMMARY

FOUND DEAD OR EUTHANIZED MORIBUND OR IN EXTREMIS

      MALE  FEMALE
 

 GROUP:

 1  2  3  1  2  2
NUMBER OF ANIMALS IN DOSE GROUP  5  5  5
NUMBER OF ANIMALS EXAMINED   0 5 0 4 5
INTESTINE             
 -RED FLUID CONTENTS  0 0 1 0 0
 EYES            
 -EYE(S)- OPACITY  0 0
 SKIN            
 -CLEAR MATTING  0
 -RED MATTING  0
 -SCABBING  0 0
 STOMACH            
 -THICK WHITE MATERIAL  0
 -DISTENDED  0
 NO SIGNIFICANT CHANGES OBSERVED - ALL EXAMINED TISSUES  0

1- 613 MG/KG 2- 1751 MG/KG 3- 5000 MG/KG

TABLE 2. SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

 MALE
 TABLE RANGE:  DAY 0 TO DAY 14
 GROUP:  1  2  3
 DISPOSITION      
 -ANIMAL FOUND DEAD 0/0 2/2  5/5 
 -TERMINAL NECROPSY 5/5 3/3 0/0
 EYES/EARS/NOSE      
 -DRIED RED MATERIAL AROUND NOSE  0/0  1/1  0/0
 ACUTES      
 -APPEARED NORMAL  70/5  46/5  0/0
 -FOUND DEAD  0/0  2/2  5/5
 -PROSTRATE  0/0  0/0  6/5
 -RESPIRATION LABORED 0/0   0/0  5/5
 -DRIED WHITE MATERIAL AROUND MOUTH  0/0  0/0  3/3
 -TWITCHING  0/0  0/0  1/1
 -MUCOID FECES  2/1  0/0  3/3
 -RESPIRATION SHALLOW  0/0  0/0  1/1
 -CLEAR NASAL DISCHARGE  0/0  0/0  1/1
 -IMPAIRED MUSCLE COORDINATION  0/0  3/1  0/0
 -DRIED YELLOW MATERIAL AROUND MOUTH  3/2  6/2  0/0
 -DRIED YELLOW MATERIAL FORELIMB(S)  0/0  3/1  0/0
 -HYPOACTIVE  0/0  4/2  0/0
 -WET YELLOW MATERIAL AROUND MOUTH  1/1  1/1  0/0
 -WET BROWN MATERIAL ANOGENITAL AREA  0/0  3/1 0/0
 -WET YELLOW MATERIAL ANOGENITAL AREA  1/1  0/0  0/0
 -DRIED BROWN MATERIAL ANOGENITAL AREA  0/0  3/1  0/0
 -DRIED RED MATERIAL AROUND MOUTH  0/0  2/1  0/0
 -HAIR LOSS VENTRAL TRUNK  11/1  0/0  0/0

1- 613 MG/KG 2- 1751 MG/KG 3- 5000 MG/KG

TABLE 2: SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

FEMALE

 TABLE RANGE:  DAY 0 TO DAY 14
 GROUP:  1  2  3
 DISPOSITION      
 - ANIMAL FOUND DEAD  0/0  4/4  5/5
 - TERMINAL NECROPSY  5/5  1/1

0/0

 ACUTES      
 - APPEARED NORMAL  82/5  12/1  0/0
 - FOUND DEAD  0/0  4/4  5/5
 - PROSTRATE  0/0  1/1  1/1
 - RESPIRATION LABORED  0/0  0/0  1/1
 - DRIED WHITE MATERIAL AROUND MOUTH  0/0  0/0  4/2
 - IMPAIRED MUSCLE COORDINATION  0/0  0/0  2/1
 - DRIED YELLOW MATERIAL AROUND MOUTH  0/0  4/2  0/0
 - HYPOACTIVE  0/0  10/5  0/0
 - WET YELLOW MATERIAL AROUND MOUTH  0/0  3/2  0/0
 - WET BROWN MATERIAL ANOGENITAL AREA  0/0  1/1  0/0
 - WET YELLOW MATERIAL ANOGENITAL AREA  0/0  6/3  0/0
 - WET CLEAR MATERIAL AROUND MOUTH  0/0  2/2  0/0
 - RALES  2/1  4/2  0/0
 - GASPING  0/0  1/1  0/0
 - DRIED BROWN MATERIAL ANOGENITAL AREA  0/0  2/1  0/0
 - DRIED RED MATERIAL AROUND MOUTH  0/0  2/1  0/0
 - DRIED CLEAR MATERIAL AROUND THE MOUTH  0/0  1/1  0/0
 - WET YELLOW MATERIAL UROGENITAL AREA  0/0  2/1  0/0
 - DRIED YELLOW MATERIAL IROGENITAL AREA  0/0  1/1  0/0
 - SOFT FECES  2/1  0/0  0/0

1- 613 MG/KG 2- 1751 MG/KG 3- 5000 MG/KG

TABLE 3. GROSS NECROPSY OBSERVATIONS INCIDENCE SUMMARY

   MALE  FEMALE
 GROUP:  1  2  3  1  2  3
 NO. OF ANIMALS IN DOSE GROUP  5  5  5  5  5  5
 NO. OF ANIMALS TERMINALLY EUTHANIZED  5  3  0  5  1  0
 SKIN            
 - RED MATTING  1  0  0  0  0  0
 NO SIGNFICANT CHANGES OBSERVED - ALL EXAMINED TISSUES  4  3  0  5  1  0

1- 613 MG/KG 2- 1751 MG/KG 3- 5000 MG/KG

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 of Consolidated Cyclohexane Dicarboxaldehydes was 1678 mg/kg with 95% confidence limits of 1448-1943 mg/kg when administered once orally via gavage to fasted male and female albino rats.
Executive summary:

The acute peroral toxicity of Consolidated Cyclohexane Dicarboxaldehydes was evaluated in this

single-dose study in rats. The test article was administered once orally via gavage to three groups

of five male and five female fasted albino rats at dose levels of 613, 1751 and 5000 mg/kg.

Mortality, clinical observations and body weight changes were evaluated over a 14-day

observation period. All animals were subjected to a gross necropsy.

All deaths were noted within one day of dosing. Mortality was 0/10, 6/10 and 10/10 for the 613,

1751 and 5000 mg/kg dose groups, respectively.

Approximately one-half of the animals were noted with various discolored areas due to

discharges/excretions. Approximately one-fourth of the animals were noted with prostration,

hypoactivity and/or labored respiration. Findings noted for four animals each or less were

mucoid feces, rales, impaired muscle coordination, gasping, shallow respiration, twitching, clear

nasal discharge, hair loss on the ventral trunk and/or soft feces. All animals that were noted with

neurological findings died. No other clinical findings were observed during the study. With the

exception of one animal noted with hair loss on the ventral trunk through study day 10, all

surviving animals appeared normal by study day 3 and throughout the remainder of the study.

One female lost 1 gram (0.4%) of body weight from study days 7 to 14, but remained above

initial (study day 0) body weight at study termination. There were no other remarkable body

weight changes noted during the study.

Five found dead animals were noted with gastrointestinal findings. Two animals were noted with

scabbing on the urogenital area and one animal was noted with opacity of the right eye. Six

animals were noted with various external mattings. There were no other gross necropsy findings

for any examined tissues.

For surviving animals at terminal necropsy, one animal was noted with red nasal matting. There

were no other gross necropsy findings for any examined tissues.

The LD50 of Consolidated Cyclohexane Dicarboxaldehydes was 1678 mg/kg with 95%

confidence limits of 1448-1943 mg/kg when administered once orally via gavage to fasted male

and female albino rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 678 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:
2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP/Guideline 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
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
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.)
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.
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
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.

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

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP/Guidline Study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products Inc., Denver, PA
- Age at study initiation: Young adult
- Weight at study initiation: 2323 to 2655 grams (males) and 2195 to 2380 grams (females)
- Housing: Individual suspended wire-mesh cages.
- Diet (e.g. ad libitum): PMI Nutrition International, Inc. Certified Rabbit LabDiet® 5322 was offered at approximately 150 g per day during the study.
- Water (e.g. ad libitum): municipal water ad libitum
- Acclimation period: The animals were acclimated to laboratory conditions for a minimum of seven days prior to initiation of dosing.

ENVIRONMENTAL CONDITIONS
- Temperature: 63-72°F
- Humidity (%): 38-70%
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

IN-LIFE DATES: From: 2001-02-20 to 2001-03-06
Type of coverage:
occlusive
Vehicle:
other: None
Details on dermal exposure:
The test article was dosed undiluted based on its specific gravity. The dose
volume was determined by dividing the dose level of 5000 mg/kg, expressed as
g/kg, by the specific gravity (1.0572 g/ml, as determined by WIL Research
Laboratories, Inc. pharmacy personnel). Individual doses were calculated based
on body weights taken just prior to dosing and the dose volume of 4.7 ml/kg.

Individual doses of the test article were applied
to the maximum area possible on the dorsal skin. The sizes of the test sites were
recorded as percentages of the clipped area of skin. Doses covered approximately
18-23% of the total body surface. The dose site was measured for a
representative animal of each sex. Each dose was applied to the unabraded skin,
overwrapped with gauze binders, occluded with plastic wrap and secured with
nonirritating tape. Collars were applied to the rabbits to prevent ingestion of the
test article and/or wrappings during the 24-hour exposure period. Upon
completion of exposure, the collars and bandages were removed and the sites
were wiped with disposable paper towels moistened with tepid tap water.
Duration of exposure:
24 h
Doses:
5000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
One group of five male and five female albino rabbits was cutaneously
administered a single dose (24-hour, occluded exposure) of Consolidated
Cyclohexane Dicarboxaldehydes at a dose level of 5000 mg/kg.

The rabbits were observed at approximately 1, 3 and 4 hours post-application on
study day 0 and once daily thereafter for 14 days.
Observations included, but were not limited to, evaluation for changes in appearance
of skin and fur, eyes, mucous membranes, respiratory and circulatory systems,
autonomic effects and central nervous system effects.

The application sites were examined for erythema, edema (see Appendix A) and other
cutaneous findings beginning approximately 30-60 minutes after bandage removal
and daily thereafter through study day 14. The areas of application were clipped free
of hair on the day prior to dosing and on study days 6 and 13.

Body weights were obtained and recorded on study days 0 (initiation), 7 and 14
(termination).

Upon termination, all rabbits were euthanized by an intravenous injection of
euthanasia solution. The major organ systems of the cranial, thoracic and abdominal
cavities were examined for all animals.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
Male: 5000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 5000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
Signs of toxicity related to dose levels:
Nine animals were noted with transient soft feces on study
days 0, 1 and/or 3. All animals appeared normal by study day
4 and throughout the remainder of the study.



Although minor fluctuations in body weight were noted, all
animals met or exceeded their initial (study day 0) body
weight at termination. There was an effect from study day 0
to 7 which was test article-related and most likely due to
severe skin irritation and not systemic toxicity. No
remarkable body weight changes were noted from study day 7
to 14.
Body weight:
Although minor fluctuations in body weight were noted, all animals met or exceeded
their initial (study day 0) body weight at termination (study day 14). There was an
effect from study day 0 to 7 which was test article-related and most likely due to
severe skin irritation and not systemic toxicity. No remarkable body weight changes
were noted from study day 7 to 14.
Gross pathology:
Effects on organs:
Two females were noted with dark red lungs (all lobes). An
additional female was noted with multiple dark red areas on
the lungs. These finding were not clearly treatment-related.
All animals were noted with scabbing of the application
site and five animals were noted with a thickened
application site.
Other findings:
Signs of toxicity (local):
Severe skin irritation was observed for all animals. Severe
erythema and edema, eschar, corrosion and exfoliation were
observed for all animals. Blanching, subcutaneous hemorrhage
and purple discoloration were noted for nine, seven and
four animals, respectively. Desquamation was observed for
all animals.

Table 1: Summary of Clinical Findings - Males

 MALE
 TABLE RANGE:  DAY 0 TO DAY 14
 GROUP:  1
 DISPOSITION  
 - TERMINAL NECROPSY  5/5
 ACUTES  
 - APPEARED NORMAL  78/5
 - SOFT FECES  7/4
 DERMAL OBSERVATIONS  
 - ERYTHEMA - MODERATE  1/1
 - ERYTHEMA - SEVERE  69/5
 - EDEMA - VERY SLIGHT  1/1
 - EDEMA - SLIGHT  3/1
 - EDEMA - MODERATE  14/5
 - EDEMA - SEVERE  52/5
 - DESQUAMATION  49/5
 - ESCHAR  69/5
 - EXFOLIATION  32/5
 - BLANCHING  13/4
 - SUBCUTANEOUS HEMORRHAGE  3/3
 - CORROSION  53/5

1- 5000 MG/KG

 FEMALES

 TABLE RANGE:

 DAY 0 TO DAY 14
 GROUP:  1
 DISPOSITION  
 - TERMINAL NECROPSY  5/5
 ACUTES  
 - APPEARED NORMAL  78/5
 - SOFT FECES  7/5
 - DRIED BROWN MATERIAL UROGENITAL AREA  1/1
 DERMAL OBSERVATIONS  
 - ERYTHEMA - SEVERE  70/5
 - EDEMA - MODERATE  6/3
 - EDEMA - SEVERE  64/5
 - DESQUAMATION  47/5
 - ESCHAR  70/5
 - EXFOLIATION  31/5
 - BLANCHING  22/5
 - SUBCUTANEOUS HEMORRHAGE  6/4
 - CORROSION  60/5
 - PURPLE DISCOLORATION  7/4

1- 5000 MG/KG

Table 2: BODY WEIGHTS (GRAMS)

 MALE
 GROUP:  5000 MG/KG
DAY 0 
 MEAN  2470
 S.D.  135.4
 N  5
  7     
    MEAN  2530
 S.D.  118.8
 N  5
  14  
 MEAN  2639
 S.D.  100.6
 N  5
    
    FEMALE
 GROUP  5000 MG/KG
 DAY 0  
 MEAN  2316
 S.D.  72.0
 N  5
  7  
 MEAN  2322
 S.D.  131.9
 N  5
  14  
 MEAN  2490
 S.D.  112.6
 N  5

 

Table 3: GROSS NECROPSY OBSERVATIONS INCIDENCE SUMMARY

   MALE  FEMALE
 GROUP:  1  1
 NUMBER OF ANIMALS IN DOSE GROUP  5  5
 NUMBER OF ANIMALS TERMINALLY EUTHANIZED  5  5
 APPLICATION SITE    
 - THICKENED  2  3
 - SCABBING  5  5
 LUNGS    
 - DARK RED AREA(S)  0  1
 - DARK RED  0  2
 NO SIGNIFICANT CHANGES OBSERVED - ALL EXAMINED TISSUES  0  0

1- 5000 MG/KG

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 of Consolidated Cyclohexane Dicarboxaldehydes was greater than 5000 mg/kg when administered once for 24 hours to the clipped, unabraded skin of male and female albino rabbits.
Executive summary:

The acute percutaneous toxicity of Consolidated Cyclohexane Dicarboxaldehydes was evaluated in this single-dose study in rabbits. The test article was administered once cutaneously at a dose level of 5000 mg/kg to a group of five male and five female albino rabbits for a 24-hour period under occlusive dressing.

Mortality, clinical observations, cutaneous findings (Method of Draize, Appendix A) and body weight changes were evaluated over a 14-day observation period. All animals were subjected to a gross necropsy.

There were no deaths during the study. Nine animals were noted with transient soft feces on study days 0, 1 and/or 3. One animal was

noted with dried brown material around the urogenital area on study day 3. All animals appeared normal by study day 4 and throughout the remainder of the study. There were no other clinical findings.

Severe skin irritation was observed for all animals. Severe erythema and edema, eschar, corrosion and exfoliation were observed for all animals. Blanching, subcutaneous hemorrhage and purple discoloration were noted for nine, seven and four animals, respectively. In addition, desquamation was observed for all rabbits. There were no other cutaneous findings. Although minor fluctuations in body weight were noted, all animals met or exceeded their initial (study day 0) body weight at termination. There was an effect from study day 0 to 7 which was test article-related and most likely due to severe skin irritation and not systemic toxicity. No remarkable body weight changes were noted from study day 7 to 14. All animals were noted with scabbing of the application site and five animals were noted with a thickened application site. There were no other treatment-related gross necropsy findings for any examined tissues.

The LD50 of Consolidated Cyclohexane Dicarboxaldehydes was greater than 5000 mg/kg when administered once for 24 hours to the clipped, unabraded skin of male and female albino rabbits.

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

Additional information

Oral:

Consolidated Cyclohexane Dicarboxaldehydes was administered once orally via gavage to three groups of five male and five female fasted albino rats at dose levels of 613, 1751 and 5000 mg/kg. Mortality, clinical observations and body weight changes were evaluated over a 14-day observation period. All animals were subjected to a gross necropsy. All deaths were noted within one day of dosing. Mortality was 0/10, 6/10 and 10/10 for the 613, 1751 and 5000 mg/kg dose groups, respectively. Approximately one-half of the animals were noted with various discolored areas due to discharges/excretions. Approximately one-fourth of the animals were noted with prostration, hypoactivity and/or labored respiration. Findings noted for four animals each or less were mucoid feces, rales, impaired muscle coordination, gasping, shallow respiration, twitching, clear nasal discharge, hair loss on the ventral trunk and/or soft feces. All animals that were noted with neurological findings died. No other clinical findings were observed during the study. With the exception of one animal noted with hair loss on the ventral trunk through study day 10, all surviving animals appeared normal by study day 3 and throughout the remainder of the study.

One female lost 1 gram (0.4%) of body weight from study days 7 to 14, but remained above initial (study day 0) body weight at study termination. There were no other remarkable body weight changes noted during the study. Five found dead animals were noted with gastrointestinal findings. Two animals were noted with scabbing on the urogenital area and one animal was noted with opacity of the right eye. Six animals were noted with various external mattings. There were no other gross necropsy findings for any examined tissues. For surviving animals at terminal necropsy, one animal was noted with red nasal matting. There were no other gross necropsy findings for any examined tissues. The LD50 of Consolidated Cyclohexane Dicarboxaldehydes was 1678 mg/kg with 95% confidence limits of 1448-1943 mg/kg when administered once orally via gavage to fasted male and female albino rats.

Inhalation:

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.

Dermal:

The acute percutaneous toxicity of Consolidated Cyclohexane Dicarboxaldehydes was evaluated in a single-dose study in rabbits. The test article was administered once cutaneously at a dose level of 5000 mg/kg to a group of five male and five female albino rabbits for a 24-hour period under occlusive dressing. Mortality, clinical observations, cutaneous findings and body weight changes were evaluated over a 14-day observation period. All animals were subjected to a gross necropsy. There were no deaths during the study. Nine animals were noted with transient soft feces on study days 0, 1 and/or 3. One animal was noted with dried brown material around the urogenital area on study day 3. All animals appeared normal by study day 4 and throughout the remainder of the study. There were no other clinical findings. Severe skin irritation was observed for all animals. Severe erythema and edema, eschar, corrosion and exfoliation were observed for all animals. Blanching, subcutaneous hemorrhage and purple discoloration were noted for nine, seven and four animals, respectively. In addition, desquamation was observed for all rabbits. There were no other cutaneous findings. Although minor fluctuations in body weight were noted, all animals met or exceeded their initial (study day 0) body weight at termination. There was an effect from study day 0 to 7 which was test article-related and most likely due to severe skin irritation and not systemic toxicity. No remarkable body weight changes were noted from study day 7 to 14. All animals were noted with scabbing of the application site and five animals were noted with a thickened application site. There were no other treatment-related gross necropsy findings for any examined tissues. The LD50 of Consolidated Cyclohexane Dicarboxaldehydes was greater than 5000 mg/kg when administered once for 24 hours to the clipped, unabraded skin of male and female albino rabbits.


Justification for selection of acute toxicity – oral endpoint
GLP guideline acute toxicity study

Justification for selection of acute toxicity – inhalation endpoint
GLP guideline acute toxicity study

Justification for selection of acute toxicity – dermal endpoint
GLP guideline acute toxicity study

Justification for classification or non-classification

Based on the acute oral toxicity value of 1678 mg/kg bw, this substance meets the criteria for classification as Harmful via the oral route according to the Dangerous Substances Directive, and as Acute oral Category 4 according to CLP.

Classification for dermal and inhalation routes is not supported by the data.