Registration Dossier

Administrative data

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
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:
2001
Report Date:
2001

Materials and methods

Test guidelineopen allclose all
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report):Consolidated Cyclohexane Dicarboxaldehydes
- Physical state:liquid
- Impurities (identity and concentrations): Cyclohexanecarboxaldehyde 0.28%, Hydroxyaldehyde 0.23%, Unknowns 0.51%
- Lot/batch No.:9-CWDY-50-O 1
- Storage condition of test material: ambient

Test animals

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

Administration / exposure

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

Results and discussion

Effect levels
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.

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.