Registration Dossier

Administrative data

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
Cross-reference
Reason / purpose:
reference to same 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:
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

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:
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

Administration / exposure

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.

Results and discussion

Effect levels
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.

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.