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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Data is from peer reviewed publication

Data source

Reference
Reference Type:
publication
Title:
Fragrance material review on alpha-iso-methylionone
Author:
A. Lapczynski
Year:
2007
Bibliographic source:
Food and Chemical Toxicology

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: see Principles below
Principles of method if other than guideline:
A 90 days Subchronic dermal toxicity study was conducted on rats to evaluate the toxic nature of test substance.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one
EC Number:
204-846-3
EC Name:
3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one
Cas Number:
127-51-5
Molecular formula:
C14H22O
IUPAC Name:
3-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data available

Administration / exposure

Type of coverage:
open
Vehicle:
not specified
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: No data available

TEST SITE
- Area of exposure: Clipped backs
- % coverage: No data available
- Type of wrap if used: No data available
- Time intervals for shavings or clipplings: No detailed data available

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data available
- Time after start of exposure: No data available

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): No data available
- Concentration (if solution): 0, 50, 170, 580 or 2000 mg/kg/day
- Constant volume or concentration used: No data available
- For solids, paste formed: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Amount(s) applied (volume or weight with unit): No data available
- Concentration (if solution): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

USE OF RESTRAINERS FOR PREVENTING INGESTION: No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data available
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations: 0, 50, 170, 580 or 2000 mg/kg/day
No. of animals per sex per dose:
15/sex/dose
Control animals:
yes
Details on study design:
No data available
Positive control:
No data available

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data available

DETAILED CLINICAL OBSERVATIONS: No data available

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: No data available

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

FOOD EFFICIENCY: Yes

WATER CONSUMPTION: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

URINALYSIS: Yes

NEUROBEHAVIOURAL EXAMINATION: No data available

OTHER: Organ weight
Sacrifice and pathology:
GROSS PATHOLOGY: No data

HISTOPATHOLOGY: Yes
Other examinations:
No data available
Statistics:
No data available

Results and discussion

Results of examinations

Clinical signs:
not specified
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Erythema, edema, and eschar formation was observed in all dosage groups
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
580 and 2000 mg/kg: Reduced body weight gain in females and in males.
Food consumption and compound intake (if feeding study):
not specified
Description (incidence and severity):
580 and 2000 mg/kg: Food consumption elevations in females, lower efficiency food utilization in both male and females.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
580 and 2000 mg/kg: lower efficiency food utilization in both male and females.
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
170 mg/kg: Changes in hematology parameters in both sexes.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
580 and 2000 mg/kg: Serum glucose levels were depressed in males at week 7 and in both sexes at termination. BUN levels increased with dose in males.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
170, 580 and 2000 mg/kg: Urine albumin levels were significantly increased in male groups at termination.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
50 mg/kg: Dose related increase in liver weight and.
170, 580 and 2000 mg/kg: Increases in the absolute and relative weights in the liver and kidneys in both sexes.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Severe tissue destruction and infection in the skin may have combined to elicit increased kidney weight at higher doses and epithelial eosinophilic globules in the convoluted tubules of the outer cortex. To determine if these effects were specific to male rat nephropathy, a review of the histopathology of kidney from rats in this study was conducted. This lesion occurred in a dose-responsive fashion in males only and was seen
also in male control rats. It was accompanied by interstitial nephritis in control and treated rats. The findings suggest an endogenous disease process which was exacerbated by the application of the irritating test material and marked skin necrosis.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
On the basis of the review of the kidney histopathology data and considering the dermal inflammation and infection in these animals, the results of this study are concluded to show a systemic NOAEL of topical alpha-isomethyl ionone of 50 mg/kg. Since erythema and eschar formation
occurred in all treatment groups, a NOAEL for this effect could not be established

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
histopathology: non-neoplastic
other: On the basis of the review of the kidney histopathology data and considering the dermal inflammation and infection in the animals
Remarks on result:
other: No toxic effects were observed

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
On the basis of the review of the kidney histopathology data and considering the dermal inflammation and infection in the rats, the results of this study are concluded to show a systemic NOAEL of topical test substance of 50 mg/kg.
Executive summary:

A dermal subchronic study was conducted on Sprague-Dawley rats (15/sex/dose). An open application of test substance at a dose of 50, 170, 580 or 2000 mg/kg was made to the clipped backs, once daily for 90 days. The controls (60 rats/sex) were not treated with the test material. Observations for signs of toxicity including erythema and eschar formation, were performed daily. Body weight and food consumption data were measured weekly. Selective hematology, clinical chemistry and urinalysis assessment were conducted at weeks 7 and 13 of the study. A complete gross necropsy on all animals and a microscopic examination of tissues in the control and high dose animals were conducted at sacrifice. No treatment related deaths occurred. On the skin at the application site there was a dose-dependent increase in the severity of erythema, and eschar formation. At 50 mg/kg: Dose related increase in liver weight and changes in urinalysis parameters at this dose . At 170 mg/kg: Changes in hematology parameters in both sexes. BUN levels increased with dose in males. Urine albumin levels were significantly increased in male groups at termination. Increases in the absolute and relative weights in the liver and kidneys in both sexes. At 580 and 2000 mg/kg: Reduced body weight gain in females and in males. Food consumption elevations in females, lower efficiency food utilization in both male and females. Serum glucose levels were depressed in males at week 7 and in both sexes at termination. BUN levels increased with dose in males. Urine albumin levels were significantly increased in male groups at termination. Increases in the absolute and relative weights in the liver and kidneys in both sexes Moderate to severe erythema and eschar formation was observed in all test groups and increased with increasing levels of test material. Severe tissue destruction and infection on doses above 50 mg/kg may have combined to elicit increased kidney weight at higher doses. Since erythema and eschar formation occurred in all treatment groups, a NOAEL for this effect could not be established. On the basis of the review of the kidney histopathology data and considering the dermal inflammation and infection in these animals, the results of this study are concluded to show a systemic NOAEL of topical test substance of 50 mg/kg.