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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:
other information
Study period:
1980
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Non-GLP, non-guideline, published in peer reviewed literature, limitations in design and/or reporting, not adequate for assessment due to endogenous disease of the test animals.

Data source

Reference
Reference Type:
publication
Title:
A toxicologic and dermatologic assessment of ionones when used as fragrance ingredients
Author:
Belsito D. et al.
Year:
2007
Bibliographic source:
Food and Chemical Toxicology 45 (2007) S130-SI67

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
no data
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
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
IUPAC Name:
3-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one
Constituent 2
Reference substance name:
Aplha-Iso-Methylionone
IUPAC Name:
Aplha-Iso-Methylionone
Details on test material:
no data

Test animals

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

Administration / exposure

Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
Via clipped skin
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
90 days
Frequency of treatment:
no data
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
50
Basis:
analytical per unit body weight
Remarks:
Doses / Concentrations:
170
Basis:
analytical per unit body weight
Remarks:
Doses / Concentrations:
580
Basis:
analytical per unit body weight
Remarks:
Doses / Concentrations:
2000
Basis:
analytical per unit body weight
No. of animals per sex per dose:
15/sex/dose
Control animals:
not specified
Details on study design:
no data
Positive control:
yes

Examinations

Observations and examinations performed and frequency:
Clinical, laboratory evaluations were conducted
Sacrifice and pathology:
Gross and histopathological evaluations were conducted.
Other examinations:
no data
Statistics:
yes

Results and discussion

Results of examinations

Clinical signs:
not specified
Dermal irritation:
effects observed, treatment-related
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Body weight gains were significantly reduced in females in the highest dose group and in males treated at 580 and 2000 mg/kg body weight/day. Total food consumption throughout the study was significantly increased in females treated at the 2 highest dose levels and there was a significant decrease in food efficiency and food intake in both sexes in the 2 highest dose groups. The body weight changes may not represent a direct, test-material-related effect many of these animals manifested severe skin lesions. There were hematological changes in the 2 highest dose groups and reduced serum glucose in the high-dose animals, all largely attributable to the inflammation and infection at the site of application.
A significant increase in serum BUN was reported in males in the top 2 dose groups. Urinalysis showed a significant increase in the incidence of albuminuria in males in the 3 highest dose groups. In the high-dose males, abundant eosinophilic globules were observed in the kidney epithelium at necropsy. At necropsy there was a significant increase in the absolute and relative liver weights in both sexes at all dose levels. Increases, most of which attained statistical significance, in the absolute and relative weights of the kidneys were reported in all but the lowest dose groups of each sex. The absolute adrenal weights were significantly increased in the 2 highest dose groups of both sexes.
The interpretation of the data is complicated by the severe skin damage at the application site, especially in the 2 highest dose groups. Depressed body weight gains and increased neutrophil count are probably attributable to infection and inflammation. Azotemia and proteinuria likely are a result of chronic severe tissue damage and infection. The liver weight increase probably resulted from induction of microsomal mixed-function oxidases. Increased adrenal weights probably reflect the response to stress caused by tissue damage and infection. 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 kidneys 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. Body weight gains were significantly reduced in females in the highest dose group and in males treated at 580 and 2000 mg/kg body weight/day. Total food consumption throughout the study was significantly increased in females treated at the 2 highest dose levels and there was a significant decrease in food efficiency and food intake in both sexes in the 2 highest dose groups. The body weight changes may not represent a direct, test-material-related effect many of these animals manifested severe skin lesions. There were hematological changes in the 2 highest dose groups and reduced serum glucose in the high-dose animals, all largely attributable to the inflammation and infection at the site of application. A significant increase in serum BUN was reported in males in the top 2 dose groups. Urinalysis showed a significant increase in the incidence of albuminuria in males in the 3 highest dose groups. In the high-dose males, abundant eosinophilic globules were observed in the kidney epithelium at necropsy. At necropsy there was a significant increase in the absolute and relative liver weights in both sexes at all dose levels. Increases, most of which attained statistical significance, in the absolute and relative weights of the kidneys were reported in all but the lowest dose groups of each sex. The absolute adrenal weights were significantly increased in the 2 highest dose groups of both sexes.
The interpretation of the data is complicated by the severe skin damage at the application site, especially in the 2 highest dose groups. Depressed body weight gains and increased neutrophil count are probably attributable to infection and inflammation. Azotemia and proteinuria likely are a result of chronic severe tissue damage and infection. The liver weight increase probably resulted from induction of microsomal mixed-function oxidases. Increased adrenal weights probably reflect the response to stress caused by tissue damage and infection. 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 kidneys 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.

Effect levels

Dose descriptor:
NOAEL
Effect level:
<= 50 mg/kg bw/day
Sex:
not specified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion