3,5,5-trimethylcyclohex-2-enone

Repeated dose toxicity: other routes

Administrative data

Endpoint:

sub-chronic toxicity: other route

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1972

Report date:

1972

Reference 2

Reference Type:

publication

Title:

Isophorone: Ambient water quality criteria

Author:

U.S. EPA (Environmental Protection Agency)

Year:

1978

Bibliographic source:

U.S. Department of Commerce, National Technical Information Service (NTIS), PB-296 798

Materials and methods

Principles of method if other than guideline:

Method: Repeated Dose Oral Toxicity; see reference

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3,5,5-trimethylcyclohex-2-enone

EC Number:

201-126-0

EC Name:

3,5,5-trimethylcyclohex-2-enone

Cas Number:

78-59-1

Molecular formula:

C9H14O

IUPAC Name:

3,5,5-trimethylcyclohex-2-enone

Details on test material:

Origin: International Chemical Corp., New York, 11 Aug 1971
- clear liquid with a mild, pungent odor
- specific gravity: 0.93

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ORGANISMS
- Number of animals: 4 per dose and sex (four groups of 4 males and 4 females)
- Diet: ad libitum, basal laboratory diet (Big Red Dog Food - Agway, Inc)
- Water: ad libitum
ENVIRONMENTAL CONDITIONS:
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
- Housing: in groups of 4, by sex, in pens 4´x 7´
- Temperature (°C): no data

Administration / exposure

Route of administration:

other: oral gelatine capsules

Vehicle:

unchanged (no vehicle)

Details on exposure:

ADMINISTRATION / EXPOSURE 
- Type of exposure: oral, in gelatine capsules once daily

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily (7 days/week)

Doses / concentrations

Remarks:

Doses / Concentrations:
35, 75 and 150 mg/kg bw d

No. of animals per sex per dose:

4 (four groups of 4 males and 4 females)

Control animals:

other: yes, concurrent

Details on study design:

Post-exposure period: none

Examinations

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS AND FREQUENCY: 
- Clinical signs: daily
- Mortality: daily
- Body weight: weekly
- Food consumption: daily
- Hematology: Blood was drawn from jugular vein monthly: erythrocyte, leucocyte and differential leukocyte  counts, hematocrit and hemoglobin 
determinations
- Biochemistry: monthly: blood glucose, blood urea nitrogen, serum  glutamic oxoloacetic transaminase, serum alkaline phosphatase, total  serum 
protein, total serum bilirubin, serum albumin lactic acid  dehydrogenase, cholesterol, calcium, phosphate, uric acid
- Urinalysis: monthly: pH, occult blood, ketones, albumin and sugar,  microscopic examination of sediment

Sacrifice and pathology:

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 
- Organ weight: Organ-body weight ratio determined: heart, liver, kidney,  spleen, thyroid, adrenals, brain
- Macroscopic: lungs, heart, intestines, kidneys, spleen, liver, urinary  bladder;  - weights: heart, liver, spleen, adrenals, thyroid, brain, kidneys
- Microscopic:  high dose and control groups:  brain, pituitary, eye, submaxillary gland, thyroid, heart, lung, liver,  kidneys, adrenals, pancreas, 
spleen, mesentery lymph nodes, stomach,  small intestine, colon, urinary bladder, bone marrow, muscle, sciatic  nerve, spinal cord, skin. 
Males: testes,  prostate, seminal vesicles;  female: ovary, uterus, mammary gland. medium and low dose groups: liver, kidney

Other examinations:

none

Statistics:

STATISTICAL METHODS: 
All data were evaluated statistically, using the student for comparison of means.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

NOAEL >= 150 mg/kg bw
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
- Mortality and time to death: no mortalities
- Clinical signs: some incidences of soft stools in 75 and 150 mg/kg bw d  groups
- Body weight gain: no significant effect - Food consumption: within normal limits
- Clinical chemistry: all values within normal limits
- Haematology: all values within normal limits
- Urinalysis: all values within normal limits
- Organ weights: no significant differences in organ-body weight ratios
- Gross pathology: all organs normal in appearance and color
- Histopathology: All experimental tissues were within normal limits and  were comparable to controls. There was no evidence of any definitive  signs  of celluar change.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 150 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: no toxicological findings

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

no remarks

Applicant's summary and conclusion

Conclusions:

In this subchronic (90 day) oral study beagle dogs were given orally gelatine capsules containing doses of 35, 75, or 150 mg isophorone/kg bw. As
the only minor clinical signs, incidence of soft stool were noted in the two upper dose levels. From the data of this study, it was concluded that the
No-Observed-Adverse-Effect-Level (NOAEL) for isophorone in dog is >= 150 mg/kg bw/day.

Executive summary:

In this guideline-comparable study groups of four male and female beagle dogs were given 90 daily oral doses of isophorone in gelantin capsules at dosage rates of 35, 75, or 150 mg/kg bw/day. Comprehensive haematology, clinical chemistry and urine analyses were carried out initially and at 1, 2 and 3 months. Apart from a mild intermittent incidence of soft stools in animals of the two high-dose groups, there was no observable effect as demonstrated by the data on general appearance and conditions as well as those from haematological or biochemical investigations. At autopsy, no changes in the organ/body weight ratios and no histopathological changes were observed. No toxic effect was found at any of the dose levels used.

Therfore, under the conditions of this study the No-Observed-Adverse-Effect-Level (NOAEL) is determined to be >= 150 mg/kg bw/day for male and female beagle dogs.