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Toxicological information

Repeated dose toxicity: other routes

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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

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1972
Report Date:
1972
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

Reference
Name:
Unnamed
Type:
Constituent
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 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.