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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
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 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:
rat
Strain:
other: Albino rats of CFE strain
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Carworth Farms
- Age at study initiation: weanling
- Diet: ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
- Housing: individually in wire mesh cages elevated above the droppings

Administration / exposure

Route of administration:
oral: feed
Vehicle:
corn oil
Details on oral exposure:
- Isophorone was added directly to the basal ration and thorougly blended in an Patterson Kelly Twin Shell Blendor;
- Fresh diets were prepared each week
- isophorone in corn oil (1:2) was blended with the diet
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
750, 1500 and 3000 ppm diet: males 57.0, 102.5 and 233.8 mg/kg bw d; females 78.9, 163.8 and 311.8 mg/kg bw d
Basis:
nominal in diet
No. of animals per sex per dose:
20
Control animals:
yes, concurrent no treatment
Details on study design:
- Post-exposure period: none
- After 4 weeks, 5 animals per sex and dose group were killed for blood analysis
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS AND FREQUENCY: 
- Clinical signs: daily
- Mortality: daily
- Body weight: weekly
- Food consumption: weekly
- Water consumption: weekly
- Ophthalmoscopic examination: none
- Hematology: after 4 weeks and at end of study: determination of  hemoglobin, hematocrit, erythrocyte counts, leukocyte counts, and  differential 
leukocyte determinations 
- Biochemistry: after 4 weeks and at end of study: blood glucose, blood  urea nitrogen, serum glutamic oxaloacetic transaminase, serum alkaline  
phosphatase, total serum protein, total serum bilirubin, serum albumin,  lactic acid dehydrogenase, cholesterol, calcium, phosphate, and uric aid 
- Urinalysis: after 4 weeks and at end of study: pH, glucose, ketones,  albumin, occult blood, microscopic examination of sediment
Sacrifice and pathology:
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 
- Organ weights: organ-body weight ratios: heart, liver, kidney,  adrenals, thyroid, brain, testes
- Macroscopic:  after 4 weeks and at study termination: lungs, heart, intestines,  kidneys, spleen, liver, urinary bladder;  - weights: heart, liver, kidney,
 adrenals, thyroid, brain, testes (males)  for 10 males and 10 females of each dose level
- Microscopic:  at study termination only: 5 males and 5 females each from high dose and  control groups: brain, pituitary, eye, thyroid, lung, heart, 
liver,  kidney, adrenals, urinary bladder, mediastinal lymph node, pancreas,  spleen, colon, bone marrow, skeletal muscle, testes and prostate (male), 
ovary and uterus (female) 5 males and 5 females each from medium and low dose groups: liver, kidney
Other examinations:
none
Statistics:
STATISTICAL METHODS: All data were evaluated statistically.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
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):
no effects observed
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: 
m: 1500 ppm diet (reduced body weight gain), equivalent to 102.5  mg/kg bw; 
f: 3000 ppm diet, equivalent to 311.8 mg/kg bw.
ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX mean daily compound consumption (data given in study):
- males 57.0, 102.5 and 233.8 mg/kg bw d 
- females 78.9, 163.8 and 311.8 mg/kg bw d
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
- Mortality and time to death: 1 m (control group), 1 f (3000 ppm) 
- deaths were due to intercurrent infection
- Clinical signs: none
- Body weight gain: 3000 ppm m: significant reduced body weight gain (P <  0.01); further observed changes returned to normal in the 
subsequent weeks
- Food/water consumption: no evidence of refusal
- Clinical chemistry: all values within normal limits
- Haematology: all values within normal limits
- Urinalysis: all values comparable to controls
- Organ weights:  kidney, testes m: slightly increased mean organ to body weight ratio  (considered not compound related by the authors; 
not statistically  significant)
- Gross pathology: All viscera were normal in appearance and color, no  lesions were observed
- Histopathology: no evidence of significant pathology

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
102.5 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: reduced body weight gain
Dose descriptor:
NOAEL
Effect level:
>= 311.8 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: no effects

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 feed study with rats the only observed effect was a reduced body weight gain in male animals. The No-Observed-
Adverse-Effect-Level (NOAEL) derived from this study is 102.5 mg/kg bw/day for male and 311.8 mg/kg bw/day for female rats.
Executive summary:

In this guideline-comparable study four groups of 20 male and 20 female CFE albino rats were dosed with 750, 1000, or 3000 ppm isophorone via diet - corresponding to 57.0, 102.5, 233.8 mg/kg bw/day for males and to 73.9, 163.8 and 311.8 mg/kg bw/day for females - daily for 13 weeks.

Isophorone in corn oil (ratio 1:2) was blended with the diet; fresh diets were prepared each week. Haematology, serum chemistry and urine analyses were carried out on five animals of each sex from each group at week 4 and at termination. Comprehensive histopathological examination was confined to five animals of each sex from the control and high dose groups. The liver and kindney from five animals of the intermediate dose levels were also examined histopathologically. Under the conditions of this study, no effects on the general appearance of the test animals, on their behaviour, on body weight gain or on food consumption were observed at a dietary level of 1500 mg/kg or less. Isophorone did not alter the composition of the formed elements of the blood, nor did it interfere with the general metabolism or with liver and kidney function. No detectable gross or microscopic pathological changes were noted in any the animals examined after 28 or 90 days of feeding. Organ/body weight ratios for vital organs were not changed.

The only observed effect was a reduced body weight gain (-12 to -13 %) in male rats at 3000 ppm (during weeks 6,7,8,9,10 and 11).

Therefore, the No-Observed-Adverse-Effect-Level (NOAEL) derived from this study is 102.5 mg/kg bw/day (equivalent to 1500 ppm) for male and 311.8 mg/kg bw/day (equivalent to 3000 ppm) for female rats.