Registration Dossier

In subchronic studies, oral administration of high doses of isophorone (NOAEL (male rat, 90 days) = 102.5 mg/kg bw/day; NOAEL (female rat, 13 weeks) = 500 mg/kg bw/day; NOAEL (male mouse, 16 days) = 500 mg/kg bw/day; NOAEL (female mouse, 16 days) = 125 mg/kg bw/day; NOAEL (dog, 90 days) >= 150 mg/kg bw/day) caused no significant toxic effects (all NOAEL values are based on slight (< 14%) reductions in body weight gain). After inhalation administration nose and eye irritation and blood and liver changes were observed (NOAEC (rat, 28 days) < 208 mg/m3).

Reference

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

Principles of method if other than guideline:

Method: Repeated Dose Toxicity; see reference

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Albino rats of CFE strain

Sex:

male/female

Details on test animals or test system 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

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

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

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.

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

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

Critical effects observed:

not specified

no remarks

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.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

102.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The test procedure of the study is in accordance with generally accepted scientific standards and described in sufficient detail with Klimisch score 1 (reliable without restriction).

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Method: Repeated Dose Inhalation Toxicity; see "Details on inhalation exposure"

GLP compliance:

no

Limit test:

yes

Species:

rat

Strain:

other: Charles River Caesarian-derived

Sex:

male/female

Details on test animals or test system and environmental conditions:

no further details

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: Air

Remarks on MMAD:

MMAD / GSD: not applicable (vapour)

Details on inhalation exposure:

ADMINISTRATION / EXPOSURE
- All exposures were conducted in 1000-liter stainless steel and glass exposure chambers. Air-flow through the chamber was maintained by a
positive pressure rotary pump located at the exhaust side of the chamber. The airflow rate was monitored by a rotameter
- System of generating particulates/aerosols: Vapor of isophorone were generated by metering the liquid into a positive pressure spray nozzle
with a infusion pump. Aerosol was introduced into a heated distilling flask. A heating mantle was used to maintain the flask at a temperature
adequate to vaporize the entering aerosol. Exposure conducted under semi-closed conditions, the total chamber
airflow was drawn through the vapor-generating flask prior to entry the chamber.
- Duration of test/exposure: 20 exposures of 6 hours each
- Type of exposure: inhalation
- Post exposure period: none
- Concentrations: nominal 250 mg/m3; daily analytical determination (208 mg/m3) may be less precise than nominal due to incomplete recovery
in analysis

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical Concentration of the chamber was determined daily by analysis of samples with a Becklman BD spectrophotometer

Duration of treatment / exposure:

28 days

Frequency of treatment:

6 hours/day; 5 days/week

Remarks:

Doses / Concentrations:
250 mg/m3 air
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
208 +/- 10 mg/m3 air (corresponds to about 36 ppm)
Basis:
analytical conc.

No. of animals per sex per dose:

10 females and 10 males

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: none

Positive control:

no positive control

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: at frequent intervals
- Mortality: at frequent intervals
- Body weight: at study initiation and termination
- Haematology: at study initiation and termination, identical 50 % of animals of each group

Sacrifice and pathology:

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: brain, pituitary, trachea, thyroid, parathyroid, lungs, heart, liver, spleen, stomach, small intestine, large intestine, adrenals,
kidneys, urinary bladder, gonads, femur
- organ weights: lungs, liver, kidneys, adrenal, spleen - Microscopic: lungs, liver, kidneys, adrenal, spleen for three males and three females of each
group

Remark: no urinalysis

Other examinations:

no other examinations

Statistics:

STATISTICAL METHODS: performed on body and organ weights

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- Mortality and time to death: no mortalities
- Clinical signs: slight nasal bleeding on day 3, reddish-brown  discoloration of the fur surrounding the nasal regions on days 6 through 8
- Body weight gain: body weight only of male rats was significantly  reduced compared to control
- Haematology: differential blood count: increase of the percentage of  lymphocytes (pre-exposure: 81.6 and 80.2 % among males and females,
resp.; postexposure: 84.6 and 86.0 %, resp.), decrease in the percentage  of segmented neutrophiles (pre-exposure: 17.4 and 18.2 % among males
and  females, resp.; postexposure: 14.6 and 13.3 %, resp.).
- Organ weights: absolute and relative liver weight only of male rats  were significantly reduced compared to control
- Gross pathology: no clear-cut compound-related abnormalities
- Histopathology: no unequivocal change

Dose descriptor:

NOAEC

Effect level:

< 208 mg/m³ air

Sex:

male/female

Basis for effect level:

other: changes in haematological parameters and reduced liver weights

Critical effects observed:

not specified

Target Organs Effects:

M: body weight gain (reduced; abs. and rel. liver weight(reduced)

M+F: lymphocytes (increased); heamoglobin (increased); neutrophils (reduced)

Conclusions:

In this subacute inhalation study with rats nose irritation and blood and liver changes were observed. The No-Observed-Adverse-Effect-Concentration (NOAEC, rat, 28 days) is determined to be < 208 mg/m3.

Executive summary:

In this subacute inhalation study 10 male and 10 female young adult Charles River CD rats were exposed (whole body) to isophorone at air concentrations of 0 or 250 mg/m³, 6 hours/day, 5 days/week, for 4 weeks. Results of daily spectroscopic determinations indicated that the average daily exposure was 208 mg/m³. Body weights measurements and heamatological studies were made before exposure and after 4 weeks. The rats were killed and gross necropsy were performed. Organ weights were determined for lungs, liver, kidney, adrenals and spleen. Histological examination of those tissues were performed in three males and three females per group. The following effects were observed: transient nasal bleeding, increased percentages of lymphocytes, decreased percentages of neutrophils and increased heamoglobin concentration in males and females and significantly lower terminal body weights and significantly decreased absolute and relative liver weights of exposed males, compared with controls.

Therefore, under the conditions of this study the No-Observed-Adverse- Effect-Concentration (NOAEC, rats, 28 d) for rats is determined to be < 208 mg/m³.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

208 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The study is well documented, meets generally accepted scientific principles, and is acceptable for assessment with Klimisch score 2 (reliable with restrictions).

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Method: Repeated Dose Inhalation Toxicity; see "Details on inhalation exposure"

GLP compliance:

no

Limit test:

yes

Species:

rat

Strain:

other: Charles River Caesarian-derived

Sex:

male/female

Details on test animals or test system and environmental conditions:

no further details

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: Air

Remarks on MMAD:

MMAD / GSD: not applicable (vapour)

Details on inhalation exposure:

ADMINISTRATION / EXPOSURE
- All exposures were conducted in 1000-liter stainless steel and glass exposure chambers. Air-flow through the chamber was maintained by a
positive pressure rotary pump located at the exhaust side of the chamber. The airflow rate was monitored by a rotameter
- System of generating particulates/aerosols: Vapor of isophorone were generated by metering the liquid into a positive pressure spray nozzle
with a infusion pump. Aerosol was introduced into a heated distilling flask. A heating mantle was used to maintain the flask at a temperature
adequate to vaporize the entering aerosol. Exposure conducted under semi-closed conditions, the total chamber
airflow was drawn through the vapor-generating flask prior to entry the chamber.
- Duration of test/exposure: 20 exposures of 6 hours each
- Type of exposure: inhalation
- Post exposure period: none
- Concentrations: nominal 250 mg/m3; daily analytical determination (208 mg/m3) may be less precise than nominal due to incomplete recovery
in analysis

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical Concentration of the chamber was determined daily by analysis of samples with a Becklman BD spectrophotometer

Duration of treatment / exposure:

28 days

Frequency of treatment:

6 hours/day; 5 days/week

Remarks:

Doses / Concentrations:
250 mg/m3 air
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
208 +/- 10 mg/m3 air (corresponds to about 36 ppm)
Basis:
analytical conc.

No. of animals per sex per dose:

10 females and 10 males

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: none

Positive control:

no positive control

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: at frequent intervals
- Mortality: at frequent intervals
- Body weight: at study initiation and termination
- Haematology: at study initiation and termination, identical 50 % of animals of each group

Sacrifice and pathology:

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: brain, pituitary, trachea, thyroid, parathyroid, lungs, heart, liver, spleen, stomach, small intestine, large intestine, adrenals,
kidneys, urinary bladder, gonads, femur
- organ weights: lungs, liver, kidneys, adrenal, spleen - Microscopic: lungs, liver, kidneys, adrenal, spleen for three males and three females of each
group

Remark: no urinalysis

Other examinations:

no other examinations

Statistics:

STATISTICAL METHODS: performed on body and organ weights

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- Mortality and time to death: no mortalities
- Clinical signs: slight nasal bleeding on day 3, reddish-brown  discoloration of the fur surrounding the nasal regions on days 6 through 8
- Body weight gain: body weight only of male rats was significantly  reduced compared to control
- Haematology: differential blood count: increase of the percentage of  lymphocytes (pre-exposure: 81.6 and 80.2 % among males and females,
resp.; postexposure: 84.6 and 86.0 %, resp.), decrease in the percentage  of segmented neutrophiles (pre-exposure: 17.4 and 18.2 % among males
and  females, resp.; postexposure: 14.6 and 13.3 %, resp.).
- Organ weights: absolute and relative liver weight only of male rats  were significantly reduced compared to control
- Gross pathology: no clear-cut compound-related abnormalities
- Histopathology: no unequivocal change

Dose descriptor:

NOAEC

Effect level:

< 208 mg/m³ air

Sex:

male/female

Basis for effect level:

other: changes in haematological parameters and reduced liver weights

Critical effects observed:

not specified

Target Organs Effects:

M: body weight gain (reduced; abs. and rel. liver weight(reduced)

M+F: lymphocytes (increased); heamoglobin (increased); neutrophils (reduced)

Conclusions:

In this subacute inhalation study with rats nose irritation and blood and liver changes were observed. The No-Observed-Adverse-Effect-Concentration (NOAEC, rat, 28 days) is determined to be < 208 mg/m3.

Executive summary:

In this subacute inhalation study 10 male and 10 female young adult Charles River CD rats were exposed (whole body) to isophorone at air concentrations of 0 or 250 mg/m³, 6 hours/day, 5 days/week, for 4 weeks. Results of daily spectroscopic determinations indicated that the average daily exposure was 208 mg/m³. Body weights measurements and heamatological studies were made before exposure and after 4 weeks. The rats were killed and gross necropsy were performed. Organ weights were determined for lungs, liver, kidney, adrenals and spleen. Histological examination of those tissues were performed in three males and three females per group. The following effects were observed: transient nasal bleeding, increased percentages of lymphocytes, decreased percentages of neutrophils and increased heamoglobin concentration in males and females and significantly lower terminal body weights and significantly decreased absolute and relative liver weights of exposed males, compared with controls.

Therefore, under the conditions of this study the No-Observed-Adverse- Effect-Concentration (NOAEC, rats, 28 d) for rats is determined to be < 208 mg/m³.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

208 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The study is well documented, meets generally accepted scientific principles, and is acceptable for assessment with Klimisch score 2 (reliable with restrictions).

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Dermal

No results from repeated-dose toxicity tests are available for the dermal route of exposure. Subacute 28 day or subchronic 90 day dermal toxicity studies are not needed, because subacute 28 day and subchronic 18 month inhalation toxicity studies are available for isophorone. According to REACH Annex IX 8.6.2, column 2 the inhalative study has to be conducted if exposition by inhalation is expected.

Inhalation

Studies are available for rats, mice, rabbits, and guinea pigs.

In rats exposed for 4 weeks (6 hours/day, 5 days/week) to 208 mg isophorone/m³ reduced body weights and decreased liver weights in males and changes in heamatological parameters in females were found (NOAEC (rat, 28 days) < 208 mg/m³) (Exxon, 1968).

In a study with 6 weeks (8 hours/day, 5 days/week) duration, at doses >= 287 mg/m³ (50 ppm) congested kidneys, dilated Bowman´s capsules and lung chages (irritation, congestion) were found in rats and guinea pigs (Smyth et al., 1942). Further findings observed in this study were blood cell changes and albuminuria at doses >= 575 mg/m³ (100 ppm) and nasal and eye irritations at 2874 mg/m³ (500 ppm).

Eye and nose irritations have also been observed in a more recent study in Wistar rats and New Zealand rabbits at 1436 mg/m³ after18 months (6 hours/day, 5 days/week) exposure. In addition at this concentration slightly increased microvacuolization of the livers was observed (Dutertre-Catella, 1976).

No effects were found in histopathological examinations of the respiratory tract of Swiss mice after exposure to 164 and 513 mg/m³ for up to 14 days (6 hours/day; 4, 9, 14 day) (Zissu, 1995).

Oral

In a guideline-comparable study with male and female CFE rats 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 - for 13 weeks, the only observed effect was a reduced body weight gain (-12 to -13 %) in male rats at the highest dose.The NOAEL derievd from this study is 102.5 mg/kg bw/day for male and 311.8 mg/kg bw/day for female rats (Rohm & Haas Co, 1972).

In two NTP-studies male and female Fischer rats were administered 0, 125, 250, 500, 1000 and 2000 mg isophorone/kg bw/day in a 16-day (dose finding) and 0, 62.5, 125, 250, 500 and 1000 mg/kg bw/day in a13-week investigation. In the dose finding study, one of five females that received 2000 mg/kg bw/day isophorone died. Effects at 1000 mg/kg bw/day were reduced body weight gain in male and female rats (< 14%). In the 13-week study,one of ten females of the top dose group died. In the 1000 mg/kg bw/day group reduced body weight gain was only seen in male rats. The NOAEL considering effects observed in both studies is

500 mg isophorone/kg bw/day for male and female rats (NTP, 1986)

After administration of isophorone up to 2000 mg/kg bw/day to male and female B6C3F1 mice for 16 days, the reported effect were mortality at 2000 mg/kg abd reduced body weight gains in male and female mice at lower dosages. In the 13 week study with dosages up to 1000 mg/kg bw/day, 3 of 10 females that received the top dose died. Final mean body weights for animals of each sex were not dose related. The NOAEL considering both studies is therefore125 mg isophorone/kg bw/day for female (derived from the 16 day study) and 500 mg isophorone/kg bw/day for male mice (derived from the 16 day study) (NTP, 1986).

In a further guideline comparable 90-day study, beagle dogs (4 animals/dose/sex) were given orally gelantine capsules containing doses of 35, 75, or 150 mg isophorone/kg bw. As the only minor clinical signs, incidences of soft stool were noted in the two upper levels (NOAEL >= 150 mg/kg bw/day for male and female beagle dogs) (Rohm & Haas Co., 1972),

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the lowest NOAEL was choosen.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The study with the lowest NOAEL was choosen.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The study with the lowest NOAEL was choosen.

According to the criteria of CLP Regulation 1272/2008 isophorone is not classified because it has a low oral repeated dose toxicity.

Effects observed in a repeated inhalative toxicity study (liver and blood changes, nose and eye irritation) do not meet the criteria for classification and labelling.