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EC number: 201-126-0 | CAS number: 78-59-1
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).
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.
Target Organs Effects:
M: body weight gain (reduced; abs. and rel. liver weight(reduced)
M+F: lymphocytes (increased); heamoglobin (increased); neutrophils (reduced)
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 .
In this 18-month inhalation study groups of 10 male and 10 female Wistar rats were exposed (whole body) to isophorone at air concentrations of 0 or 1436 mg/m3 (250 ppm) for 6 hours/day, 5 days/week. Slight conjunctivitis and irritation of the nasal mucosa with a bloody discharge were observed in males and females. In the lungs of the animals, frequent haemorrhages were found with oedema in the alveoli. Additionally, microvacuolization was found in the liver of the treated male and female rats.
Therefore, under the conditions of this study the No-Observed-Adverse-Effect-Concentration (NOAEC, rat, 18 months) for rats is determined to be < 1436 mg/m3.
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.
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).
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),
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.
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