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EC number: 207-434-1 | CAS number: 471-01-2
Endpoint summary
Administrative data
Description of key information
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 NOAELs are based on slight (<14%) reductions in body weight gain). After inhalational administration nose and eye irritation and blood and liver changes were observed (NOAEL (rat, 28 days) < 208 mg/m3).
Key value for chemical safety assessment
Additional information
Oral
Male and female Fischer rats were administered 0, 125, 250, 500, 1000 and 2000 mg isophorone/kg bw/day in a 16 day and 0, 62.5, 125, 250, 500 and 1000 mg/kg bw/day in a 13 week investigation, the former being a dose finding study for the latter.
In the dose finding study, one of five males and four of five females that received 2000 mg/kg bw/day isophorone died. Effects at 1000 mg/kg bw/day were reduced body weight gains in male (-13.9%) and female rats (-6.7%).
In the 13-week study, one of ten females of the tope dose group died. In the 1000 mg/kg bw/day group reduced body weight gain was only seen in male rats (-5.1%). The NOAEL considering effects observed in both studies is 500 mg isophorone/kg bw/day for male and female rats (NTP, 1986).
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 3000 ppm (during weeks 6,7,8,9,10 and 11). The NOAEL derived from this study is 102.5 mg/kg bw/day for male and 311.8 mg/kg bw/day for female rats (Rohm & Haas, 1972b).
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 and reduced body weight gains in male (max. -7.8%) and female (max. -9.3%) 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 therefore 125 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 (Rohm & Haas Co., 1972a), beagle dogs (4 animals/dose/sex) were given orally gelatine capsules containing doses of 35, 75, or 150 mg isophorone per kg bodyweight. As the only minor clinical signs, incidences of soft stool were noted in the two upper dose levels.
NOAEL: > 150 mg/kg bw/day for male and female beagle dogs.
Inhalation
Studies are available for rats, mice, rabbits, and guinea pigs.
In rats exposed for 4 weeks to 208 mg/m3 isophorone reduced body weights in males, changes in haematological parameters and reduced liver weights in males and females were found (Exxon, 1968).
In a study with 6 weeks duration, at doses ≥ 287 mg/m3 congested kidneys, dilated Bowman’s capsules and lung changes (irritation, congestion) were found in rats and in guinea pigs (Smyth et al., 1942). Further findings observed in this study were blood cell changes and albuminuria at doses ≥ 575 mg/m3 and eye and nasal irritations at 2874 mg/m3. Eye and nose irritations have also been observed in a more recent study in Wistar rats andrabbits at 1436 mg/m3 after 18 months 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 (Zissu, 1995).
Justification for classification or non-classification
Based on the available oral and inhalation repeated dose toxicity studies, isophorone does not need to be classified for repeated dose toxicity according to Directive 67/548/EEC and according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.
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