Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Additional information

In vitro studies

Severaltests with S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 with and without S9 were negative (Mortelmans et al., 1986; NTP, 1986; Hossack et al., 1978a; Huels AG, 1988b).

The mouse lymphoma tests were primarily negative. In the presence of metabolic activation only one positive result was obtained (Honma et al., 1999a). Without metabolic activation some studies gave negative results (O’Donoghue et al., 1988, Honma et al., 1999a), others positive results (McGregor et al., 1988). Positive results were found only at reduced RTG (relative total growth) values (McGregor et al., 1988). In one study, the incubation time was increased to 24 h to render the test system especially sensitive for the detection of clastogens and spindle poisons. In this study, isophorone was positive in one of two trials (Honma et al., 1999b).

In a cytogenetic assay with Chinese Hamster Ovary (CHO) cells, no significant increase in chromosomal aberrations was observed (Gulati et al., 1989; NTP, 1986). A further chromosomal aberration assay performed on Chinese hamster lung (CHL) cells was positive with isophorone with metabolic activation only after a modified treatment of the cells (cells are treated for 6 h and then cultured in fresh medium for another 18 h) (Matsuoka et al., 1996). Increased chromosome aberrations without metabolic activation were only observed at cytotoxic concentrations (Matsuoka et al., 1996).

Gulati et al. (1989) reported a significant increase in SCE frequency at concentrations of 500 – 1000 mg/l induced by isophorone only in the absence of S9 mix (no increase in the presence of Aroclor 1254-induced rat liver S9 mix). As these high isophorone concentrations were cytostatic, increased SCE frequencies could only be detected after delayed harvest.

Isophorone was tested for the induction of unscheduled DNA synthesis (UDS) in rat primary hepatocytes. Concentrations ranged from 0.005 - 0.4 μl/ml, the highest concentration being toxic. No increase in the mean nuclear grain count (as compared to controls) or in the incidence of cells undergoing repair was detected at any dose level (O’Donoghue et al., 1988; Microbiological Associates, 1984b).


In vivo studies

In a mouse micronucleus assay, 496.8 mg/kg (= LD20 = MTD) isophorone was administered i.p. to 5 male and 5 female CD-1 mice per group. Sampling time was 12, 24, 48 hrs post dosing. Significant increases in the number of micronucleated polychromatic erythrocytes (PCE) were not observed (O’Donoghue et al., 1988; Microbiological Associates, 1984a). Likewise, in a study with CFLP mice (5 animals/dose/sex; gavage doses of 450, 900, 1800 mg/kg given in 2 equal parts [i.e. half of total dose] separated by an interval of 24 hrs) a negative result was obtained 6 hours after the last dosage of isophorone (Hossack et al., 1978b).

In a DNA binding study, male and female F344 rats and B6C3F1 mice (25 animals/group) were administered 500 mg/kg [1,3,5-14C]-isophorone. Livers and kidneys (target organs in the NTP carcinogenicity study) were removed after 24 hrs. There was no binding of isophorone or its metabolites to DNA of these organs (Thier et al.,1990).

In a Sex Linked Recessive Lethal (SLRL) test with Drosophila melanogaster, fruit flies were fed a diet containing 2000 mg/kg isophorone. After 72 hrs of exposure, surviving males were mated. As feeding exposure was found to be non-mutagenic, 2 - 3 day old males were then injected with a 0.7 % NaCl solution containing 12,500 mg/l isophorone. 24 hrs post injection, males were mated. Again there was no indication of a mutagenic effect (Foureman et al., 1994).

Short description of key information:
Although in one standard mouse lymphoma assay a positive result was observed, the majority of in vitro genotoxicity studies revealed clearly negative results. Together with the negative in vivo results and the negative DNA binding assay, the overall conclusion is that isophorone is not mutagenic.

Endpoint Conclusion:

Justification for classification or non-classification

Based on the results of the genetic toxicity tests, isophorone does not need to be classified 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.