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Toxicological information

Carcinogenicity

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Description of key information

Two  inhalation, carcinogenicity studies conducted according to GLP and to OECD test guideline 451 reported carcinogenicity NOECs for isopropyl alcohol (IPA) of 5000 ppm (Burleigh-Flayer and Wagner, 1993; Burleigh-Flayer and Benson, 1994).

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
NOAEC
12 290 mg/m³

Additional information

The carcinogenicity of isopropyl alcohol (IPA) was evaluated in a 2-year carcinogenicity study in rats (Burleigh-Flayer and Benson, 1994). This GLP study was conducted according to OECD test guideline 451. IPA was administered by inhalation at nominal concentrations of 0, 500, 2500, or 5000 ppm to Fischer 344 rats for 2 years, 6 hours/day, 5 days/week (65 rats/sex/group). A subset of 10 animals/sex/group was sacrificed halfway through the study for analysis. All animals underwent complete gross necropsy and microscopic examinations.   There were no differences in survival reported. Observed clinical signs included hypoactivity and lack of a startle reflex, starting at 2500 ppm in both male and female rats. Narcosis was observed in male and female rats at the 5000 ppm dose level. During non-exposure periods, emaciation and dehydration were observed in the high-dose males. Increased number of rats with urine stains (males and females) and swollen periocular tissue (females) were observed in high-dose rats. Female rats in the mid-dose group also had increased incidence of urine stains. Transient decreases in body weight were initially noted in both male and female rats. By week 72, all IPA-treated female body weights were increased compared to controls and body weights for the 2500 ppm and 5000 ppm males were increased compared to controls by week 6.   Decreased urine osmolality and increased urine volume were noted for high-dose male and female rats by week 104. Increased total urine protein also was reported for high-dose males.   At the interim sacrifice, absolute and relative kidney weights were increased for male rats in the 5000 ppm group. These kidney weight changes were not present in males during the terminal sacrifice; however, terminal absolute and relative kidney weights were increased in the 5000 ppm females. Interim and terminal relative liver weights were increased for male rats in the 2500 ppm group. Terminal absolute and relative liver weights were increased for females in the 5000 ppm group. Increases in liver weights were attributed by the study authors to microsomal enzyme induction. Concentration-related increases in interim absolute and relative testes weights were observed, achieving statistical significance in the 5000 ppm group. These changes in testes weights were no longer apparent during the terminal sacrifice. Increase in interim relative and absolute lung weights were reported in high-dose females; however, these changes were not noted at the terminal sacrifice.   Gross pathology observations included an increase in granular kidneys in male rats at 2,500 and 5000 ppm during the interim sacrifice and at 5000 ppm during the terminal sacrifice. Gross findings from preterminal animals included increased incidence of thickened stomachs in the mid-dose males and high-dose males and females, granular kidneys in mid- and high-dose males and females, and color change of the kidneys in mid- and high-dose males.    Histopathology of non-neoplastic lesions reported an increase in frequency of testicular seminiferous tubule atrophy in high-dose males at the interim sacrifice. Findings reported for male premature decedents in the 2500 and 5000 dose groups included kidney lesions, and mineralization of the heart, aorta, vasculature, stomach, larynx, trachea, lungs, kidney, cornea, and testes. Findings of basophilic cell foci in the liver, splenic haemosiderosis, rhinitis, and squamous metaplasia of the respiratory epithelium of the nasal cavity also were reported for high-dose premature decedent males. In premature decedent high-dose females, increased frequencies of mineralization in the heart, aorta, vasculature, stomach, larynx, trachea, lungs, and kidney were noted. Additionally, increases in myocardial degeneration, atrial thromobosis, splenic haemosiderosis, ocular keratitis, inflammatory and metaplastic changes in the nasal cavity, squamous metaplasia of the respiratory epithelium and glandular ectasia in the gastric mucosa also were reported. In surviving female rats, an increased severity of glomerulosclerosis and renal disease was noted at the 5000 ppm concentration level.   Histopathology of neoplastic lesions indicated a dose-dependent increase in interstitial cell adenomas of the testis in male rats at all sampling time points, including premature decedents. The study authors postulated that these changes represented marked hyperplasia and were not representative of growth. Additionally, the increased incidence of testicular tumors appeared to be reflective of lower incidence in the control group. The study authors noted that testicular adenomas are a common finding in aged male rats and that historical incidence of this finding has been reported to be high as 88%, which is much higher compared to an incidence of 64.9% reported for control animals in the study. Therefore, the testicular adenomas were considered possibly spurious by the study authors. There were no increases in neoplastic lesions reported for females.   Given the irrelevance of the neoplastic lesions in this rat study to humans, a carcinogenicity NOEC of 5000 ppm was identified by the study authors.  

Further information on the carcinogenicity of IPA was provided by another key GLP carcinogenicity report; an 18 -month study in CD-1 mice (equivalent to OECD test guideline 451) which used concentration levels of 0, 500, 2500, or 5000 ppm (Burleigh-Flayer and Wagner, 1993). The study authors noted afew microscopic non-neoplastic lesions in IPA exposed animals; however, these findings were minimal in degree and deemed (by the study authors) to be not biologically significant. There were no increased frequencies of neoplastic lesions noted for male or female mice from any test substance exposure group. Clinical signs noted in some male and female mice during exposures to 5000 ppm included hypoactivity, lack of a startle reflex, ataxia, prostration, and narcosis. Hypoactivity, lack of startle reflex, and narcosis were also noted in some male and female animals during exposure to 2500 ppm. No clinical signs were noted for male or female animals during exposure to 500 ppm. A NOEC of 5000 ppm for carcinogenicity was reported.

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for this endpoint, as set out in Regulation (EC) No. 1272/2008.