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Description of key information

Rats: No effect level >3000mg/kg bw/day
Mice (B6C3F1):Females: NOAEL>4400mg/kg bw/day (cancer), Males: NOAEL>4250mg/kg bw/day (based on historic control data), Males BMDL10=1400mg/kg bw/day (based on concurrent control data) \
Two inhalation, carcinogenicity studies conducted according to GLP and to OECD test guideline 451 reported carcinogenicity NOECs for isopropyl alcohol (IPA) of 5000 ppm (=12290 mg/m3) (Burleigh-Flayer and Wagner, 1993; Burleigh-Flayer and Benson, 1994).

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
12 290 mg/m³

Justification for classification or non-classification

As both ethanol and isopropanol are not classified for carcinogenicity it can be concluded that the reaction mass does not need to be classified as a carcinogen according to DSD or CLP.


The only significant findings in animals are of low concern for the following reasons:

- tumour type is known to have a high background incidence in the species coupled with significantly low incidence in concurrent control compared to historic control.

- lack of progression to malignancy at 'lower' exposure levels (bearing in mind context of very high doses anyway, well above normal limit dose values).

- single sex response.

- single species response.

It should be noted that the International Life Sciences Institute published an extensive review of the health issues relating to alcohol consumption (“Health issues relating to alcohol consumption”, ILSI, 1999) and concluded that ethanol is not a carcinogen by standard laboratory tests using animals.

In humans, the only epidemiology data that could be relevant to the hazard presented through the use of ethanol as a chemical substance at the workplace and in consumer products is that relating to breast cancer. However, the available data shows that, at the doses likely to be relevant to such uses, there is no convincing evidence of any breast cancer hazard.

Overall, there is no compelling evidence to warrant a classification of ethanol for cancer in the context of the relevant classification and labelling regulations for chemical substances.


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

Additional information

There are no data available for the reaction mass. Based on the data available for the two constituents it can be concluded that overall on a weight of evidence basis the reaction mass should not be considered as a carcinogen.



In a study designed and conducted to determine the long-term toxicity and carcinogenicity of urethane in ethanol, groups of mice were exposed to ethanol at concentrations up to 5% in drinking water for a period of 2 years, with control groups consuming drinking water alone. From the data it was possible to ascertain that the most significant effect with respect to dose and cancer end points was a dose related increase in the rate of hepatocellular adenomas for male mice in comparison with the concurrent controls. The species of mouse used in this study is known to have a high spontaneous incidence of these tumours. In comparison to historic controls, the incidence rate in the ethanol dosed animals was not high and the controls were significantly lower (although it should be noted that no historic control information was available for animals on the study diet used.) Analysis of the data using the Benchmark dose approach showed a BMDL10 of 1400mg/kg for liver adenomas in males. There was no significant increase in tumour rates (including mammary tumours) in females.

In a study to assess the carcinogenic potential of ethanol, groups of rats were exposed to ethanol at concentrations of 1% and 3% in a liquid semi-synthetic diet for a period of 2 years, approximately equivalent to 1 and 3g/kg respectively. Each dose group used a control matched for caloric content using glucose. From the data it was possible to conclude that ethanol did not cause any treatment related increase in tumours. There was some evidence of non-neoplastic effects, but it was not possible to determine a no effect level for these from the data available and this study design.



IARC concluded that there is evidence that consumption of alcoholic beverages is causally related to cancer in the oral cavity, pharynx (excluding nasopharynx), larynx, oesophagus and liver (IARC monographs on the evaluation of carcinogenic risks to humans. Alcohol Drinking”, volume 44, 1988). More recently they have added breast cancer and colorectal cancer to this list (IARC monographs on the evaluation of carcinogenic risks to humans. Consumption of Alcoholic beverages and ethyl carbamate (urethane)”, volume 96, 2007) They reported no conclusive evidence of a link with cancer in any other organ. It is notable that, with the exception of the liver and breast cancers, the susceptible tissues are those that would be in direct contact with almost undiluted beverage during consumption. This was noted by IARC as likely to cause local irritation.  It is reasonable to postulate that the mode of action is likely to proceed through exposure to high local concentrations of ethanol and its metabolites leading to persistent irritation, and eventually hyperplasia and finally tumour formation. Such a mechanism would not be relevant to exposure via other routes. The exception to this is the liver, which would not be in direct contact with beverages but, as the primary site of metabolism, does see high concentrations of ethanol and its metabolites.

The UK Committee on the Carcinogenicity of Chemicals in Food, Consumer Products and the Environment reviewed the 1988 IARC monograph with the objective of estimating the relative risks of developing the cancers identified as causally associated with alcohol drinking (Sensible Drinking”, Report by the UK department of Health, 1995). The committee estimated the level of alcohol drinking which produced convincing evidence of an increase in the relative risk of cancer at susceptible sites. The group concluded that there is no convincing evidence that the carcinogenic effects of alcoholic beverages in humans occurs as a result of the mutagenic effect of ethanol, acetaldehyde or other beverage constituents. For the oral cavity, pharynx, larynx and oesophagus, alcohol consumption in excess of 30-40g per day is necessary before there is a convincing increase in the relative risk of cancer. Most prospective and case-controlled investigations support the conclusion that only heavy drinking (>80g/day) is associated with hepatocellular carcinoma. The overall conclusion of this review was that consumption of between 3-4 units of alcohol per day (21-28g ethanol) per day does not accrue significant healthrisks. The German MAK commission have also reviewed the data on ethanol and agreed that carcinogenisis of the mouth, throat, larynx and gullet are as a result of local irritancy effects. They also concluded that there is no convincing evidence that ethanol can produce hepatocellular tumours alone and that cirrhosis as a pre-cancerous lesion probably plays a casual role.

The only finding that needs further consideration is breast cancer. Both the European Chemicals Bureau (classification proposal ECBI/22/06 -2006) and the Dutch Expert Committee on Occupational Standards (Ethanol -an evaluation of the health effects from occupational exposure, Health Council of the Netherlands, 06OSH/2006) concluded that this was the most sensitive cancer end point. For this reason, only the available epidemiology data that has looked at the link between drinking and breast cancer has been summarised here.

The available toxicokinetic data suggests that continuous exposure to ethanol vapour at 1000ppm for 8 hours is likely to lead to a similar cumulative exposure as a single strong beverage containing 10g ethanol. Higher exposures over such a duration are unlikel due toth e discomfort effects of ethanol at high concentrations. (Resultant blood ethanol levels will of course be orders of magnitude lower from inhalation exposure compared to oral consumption due to the different timescales involved.) Therefore, by extrapolation, to assess the relevant hazard from ethanol, this is the sort of consumption range that should be examined.


Summary of available epidemiology data on breast cancer


To examine the association between drinking patterns of alcoholic beverages, particularly wine, and breast cancer, a case-control study was conducted among 437 newly-diagnosed breast cancer cases and 922 residence and age-matched controls. Details on drinking patterns were obtained by questionnaire. Women who reported an average consumption of less than 1.5 drinks per day, primarily as wine, (equivalent to 10 - 15 g ethanol/day) had a lowered risk of breast cancer when compared to non-drinkers.


A retrospective case-control study was conducted between 1991 - 1994 involving 989 women with breast cancer and 1350 (non-cancer) hospital controls. Alcohol consumption was associated with an increased breast cancer risk; for women who reported consuming <13.8 g ethanol/day compared with non-drinkers, with an increased risk for those consuming at least 13.8 g ethanol/day. There was a stronger association between alcohol consumption and breast cancer for oestrogen receptor positive (ER+) cancers than for oestrogen receptor negative (ER-) ones, with a dose-response relationship for ER+ tumours, but not for ER-.


A cohort study among 70,033 women, 2829 of whom developed breast cancer, found no significant increase in breast cancer risk for those consuming <1 drink/day versus lifelong alcohol abstainers. A small but significant and increasing risk was found for those consuming 1 -2 drinks/day, >=3 drinks/day. Increased breast cancer risk was concentrated in women with oestrogen receptor positive tumours. The investigators concluded that a hormone-related mechanism is responsible for the increased risk of breast cancer with alcohol drinking, with a threshold in the broad 1 - 2 drinks/day range.


A meta-analysis of 53 epidemiologic studies was performed involving 153,582 participants (58,515 cases and 95,067 without the disease), to examine the association between alcoholic beverage consumption (and tobacco use) and invasive breast cancer risk. This analysis was said to represent over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer. There was no statistically significant increased risk of breast cancer with a reported median daily intake of alcohol below about 8 g, with high consumption of 15-24g/day only becoming associated with increased risk.


A meta-analysis of 42 epidemiologic studies (published prior to 2000) providing data on 41,477 incident cases of breast cancer and quantifiable alcohol consumption data were assessed to examine the dose-response relation between alcohol consumption and incident breast cancer risk, and to assess whether this risk differed according to beverage type and various study characteristics.


The risk of invasive breast cancer was assessed in relation to total daily alcohol consumption among 66,561 postmenopausal women. Multivariate relative risks (RR) and 95% confidence intervals (CI) for categories of daily alcohol intake and risk of incident breast cancer were not statistically significantly increased in postmenopausal women consuming less than 15 g alcohol per day, compared to non-drinkers. Only in the highest category of alcohol consumption (at least 15 g/day),was the risk of incident breast cancer was statistically significantly increased, and this was only just significant.


In a US Study involving over 100,000 women aged 25-42 years, the risk of invasive breast cancer was assessed in relation to total daily alcohol consumption during the past year, and the number of alcoholic beverages consumed per week during different time periods and over the participants lifetime. Less than 5% of the women drank more than one alcoholic beverage/day, and 97% of the cohort were premenopausal at baseline. Multivariate relative risks (RR) and 95% confidence intervals (CI) for categories of daily alcohol intake and risk of invasive breast cancer were not statistically significantly increased in women consuming alcohol in the year before joining the cohort ("previous year") at any intake level up to and including the highest consumption group (>20 g/day), compared to non-drinkers. When assessing the relationship of alcoholic beverage consumption in each of four time periods during the patients lives, no statistically significant increases in breast cancer risk were seen in those women reportedly consuming at least 5 drinks per week at ages 15-17, 18-22, and 31-40 years, or in women consuming less than 5 drinks per week (ingesting up to 10 g alcohol/day) in any of the four time periods, compared to non-drinkers. Only those women who reported consuming either 5-6 drinks/week or more than 6 drinks/week between the ages of 23-30 showed a marginally statistically significantly increased risk of invasive breast cancer, compared to non-drinkers. For average lifetime alcohol consumption (assessed as number of alcoholic beverages per week), no statistically significant increases in breast cancer risk were seen in any category of intake, including at up to at least 10 alcoholic beverages per week, compared to non-drinkers.


The risk of invasive breast cancer associated with total daily alcoholic beverage consumption, and the influence of drinking patterns (frequency) and age at starting to drink were assessed. in 103,460 “at-risk” Californian teachers (and administrators), aged under 85 years. Multivariate relative risks (RR) and 95% confidence intervals (CI) for categories of total daily alcohol intake through drinking alcoholic beverages and risk of invasive breast cancer were not statistically significantly increased in those women consuming less than 20 g/alcohol day in the year before joining the cohort ("past year"), compared to non-drinkers and no clear pattern was seen for consumption during earlier periods of life. A marginally statistically significant increase in breast cancer risk was observed in those who reported consuming at > 20 g alcohol/day in the "past year. Sporadic drinkers (consuming alcohol on 4 or less days/week) were not associated with an increased risk of breast cancer, compared to non-drinkers.


To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption, and to assess whether certain (dietary and non-dietary) factors modify the association, the results from seven prospective studies were pooled. The studies included a total of 322,647 women (aged 34 to 93 years of age) evaluated for up to 11 years, and included 4335 participants diagnosed with incident invasive breast cancer. Of these breast cancer cases, 2873 consumed alcoholic beverages (at varying amounts), and 1462 were described as current non-drinkers. In the four categories in which the women were consuming on average less than 30 g alcohol/day, no statistically significant increase in breast cancer risk was seen, compared to the non-drinkers. Only in those who consumed between 30 to 60 g alcohol/day compared to the non-drinkers was a significant association found. For alcohol intakes less than 60 g/day, breast cancer risk increased linearly with increasing alcohol intake but this relationship only reached statistical significance at above about 15 g alcohol/day.

In a prospective cohort study, a total of 445 primary breast cancer cases were diagnosed from 23,778 postmenopausal Danish women in the nearly 5 year follow-up period. Adjusted relative risks (RR) and 95% confidence intervals (CI) for breast cancer were not statistically significantly increased in women who self-reported consuming less than 24 g alcohol/day, compared to the "reference group" (who reported ingesting up to 6 g alcohol/day). However, in those consuming between 24 and 60 g alcohol/day showed a statistically significant increased risk of breast cancer. Although the trend between total alcohol intake (when treated as a continuous variable) and breast cancer showed a statistically significant increase in risk per 10 g/day increment in alcohol consumption, this does not appear to apply at low levels of consumption. Indeed, abstainers and those reporting only "occasional" drinking appeared to be at slightly increased risk compared to those who reported regularly consuming up to 6 g/day. Drinking frequency was without a significant impact on breast cancer risk in this cohort.


A combined total of 5048 women were selected from the original Framingham (Massachusetts) Study and the Offspring Cohort, and a total of 287 incident breast cancer cases were diagnosed in the more than 40, and up to 24, years of follow-up, respectively. 

When combining the two cohorts, adjusted rate ratios (RR) and 95% confidence intervals (CI) for average daily alcohol intake and risk of incident breast cancer were not statistically significantly increased in women who reported consuming alcohol at any of the three categories assessed (<5 g/day, 5 to <15 g/day, and15 g/day), compared to non-drinkers. Of the women who reported alcohol consumption in the highest category (15 g/day), the median intake was 24 g alcohol/day (about two typical drinks). The findings suggest that the light consumption of alcohol or any type of alcoholic beverage is not asociated with increased breast cancer risk.




In one study which found a small but significant correlation between breast cancer and alcohol consumption, the investigators note that the “question of causality remains unclear”, and that, given the modest size of the relation between alcohol consumption and breast cancer risk, “is likely to remain controversial because, in this instance, it is beyond the resolution of epidemiologic methods, as the possibility of confounding or other bias seems difficult to exclude”. This cautionary note becomes even more relevant if you consider that, for the purposes of extrapolation to the occupational and/or consumer exposure situation, the primary concern is with data from the lower exposures where causality is even less clear and exposure measurements even more variable and imprecise. Using such data to extrapolate from one hypothesis (oral consumption of alcoholic beverages causes breast cancer) to another fundamentally different one (exposure of workers to industrial ethanol or to consumers from the use of ethanol containing products) is a massive leap of faith with a very unsound scientific basis. Even so, the data does conclusively indicate that exposure to small amounts of ethanol does not cause a significant increase in breast cancer. Cumulative exposure to ethanol from inhalation or dermal exposure could not reach the higher exposure levels where there is some evidence for increase effects in humans. This is without even considering the evidence suggesting that breast cancer may be hormone mediated and therefore likely to involve a threshold mechanism, in which case blood ethanol concentrations are likely to be more important rather than cumulative exposure.

Although the use of ethanol in alcoholic beverages is outside the scope of REACH, these data can provide some insight into any risks that might be associated with industrial or other consumer use of ethanol (primarily involving the inhalation or dermal routes), using route to route extrapolation. Whilst breast cancer appears to occur via a systemic exposure pathway, available data supports the hypothesis that ethanol is extremely unlikely to pose any breast cancer risk at the levels of exposure encountered through industrial or other consumer use.



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.