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Based on the information of the constituents, the NOAECs observed ranged from 3500 mg/m3 for hexanol to 31,680 mg/m3 for propylene dimers. This indicates that the UVCB substance is of low repeated dose toxicity and does not require classification for repeated dose toxicity. IPE comprises approximately 50% of the UVCB substance and is therefore the main constituent. The C6 alkanes/alkenes are with 20% the second large constituent. The NOAECs of both IPE and C6 alkanes/alkenes, together accounting for approximately 70% of the UVCB substance, are in the same order of magnitude (3300 ppm and 3000 ppm, respectively). It is therefore reasonable to use the data of the main constituent IPE as the basis for the CSA.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
13 800 mg/m³

Additional information

The substance Reaction Products of C3 alcohols and C3 alkenes obtained as by-products from the manufacture of propan-2-ol by hydration of propylene is a UVCB substance. The main constituent (approximately 50%) is isopropyl ether. Minor constituents are propylene dimers (~20%, C6 hydrocarbons, mainly C6 alkenes), propylene trimers (~10%, C9 hydrocarbons), hexanols (~10%) and C3 alcohols (~10% consisting of both isopropanol and n-propanol).

The toxicological properties of the UVCB substance after repeated exposure can be predicted based on the toxicological properties of its main constituents after repeated exposure.


The repeated dose toxicity of isopropyl ether (IPE, also known as diisopropylether or DIPE) has extensively been assessed in several inhalation studies in multiple species, including rats, guinea pigs, rabbits and monkeys. In the most recent and well-described study, rats were exposed to 0, 480, 3300, and 7100 ppm IPE for 6 hours/day, 5 days/wk for 13 weeks. Increases in liver and kidney weights were seen at 3300 and 7100 ppm in both males and females. Some evidence of increased incidence of hyaline droplets in kidney proximal tubules was observed in high dose males only. No effects on serum chemistry, hematology, or pathology were noted at any dose level. The no observed effect concentration (NOEC) for this study was 480 ppm (Dalbey and Feuston, 1996). The authors did not derive a NOAEC, however, based on minimal kidney effects in the high-dose males, of which the relevance to man is unclear, a conservative NOAEC could be established at 3300 ppm (13,800 mg/m3).

Data from a developmental toxicity study with IPE confirm this NOAEC. Rats were administered 0, 430, 3095, and 6745 ppm IPE for 6 hours/day on gestations days 6-15. Maternal effects at the high dose included increased salivation and lacrimation during and immediately following exposure. A slight decrease in food consumption was noted at 3095 and 6745 ppm. A concentration-related increase in the incidence of rudimentary ribs was observed (statistically significant at 3095 and 6745 ppm), but the significance of this finding is not known. No changes in reproductive organ weights and structure or sperm and spermatid number at any dose group were noted. The NOEC for both maternal and developmental effects under conditions of this study was 430 ppm (Dalbey and Feuston, 1996). The authors did not derive a NOAEC, but since no significant adverse effects were noted at all concentrations, the NOAEC could be established at 6745 ppm.


Data on propylene dimers can be derived by reading across from data on C6 alkanes and C6 alkenes.  Information on the repeated dose toxicity for C6 alkanes can be derived from a 2-year carcinogenicity study of commercial hexane. Commercial hexane contains approximately 52% of n-hexane, and for the remaining 48% hexane isomers, including 2-methyl pentane.

In a two part study, the oncogenic effects of inhalation exposure to commercial hexane (approximately 52% n-hexane) were evaluated male and female mice and male and female rats (Daughtrey, 1999). In Part I of the study groups of 50 male and 50 female rats were exposed to 0, 900, 3000, or 9016 ppm of test substance for 6 hrs/day, 5 days/week, for 2 yrs. Mortalities of exposure groups were consistent with control groups. Body weight gain was significantly reduced in exposure groups. Histopathology revealed dose-related irritation-related effects in the nasoturbinal tissue in all exposure groups. Therefore, there was no NOAEC level for local irritation effects. The LOAEC level for both sexes was 900 ppm for irritation. No oncogenic effects were seen in the exposure groups. The NOAEC for systemic effects was 9016 ppm in rats of both sexes.

In Part II of the study groups of 50 male and 50 female mice were exposed to 0, 900, 3000, or 9018 ppm (0, 3168, 10560, 31680 mg/m3) of commercial hexane (52% n-hexane) for 6 hrs/day, 5 days/week, for 2 yrs. Mortalities of exposure groups were consistent with control groups. Histopathology revealed increased liver masses and nodules in female mice at the 9018 ppm exposure group. As referenced by the National Toxicology Program, liver tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice. Therefore, the increased incidence of liver masses and nodules in female mice are deemed of questionable relevance for human health risk assessment.  Therefore, the NOAEC level for oncogenic effects in mice is 9018 ppm (31,680 mg/m3).

Additional information confirming the low repeated dose toxicity potential of 2-methyl pentane can be derived from a two-generation reprotoxicity study on commercial hexane. In this study the effect of inhalation of commercial hexane (52% n-hexane) on reproduction in rats was determined (Daughtrey, 1994). Groups of 25 male and 25 female rats were exposed to nominal concentrations of 0, 900, 3000, or 9000 ppm of commercial hexane for 6 h a day, 5 or 7 days a week, over two generations. In addition to pre-breed exposures of 10 weeks' duration, exposures continued through mating, gestation and lactation. Reproductive parameters were similar in exposure groups and control groups. There was reduced body weight in the F1 and F2 generation in both sexes in the 9000 ppm exposure group in both adults and offspring. The NOAEC is therefore 3000 ppm (10,560 mg/m3), and the LOAEC is 9000 ppm (31680 mg/m3). Since there were no adverse effects in offspring without adverse maternal effects, the NOAEC for reproduction is 9000 ppm (31,680 mg/m3).


A 90-day inhalation study with hex-1-ene is representative for the C6 alkene repeated dose toxicity. In this study, Neodene 6 alpha olefin was administered to forty Fischer 344 rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 300, 1000, or 3000 ppm (corresponding to 0, 1033, 3442, or 10,326 mg/m3) for 6 hours a day, 5 days a week, for 13 weeks (Bennick et al., 1984). Ten of the animals/sex/concentration were used for neuromuscular testing, ten of the animals/sex/concentration were sacrificed after 7 weeks of exposure, and twenty animals/sex/concentration were sacrificed after 13 weeks of exposure.

Subchronic inhalation of Neodene 6 alpha olefin for 13 weeks did not produce any adverse respiratory, neuromuscular, or testicular effects in rats. Decreased body weight was observed in 3000 ppm females (statistically significant) and males (statistically significant only sporadically). Decreased absolute liver and kidney weights were observed in 3000 ppm females; however, these findings were considered secondary to reduced body weight in the absence of histopathological findings in these organs. There were statistically significant differences in haematology and clinical chemistry values, but the changes were slight (generally within 5% of the control), were not dose related, and/or not associated with any histopathology findings. Increased phosphorus levels were reported in males at all treatment levels and females exposed to 1000 and 3000 ppm hex-1-ene. The toxicological significance of these findings is doubtful. The NOAEC is 3000 ppm (10,326 mg/m3) based on a lack of toxicologically relevant findings at the highest concentration tested.


Data on propylene trimers can be derived by reading across from data on C9 alkanes and C9 alkenes.

A 13-week inhalation toxicity study was conducted using wholly vaporized light alkylate naphtha distillate (a stream containing mainly C7-9 alkanes) (Schreiner et al., 1998). Male and female rats were exposed by inhalation in whole-body exposure cages 6 hours/day, 5 days/week for 13 weeks at analytical concentrations of 0, 668, 2220, and 6646 ppm. No test-related observations were noted in the exposure chambers during

any exposure period for any treatment groups or during non-exposure periods. From weekly clinical observations, the only apparent treatment-related finding was an increased incidence of red facial staining in both male and female rats in the high dose group. At week 13, there were statistically significant dose-related increases in absolute and relative kidney weights in males of all 3 treatment groups. The kidney weights of high-dose males remained elevated after the recovery period. These increases correlated with microscopic observations of hyaline droplet formation in the proximal convoluted tubules considered to contain an alpha2-microglobulin-hydrocarbon complex as well as an increase in incidence and severity of nephropathy and dilated tubules at the corticomedullary junction. These microscopic finding are characteristic of light hydrocarbon nephropathy also known as hyaline droplet nephropathy and are male rat specific. Therefore these effects are not considered to be relevant to humans. Statistically significant increases in absolute and relative liver weights were observed in high-dose male and female rats at week 13 after sacrifice. Differences were not present after the recovery period and had no microscopic correlate. Thus, the NOAEC for systemic toxicity was 8117 mg/m³ corresponding to 2200 ppm.

These findings are supported by a 13-week inhalation study (similar to OECD 413) with hydrocarbons, C7-C9, n-alkanes, isoalkanes, cyclic, which were administered via whole body inhalation to male rats at concentrations of 0, 280, 600, and 1200 ppm for 6 hours/day, 5 days/week, for 13

weeks (Carpenter et al., 1975). The NOAEC was estimated to be 5800 mg/m³ corresponding to 1200 ppm, the highest dose tested.


Information on the repeated dose toxicity for hexanol can be derived from a thirteen-week dietary feeding study in the rat. In this study rats were exposed to 1-hexanol via the diet (1% to 6%) during a 13 week treatment period. No signs of toxicity were recorded at diet concentrations of 1%. No microscopic alterations were recorded at any treatment level.  Examination of the testes and ovaries did not reveal any abnormality. The NOAEL was established at 1%, equivalent to 1127 mg/kg bw (ECB, 2000).

Information confirming the low repeated dose toxicity potential of hexanol can be derived from a developmental toxicity study, in which inhalation of saturated vapours of 1-hexanol (3500 mg/m3, 7 hr/day, GD 1-19) resulted in no significant signs of maternal or foetal toxicity. The NOAEC for both maternal and fetal effects for this study was the limit dose of 3500 mg/m3(Nelson et al., 1989).


Long-term repeated dose data on C3 alcohols are derived from isopropanol. No suitable long-term data on n-propanol could be located.

A GLP whole-body inhalation oncogenicity study in Fischer 344 rats with isopropanol concentrations of 0, 500, 2500, 5000 ppm for 6 hours/day 5 days/week for 104 weeks was conducted according to OECD test guideline 451 (Bushy Run Research Center, 1994). The report allows to conclude on a NOAEC of 5000 ppm (equivalent to 12,500 mg/m3). Exposure of rats to isopropanol vapour for 24 months produced clinical signs of toxicity, changes in body weight, and urinalysis and urine chemistry indicative of kidney changes in the 2500 and 5000 ppm groups. These changes were considered by the study authors to be indicative of chronic progressive nephropathy, a spontaneous lesion in aging rats which tends to be more prominent in male than female rats. Based on human and animal evidence relating to CPN, Hard et al. (2009; Gordon C. Hard, Kent J. Johnson, Samuel M. Cohen; Critical Reviews in Toxicology; 2009, Vol. 39, No. 4, Pages 332-346; A comparison of rat chronic progressive nephropathy with human renal disease) have concluded that this is a rodent-specific lesion which should not be regarded as an indicator of human toxic hazard. The only neoplastic lesion which was elevated was an increase in Leydig cell tumours in male rats. This is also a common spontaneous lesion in male rat which is very common in the rat strain used for this evaluation, F-344. The authors observed that the statistical significance attached to the frequency of this observation was probably due to the unusually low incidence in the concurrent control group. No increase in neoplastic lesions were noted in female rats.


Taking all repeated dose toxicity information of the constituents together, the NOAECs observed ranged from 3500 mg/m3 for hexanol to 31,680 mg/m3 for propylene dimers This indicates that the UVCB substance is of low repeated dose toxicity and does not require classification for repeated dose toxicity.



Bennick, J. E., Malley, L. A., Patterson, D. R., Lu, C. C. (1984). 90-Day vapor inhalation study in rats with Neodene® 6 alpha olefin. Testing laboratory: Westhollow Research Center, Houston, Texas. Report no.: WRC RIR-362. Owner company: Shell Development Company. Report date: 1984-04-03.


Bushy Run Research Center (1994). Isopropanol Vapor Inhalation Oncogencity Study in Fischer 344 Rats. Testing laboratory: Bushy Run Research Center, 6702 Mellon Road, Export Pennsylvania 15632-8902. Report no.: 91N0133. Owner company: American Chemistry Council, Inc. Report date: 1994-06-02


Carpenter, C. et al. (1975). Petroleum hydrocarbon toxicity studies II. Animal and human response to vapours of varnish makers and painters naphtha. Tox. Appl. Pharmacol. 32: 263-281.


Dalbey W. and Feuston M. (1996) Subchronic and developmental toxicity studies of vaporized diisopropyl ether. J. Toxicol. Environ. Health 49: 29-43.


Daughtrey W.C., Neeper-Bradley T., Duffy J., Haddock L., Keenan T., Kirwin C., and Soiefer A. (1994) Two-generation reproduction study on commercial hexane solvent. J. Appl. Toxicol. 14(5):387-393.


Daughtrey W., Newton P., Rhoden R., Kirwin C., Haddock L., Duffy J., Keenan T., Richter W., and Nicolich M. (1999) Chronic inhalation carcinogenicity study of commercial hexane solvent in F-344 rats and B6C3F1 mice. Toxicol. Sci. 48(1):21-29.


European Chemicals Bureau – ECB (2000) IUCLID Data Set, Hexan-1-ol (CAS#: 111-27-3). Citing: Scientific Associates, Inc. (1966) Exhibit II. Final report on thirteen-week subacute feeding of Alfol 6 and Alfol 16 to rats.


Hine C., Anderson H., and Kodama J. (1955) Sensory thresholds of certain Shell organic solvents, Progress Report 1, Report to Shell Development Company, November 15, UC Report #247.


Nelson B.K., Brightwell W.W., Khan A., Krieg E.F., Jr., and Hoberman A.M. (1989) Developmental toxicology evaluation of 1-pentanol, 1-hexanol, and 2-ethyl-1-hexanol administered by inhalation to rats. J. Am. Coll. Toxicol. 8(2):405-410.


Schreiner, C. et al. (1998). Toxicity evaluation of petroleum blending streams: inhalation subchronic toxicity/neurotoxicity study of a light alkylate naphtha distillate in rats. J. Toxicol. Env. Health (Part A) 55:277-296.


Silverman L., Schulte F., and First M. (1946) Further studies on sensory response to certain industrial solvent vapors. J. Ind. Hyg. Toxicol. 28(6):262-266.

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.