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EC number: 701-241-0
CAS number: -
The test item has the main constituent of isopropyl ether (approximately
50%). Minor constituents comprise propylene dimers (approximately 20% C6
hydrocarbons, mainly C6 alkenes), propylene trimers (approximately 10%
C9 hydrocarbons), hexanols (approximately 10%) and C3 alcohols
(approximately 10% consisting of both isopropanol and n-propanol). Read
across from diisopropylether (DIPE) and other constituents is justified
on the basis that NOAECs reported for the constituents of this UVCB
range from 3500 mg/m3 for hexanol to 31680 mg/m3 for
propylene dimers, which can be considered indicative of low toxicity for
this UVCB substance. DIPE comprises approximately 50% of the UVCB
substance and is, therefore, the main constituent. The C6
alkanes/alkenes are, with 20%, the second largest constituent. A
regulatory design 90-day toxicity study in rats (Dalbey and Feuston,
1996) was conducted via the inhalation route with a vaporised sample of
commercial grade DIPE for 6 hours/day and 5 days/week. The study
included both untreated and sham-exposed controls and groups treated at
480, 3300 or 7100 ppm DIPE (equivalent to 2000, 13800 and 29700 mg DIPE/m3).
DIPE itself accounted for 91-95% of the vapours and resulted in some
renal and hepatotoxicity at the treatment levels of 3300 and 7100 ppm
with males being more severely affected than females and organ weight
changes only associated with pathological changes at the 7100 ppm level.
The treatment level of 480 ppm was without effect. At these moderately
toxic exposure levels in a 90-day toxicity setting in rats, the
read-across substance, DIPE, demonstrated a No Observed Adverse Effect
Concentration (NOAEC) via the inhalation route of exposure of 3300 ppm
(equivalent to 13800 mg/m3).
Table 1. Mean parameters ( ±SD)
of hematology and serum chemistry that had significant differences
between exposed and control groups following subchronic exposures.
480 ppm DIPE
3300 ppm DIPE
7100 ppm DIPE
0.61 ± 0.06
0.64 ± 0.04
0.67 ± 0.06
0.69 ± 0.03b
71 ± 10
74 ± 13
77 ± 17
77 ± 9
95 ± 22d
11 ± 5
16 ± 7
13 ± 6
9 ± 3c
92 ± 3
92 ± 4
90 ± 6
90 ± 4
87 ± 6b
1 ± 2
2 ± 2
3 ± 2b
4.96 ± 0.35
4.68 ± 0.24
4.58 ± 0.41
4.51 ± 0.37b
4.45 ± 0.40b
88 ± 5
86 ± 6b
85 ± 7b
86 ± 3b
apercent of total white blood cells.
bSignificantly different from untreated controls.
cSignificantly different from sham-exposed controls.
dSignificantly different from both control groups.
Read across from diisopropylether (DIPE) is justified on the basis that
NOAECs reported for the constituents of this UVCB range from 3500 mg/m3
for hexanol to 31680 mg/m3 for propylene dimers, which
can be considered indicative of low toxicity for this UVCB substance.
DIPE comprises approximately 50% of the UVCB substance and is,
therefore, the main constituent. The C6 alkanes/alkenes are, with 20%,
the second largest constituent. The NOAECs of both DIPE 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,
Mild hypertrophy was observed at the high-dose in combination with 39%
(male) and 18% (female) increased absolute liver weight. The high dose
of 7100 ppm was considered to be the LOAEC effect level.
At the mid-dose, no histopathological changes were observed. Absolute
liver weight gain was 26% in males only; 6% in females. Sorbitol
dehydrogenase dropped from 11(5) or 16(7) IU/L in controls to 9(3) IU/L.
The absolute liver weight gain seen only in males, and unaccompanied by
other effects, is considered to be a suitable NOAEC.
Based on "adverse liver effects" criteria by TERA (Toxicology Excellence
for Risk Assessment): presence of histopathology (moderate hypertrophy)
in combination with statistically significant absolute or relative
weight changes; or liver weight change >10%; or doubling of serum levels
of liver enzyme activity.
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
(equivalent to 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 biological 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
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
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
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
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
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 (CPN), 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:
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
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.
The substance does not meet the criteria for classification and
labelling for this endpoint, as set out in Regulation (EC) NO. 1272/2008.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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