Alcohols, C12-14

Carcinogenicity

Description of key information

The genotoxic potential of the long chain alcohols has been well investigated, both in vitro and in vivo and no concerns were identified for genotoxicity. Furthermore they lack structural elements of concern for interaction with DNA . Together with the lack of response upon repeated application the skin painting studies long chained alcohols are regarded to be of little concern regarding carcinogenicty.
There are conclusive but not suffcient data for the classification of substance Alcohols, C12-14  with regard to carcinogenicity.
Carcinogenicity: IARC, NTP, ACGIH and OSHA do not classify this substance or its components as a carcinogen or suspect carcinogen.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

other: published data

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

no

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: 42 days
- Weight at study initiation: Males: mean 103 g (range 86-126); females: 81 g mean (range 64-95)
- Fasting period before study:
- Housing: singly in stainless steel cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Doses were prepared daily by dispersing 2EH in an aqueous solution of Cremophor EL (5 µg/100 ml) by ultra high speed sonication for 1 min.
Homogeneity was maintained by magnetic stirring throughout dosing.


VEHICLE
- Justification for use and choice of vehicle (if other than water): a surfactant (Cremophor) was used to facilitate mixing 2-EH with water
- Concentration in vehicle: 5 µg/100 ml
- Amount of vehicle (if gavage): dose volume was 10 ml/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity was checked before the onset of dosing and after 5 months of dosing, and concentrations of 2EH were checked quarterly,
by gas chromatography.

Duration of treatment / exposure:

24 months

Frequency of treatment:

5 days/week

Post exposure period:

none

Remarks:

Doses / Concentrations:
0 (water), 0 (vehicle), 50, 150, 500 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

50

Control animals:

other: concurrent water and vehicle controls

Details on study design:

Post-exposure period: none
- Dose selection rationale: based on the results of a 90-day rat study
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: n.a.
- Post-exposure recovery period in satellite groups: n.a.
- Section schedule rationale (if not random): n.a.

Positive control:

not required

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observations for clinical signs and mortalities were made twice daily on dosing days and once daily on weekends.
- Cage side observations checked in table [45-48, study report] were included.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed examinations and palpations were made weekly.


DERMAL IRRITATION (if dermal study): n.a.
- Time schedule for examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were determined before the onset of dosing, weekly in the first 13 weeks and monthly thereafter.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: n.a.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: n.a.


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): n.a.
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Differential blood counts were made on blood collected by tail vein puncture at 52 weeks and termination. Blood smears were counted visually
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: no data
- Parameters checked in table [49-83] were examined.
CLINICAL CHEMISTRY: No
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.


URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:


OTHER: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes.
Complete gross necropsies were performed on all animals at sacrifice, on decedents, and on sacrificed moribund animals. Weights of
exsanguinated animals and of stomachs, livers, kidneys, spleens, brains, and testes were taken for all animals sacrificed according to schedule.

HISTOPATHOLOGY: Yes.
Tissues from gross lesions and all organs and tissues listed in the guidelines were fixed in 4% formaldehyde solution. Microscopic
examination was performed after hematoxylin and eosin staining. Gross lesions, all tissues from water and vehicle controls and from highdose
groups, and kidneys, fore- and glandular stomachs, livers, lungs, and testes from low- and mid-dose groups were examined microscopically.

Statistics:

Means and standard deviations were calculated for body weights, food consumption, and absolute and relative organ weights.
Data from water and vehicle controls were compared by Student's / test (Winer, 1971). Data from test groups were compared with vehicle controls
by ANOVA followed by Dunnett's test (Dunnett, 1955, 1964). Microscopic observations were tested for significance by a pairwise (one-tailed) comparison with vehicle controls using Fisher's exact test (Siegel, 1956). Hepatocellular carcinoma data were also tested for trends among dose levels by the time-independent Cochran-Armitage (Armitage, 1955) and the simple Peto (Peto et ai, 1980) tests and by the time-dependent Peto test (Tarone, 1975). Mortality and hepatocellular carcinoma data were fitted by the time-dependent multistage Weibull dose-response model (Hartley et al, 1981).

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Mortality was moderate in the rat during the first 78 weeks of dosing except for females at 500 mg/kg. A considerable increase in mortality in rats occurred in control and treatment groups between 78 weeks and final sacrifice.
Mortalities in male rats were not dose-related; the 38% mortality at 500 mg/kg was exceeded by that at 50 mg/kg (46%).
The mortality increase at 500 mg/kg in females was clearly dose-related and amounted to 52% of the animals in the group.

Clinical findings:
Clinical observations related to treatment with 2EH were limited to dose-related
increases in the number of rats in poor general condition, defined as lethargy and unkemptness, and with labored breathing.
The incidence of poor general condition (number of daily observations per number of affected rats) was:
Group poor general condition labored breathing
------------------------------------------------------------
Vehicle control
Males 62/12 2/1
Females 34/8 9/3

500 mg/kg bw/day
Males 200/14 41/4
Females 248/41 75/12
------------------------------------------------------------

BODY WEIGHT AND WEIGHT GAIN
At the end of treatment statistically significant differences from vehicle controls were for rats:
Males - 5 % at 50 mg/kg, - 1 1% at 150 mg/kg, and - 2 3% at 500 mg/kg;
Females - 9% at 150 mg/kg and - 2 1% at 500 mg/kg.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Male and female rats showed no overall differences in food consumption from vehicle controls at any dose level.

FOOD EFFICIENCY
n.a.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
n.a.

OPHTHALMOSCOPIC EXAMINATION
n.a.
HAEMATOLOGY
There were no treatment-related differences from controls in white cell morphology in rats after 12, 18, and 24 months of treatment with 2EH
(data not shown). In male rats at 500 mg/kg there were slight morphological changes in red cells at 12 months only, manifested as an increased incidence of anisocytosis (9/46 animals), predominantly as microcytosis (5/46 animals). These changes were not observed in controls.


CLINICAL CHEMISTRY
n.a.

URINALYSIS
n.a.

NEUROBEHAVIOUR
n.a.
ORGAN WEIGHTS
Relative organ weights (statistically significant changes, compared with vehicle control):

Group Organ , sex, effect
------------------------------------------------------------------------------------------------------------------------------
50 mg/kg bw/d: stomach: small increase, F 6%*
150 mg/kg bw/d: stomach, M 7% and F 9%; liver, F 11%; kidneys, M 22% and F 7%; brain, M and F 19%)
500 mg/kg bw/d: stomach, M 21% and F 20%; liver, F 13%; kidneys, M 19% and F 14%; brain, M 19% and F 18%; testis, 21%
------------------------------------------------------------------------------------------------------------------------------
GROSS PATHOLOGY
There were few changes; cf. original reference

HISTOPATHOLOGY: NON-NEOPLASTIC
There were significantly increased incidences of changes in the male and female hig dose groups seen in stomach, liver, lung, sleen, lymph nodes, and prostrate (most at p<0.01 level of significance). For details see original publication.

HISTOPATHOLOGY: NEOPLASTIC
The incidence of neoplastic lesions was not increased in treated groups (cf. table).

HISTORICAL CONTROL DATA (if applicable)
n.a.
OTHER FINDINGS
none

Relevance of carcinogenic effects / potential:

2-Ethylhexanol was not oncogenic in the rat under the conditions of this assay. In both sexes the sum of primary tumors, the sum of benign tumors and the sum of malignant tumors was lower in the top dose group than in either the vehicle control or the water control groups.
2-ethylhexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: absence of neoplastic lesions

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: increased mortality

Remarks on result:

other: Effect type: toxicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

768.05 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Correcting for molecular weight, a conservative NOAEL of 768.05 mg/kg bw/day can be derived (500 x 200) / 130.2 =768.05 mg/kg bw/day

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Histopathology: The incidences of neoplastic lesions were not significantly increased in treated rats (table).    

	Number of animals with microscopic findings (%)
	All animals				Decedents and  moribunds
Dose (mg/kg bw/d)	0 (vehicle)	50	150	500	150	500
Males, liver
Adenoma	0	0	2	0	0	0
Carcinoma	2	6	6	2	6	5
Females, liver
Carcinoma	2	2	4	0	8	0

Conclusions:

2-Ethylhexanol was not carcinogenic in the Fischer F344 rat. 2-ethylhexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.

Executive summary:

2-Ethylhexanol was not oncogenic in the Fischer F344 rat in a valid GLP carcinogenicity study (Astill et al., 1996).In both sexes the sum of primary tumors, the sum of benign tumors and the sum of malignant tumors was lower in the top dose group than in either the
vehicle control or the water control groups.

A dose related increase in mortality was observed in female rats, with 52% mortality in those given 500mg/kg bw/day 2-EH. Dose related reductions in weight gain were observed. Increased focal lesions and lung discoloration was observed in rats at 500 mg/kg bw/day. The 50 mg/kg bw/day dose produced a 6% increase in relative female stomach weight. Significant increases in stomach, kidney and brain relative weights were observed in male rats at 150 mg/kg bw/day 2-EH with testis relative weight
increase at 500 mg/kg bw/day. Female rats had significantly increased stomach, liver, kidney and brain relative weights at the 150 and 500 mg/kg bw/day doses. 2-ethyl hexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

768.05 mg/kg bw/day

Study duration:

chronic

Species:

rat

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

other: published data

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

no

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: 42 days
- Weight at study initiation: Males: mean 103 g (range 86-126); females: 81 g mean (range 64-95)
- Fasting period before study:
- Housing: singly in stainless steel cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Doses were prepared daily by dispersing 2EH in an aqueous solution of Cremophor EL (5 µg/100 ml) by ultra high speed sonication for 1 min.
Homogeneity was maintained by magnetic stirring throughout dosing.


VEHICLE
- Justification for use and choice of vehicle (if other than water): a surfactant (Cremophor) was used to facilitate mixing 2-EH with water
- Concentration in vehicle: 5 µg/100 ml
- Amount of vehicle (if gavage): dose volume was 10 ml/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity was checked before the onset of dosing and after 5 months of dosing, and concentrations of 2EH were checked quarterly,
by gas chromatography.

Duration of treatment / exposure:

24 months

Frequency of treatment:

5 days/week

Post exposure period:

none

Remarks:

Doses / Concentrations:
0 (water), 0 (vehicle), 50, 150, 500 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

50

Control animals:

other: concurrent water and vehicle controls

Details on study design:

Post-exposure period: none
- Dose selection rationale: based on the results of a 90-day rat study
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: n.a.
- Post-exposure recovery period in satellite groups: n.a.
- Section schedule rationale (if not random): n.a.

Positive control:

not required

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observations for clinical signs and mortalities were made twice daily on dosing days and once daily on weekends.
- Cage side observations checked in table [45-48, study report] were included.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed examinations and palpations were made weekly.


DERMAL IRRITATION (if dermal study): n.a.
- Time schedule for examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were determined before the onset of dosing, weekly in the first 13 weeks and monthly thereafter.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: n.a.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: n.a.


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): n.a.
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Differential blood counts were made on blood collected by tail vein puncture at 52 weeks and termination. Blood smears were counted visually
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: no data
- Parameters checked in table [49-83] were examined.
CLINICAL CHEMISTRY: No
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.


URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:


OTHER: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes.
Complete gross necropsies were performed on all animals at sacrifice, on decedents, and on sacrificed moribund animals. Weights of
exsanguinated animals and of stomachs, livers, kidneys, spleens, brains, and testes were taken for all animals sacrificed according to schedule.

HISTOPATHOLOGY: Yes.
Tissues from gross lesions and all organs and tissues listed in the guidelines were fixed in 4% formaldehyde solution. Microscopic
examination was performed after hematoxylin and eosin staining. Gross lesions, all tissues from water and vehicle controls and from highdose
groups, and kidneys, fore- and glandular stomachs, livers, lungs, and testes from low- and mid-dose groups were examined microscopically.

Statistics:

Means and standard deviations were calculated for body weights, food consumption, and absolute and relative organ weights.
Data from water and vehicle controls were compared by Student's / test (Winer, 1971). Data from test groups were compared with vehicle controls
by ANOVA followed by Dunnett's test (Dunnett, 1955, 1964). Microscopic observations were tested for significance by a pairwise (one-tailed) comparison with vehicle controls using Fisher's exact test (Siegel, 1956). Hepatocellular carcinoma data were also tested for trends among dose levels by the time-independent Cochran-Armitage (Armitage, 1955) and the simple Peto (Peto et ai, 1980) tests and by the time-dependent Peto test (Tarone, 1975). Mortality and hepatocellular carcinoma data were fitted by the time-dependent multistage Weibull dose-response model (Hartley et al, 1981).

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Mortality was moderate in the rat during the first 78 weeks of dosing except for females at 500 mg/kg. A considerable increase in mortality in rats occurred in control and treatment groups between 78 weeks and final sacrifice.
Mortalities in male rats were not dose-related; the 38% mortality at 500 mg/kg was exceeded by that at 50 mg/kg (46%).
The mortality increase at 500 mg/kg in females was clearly dose-related and amounted to 52% of the animals in the group.

Clinical findings:
Clinical observations related to treatment with 2EH were limited to dose-related
increases in the number of rats in poor general condition, defined as lethargy and unkemptness, and with labored breathing.
The incidence of poor general condition (number of daily observations per number of affected rats) was:
Group poor general condition labored breathing
------------------------------------------------------------
Vehicle control
Males 62/12 2/1
Females 34/8 9/3

500 mg/kg bw/day
Males 200/14 41/4
Females 248/41 75/12
------------------------------------------------------------

BODY WEIGHT AND WEIGHT GAIN
At the end of treatment statistically significant differences from vehicle controls were for rats:
Males - 5 % at 50 mg/kg, - 1 1% at 150 mg/kg, and - 2 3% at 500 mg/kg;
Females - 9% at 150 mg/kg and - 2 1% at 500 mg/kg.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Male and female rats showed no overall differences in food consumption from vehicle controls at any dose level.

FOOD EFFICIENCY
n.a.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
n.a.

OPHTHALMOSCOPIC EXAMINATION
n.a.
HAEMATOLOGY
There were no treatment-related differences from controls in white cell morphology in rats after 12, 18, and 24 months of treatment with 2EH
(data not shown). In male rats at 500 mg/kg there were slight morphological changes in red cells at 12 months only, manifested as an increased incidence of anisocytosis (9/46 animals), predominantly as microcytosis (5/46 animals). These changes were not observed in controls.


CLINICAL CHEMISTRY
n.a.

URINALYSIS
n.a.

NEUROBEHAVIOUR
n.a.
ORGAN WEIGHTS
Relative organ weights (statistically significant changes, compared with vehicle control):

Group Organ , sex, effect
------------------------------------------------------------------------------------------------------------------------------
50 mg/kg bw/d: stomach: small increase, F 6%*
150 mg/kg bw/d: stomach, M 7% and F 9%; liver, F 11%; kidneys, M 22% and F 7%; brain, M and F 19%)
500 mg/kg bw/d: stomach, M 21% and F 20%; liver, F 13%; kidneys, M 19% and F 14%; brain, M 19% and F 18%; testis, 21%
------------------------------------------------------------------------------------------------------------------------------
GROSS PATHOLOGY
There were few changes; cf. original reference

HISTOPATHOLOGY: NON-NEOPLASTIC
There were significantly increased incidences of changes in the male and female hig dose groups seen in stomach, liver, lung, sleen, lymph nodes, and prostrate (most at p<0.01 level of significance). For details see original publication.

HISTOPATHOLOGY: NEOPLASTIC
The incidence of neoplastic lesions was not increased in treated groups (cf. table).

HISTORICAL CONTROL DATA (if applicable)
n.a.
OTHER FINDINGS
none

Relevance of carcinogenic effects / potential:

2-Ethylhexanol was not oncogenic in the rat under the conditions of this assay. In both sexes the sum of primary tumors, the sum of benign tumors and the sum of malignant tumors was lower in the top dose group than in either the vehicle control or the water control groups.
2-ethylhexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: absence of neoplastic lesions

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: increased mortality

Remarks on result:

other: Effect type: toxicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

768.05 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Correcting for molecular weight, a conservative NOAEL of 768.05 mg/kg bw/day can be derived (500 x 200) / 130.2 =768.05 mg/kg bw/day

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Histopathology: The incidences of neoplastic lesions were not significantly increased in treated rats (table).    

	Number of animals with microscopic findings (%)
	All animals				Decedents and  moribunds
Dose (mg/kg bw/d)	0 (vehicle)	50	150	500	150	500
Males, liver
Adenoma	0	0	2	0	0	0
Carcinoma	2	6	6	2	6	5
Females, liver
Carcinoma	2	2	4	0	8	0

Conclusions:

2-Ethylhexanol was not carcinogenic in the Fischer F344 rat. 2-ethylhexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.

Executive summary:

2-Ethylhexanol was not oncogenic in the Fischer F344 rat in a valid GLP carcinogenicity study (Astill et al., 1996).In both sexes the sum of primary tumors, the sum of benign tumors and the sum of malignant tumors was lower in the top dose group than in either the
vehicle control or the water control groups.

A dose related increase in mortality was observed in female rats, with 52% mortality in those given 500mg/kg bw/day 2-EH. Dose related reductions in weight gain were observed. Increased focal lesions and lung discoloration was observed in rats at 500 mg/kg bw/day. The 50 mg/kg bw/day dose produced a 6% increase in relative female stomach weight. Significant increases in stomach, kidney and brain relative weights were observed in male rats at 150 mg/kg bw/day 2-EH with testis relative weight
increase at 500 mg/kg bw/day. Female rats had significantly increased stomach, liver, kidney and brain relative weights at the 150 and 500 mg/kg bw/day doses. 2-ethyl hexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

33.4 mg/m³

Study duration:

chronic

Species:

rat

Quality of whole database:

Inhalation effects:
There are no Inhalation Carcinogenic studies available.
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat 768.05 mg/kg bw/day
÷1.15m3/kgbw
÷20m3/mice
NOAECrat 33.4 mg/m3

Carcinogenicity: via dermal route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: dermal

Type of information:

other: published data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Skin tumour promotion study in mice initiated with 7,12-dimethylbenz(a)anthracene

GLP compliance:

no

Species:

mouse

Strain:

Swiss

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: The Chicago Medical School, Chicago, Illinois
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: in groups of 10 over dried corn-cob shavings in methacrylate cages
- Number of animals: 30-50 female swiss mice/group

Route of administration:

dermal

Vehicle:

other: cyclohexane

Details on exposure:

ADMINISTRATION / EXPOSURE
- Duration of test/exposure: 60 weeks
- Type of exposure: dermal (application to shorn dorsal skin) thrice weekly for 60 weeks.
- Post exposure period: None
- Vehicle: cyclohexane
- Concentration in vehicle: 20%
- Total volume applied: (1 drop approx. 2ul)
- Doses: 4 ug/mouse. Total dose ca 720 mg for each alkanol.

The mice received a single initiating dose of 7,12-dimethylbenz[a]anthracene in acetone followed one week later by the application (described above) of various alkanols ranging in carbon chain length from C6 to C18, for 60 weeks.
Non-initiated groups were included for decanol and dodecanol, these animals received an initial application of acetone alone prior to exposure to the alkanols.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

60 weeks

Frequency of treatment:

three times weekly

Post exposure period:

none

Remarks:

Doses / Concentrations:
4 mg/mouse in cyclohexane
Basis:
other: nominal - single drop of solution applied to the skin using a dropper

No. of animals per sex per dose:

50 intitiated females

Control animals:

other: non-initiated animals treated with other alkanols

Details on study design:

The mice received a single initiating dose of 7,12-dimethylbenz[a]anthracene in acetone followed one week later by the application of octadecanol over the area of initiated skin

Positive control:

no positive control

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION (if dermal study): Yes

BODY WEIGHT: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Animals were probably examined weekly for skin tumours

Sacrifice and pathology:

GROSS PATHOLOGY: No data

HISTOPATHOLOGY: Presumably yes

Other examinations:

Skin tumour development was reported and the degree of skin irritation at the application site was assessed.

Statistics:

none

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY: 36/50 animals survived until the end of the treatment period. Clinical signs were not reported

GROSS PATHOLOGY: no animals developed skin tumours; no tumours were seen in uninitiated animals treated with other alkanols

OTHER FINDINGS: Hexan-1-ol caused severe irritation at the application site

Relevance of carcinogenic effects / potential:

In this study, published in 1966, the tumour promoting activity of a range of alcohols, including C8-C18 alkanols was investigated in mice. Although no skin tumour promoting effect was observed, some tumour promoting activity was observed in the other alcohols; the maximum effect being observed at C10 (decanol). It was also noted that skin irritation was present at the application site in all of these skin painting experiments; the most severe irritation being observed with the C10 and C12 alcohols. Unfortunately this is a significant confounder in skin painting studies and its role in tumour development of non Genotoxic chemicals has been well established. (Nessell et al 1998, 1999)

Dose descriptor:

NOAEL

Effect level:

ca. 4 other: mg/mouse per application

Sex:

female

Basis for effect level:

other: histopathology: no skin tumours

Remarks on result:

other:

Remarks:

Effect type: other: skin tumour promotion (migrated information)

Dose descriptor:

NOAEL

Effect level:

133 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: histopathology: no skin tumours (NOAEL = 133 mg/kg bw per application, assuming a body weight of 30 g)

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

No skin tumours appeared in the non-initiated groups tested.

The incidence of tumour-bearing mice in the initiated groups is as follows:

 

                 hexanol = 0/50

                 octanol = 1/40 (appeared at week 24 and developed into asquamous cell carcinoma)

                 decanol = 6/30 (appeared between weeks 25-36; 2 developed intoa squamous cell carcinomas)

                 dodecanol = 2/30 (appeared at week 39 and 49)

                 tetradecanol = 2/50 (appeared at week 24 and 26; 1 developed

                 into a squamous cell carcinoma)

                 hexadecanol = 1/40 (appeared at week 53)

                 octadecanol = 1/40 (appeared at week 30)

 

The authors conclude that decanol is a tumour promoting agent and that weak activity is probable with octanol, dodecanol, tetra, hexa and octa decanol. Hexanol was inactive. The  authors also note that skin irritation was observed with all the alkanols and was severe with decanol and dodecanol.

Conclusions:

In this comparative study, published in 1966, the authors investigated the tumour promoting activity of C6-C18 alkanols.No skin tumours appeared in the non-initiated groups tested.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

133 mg/kg bw/day

Study duration:

chronic

Species:

rat

Justification for classification or non-classification

Based on the hazard assessment of Alcohols, C12-14 in section 2.1 and 2.2. in IUCLID 6., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health”, according to the EU’s list of dangerous substances (OJEC No L200/130.7.99) and according to the criteria described in Directive 67/548 and in the CLP Regulation:

 

 

Directive 67/548	Carcinogenicity Carc. Cat. 1; R45 May cause cancer. Carc. Cat. 1; R49 May cause cancer by inhalation. Carc. Cat. 2; R45 May cause cancer. Carc. Cat. 2; R49 May cause cancer by inhalation. Carc. Cat. 3; R40 Limited evidence of a carcinogenic effect.
CLP	Carcinogenicity Carc. 1A Carc. 1B Carc. 2 H350: May cause cancer <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>. H351: Suspected of causing cancer <state route of exposure if it is conclusively proven that no other routs of exposure cause the hazard>.

 

It is concluded that the Alcohols, C12-14 does not meet the criteria to be classified for human health hazards for Carcinogenicity.

 

 

Additional information

Carcinogenicity

Studies in animals.

Data availability.There are no data available for the category of the long chained alcohols reporting in detail about carcinogenicity studies according to current testing standards. Several of the linear alcohols have been tested in experimental investigations studying the potential for initiation, promotion or co-carcinogenicity, however as a rule these data have a low reliability and suffer from significant shortcomings regarding the reporting details, the number of animals, the use of non-standardised or unvalidated protocols, and lack of control of confounders (e.g. local irritation). As a whole the information available on carcinogenicity is regarded to have limited reliability.

Hexanol-1, 1-octanol, 1-decanol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol and 1-octadecanol were tested in one or more mouse skin painting studies using applications 2 - 3 times weekly for periods up to 60 -70 weeks. Development of local skin tumours was not reported in any of these assays. All of these experiments were conducted as part of investigative studies into co-carcinogenicity or tumour promotion properties of aliphatic alcohols (Sicé, 1966; Bingham, 1969; Van Duuren, 1976). 

The aliphatic alcohols were applied repeatedly over periods up to 60 weeks to the skin of mice that had been initiated or were co-exposed with carcinogens such as 7, 12-dimethylbenz[a]-anthracene or benzo[a]pyrene (B[a]P). In most of the experimental protocols the application of aliphatic alcohols induced significant dermal irritation at the site of treatment and led to formation of local tumours; in some cases a decrease in latency of tumour development or co-carcinogenicity was reported (Sicé, 1966; Van Duurenet al., 1976; Bingham, 1969).

In other assays 1-octanol, 1-dodecanol or 1-octadecanol were repeatedly injected into the peritoneal cavity or implanted in the bladder of mice. No induction of primary lung tumours was recorded, however a low incidence of benign bladder tumours was reported (Stoner, 1973; Bryanet al, 1966). Ando (1972) published a study in which small groups of mice (n = 4-6), implanted intra-peritoneally with Ehrlich ascites tumour cells, were exposed i.p. to different doses of 1-decanol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol and 1-octadecanol once daily for 5 consecutive days. Although a prolongation of survival time was observed, no conclusions can be drawn regarding the carcinogenic potential of these alcohols.

Conclusion.Several members of the category of the long chained alcohols have been tested as control substances in skin painting studies. Even taking into account the limitations of these experiments, the data show that none of aliphatic alcohols tested have a potential to induce local skin tumours upon repeated dermal application at or above the maximum tolerated (irritant) dose. However, these data are unsuitable to assess properties such as co-carcinogenicity or tumour promotion for this category of alcohols. Most of the study protocols considered here have almost certainly induced considerable local effects, however details of the irritation responses are limited and were reported only in a few cases. Irrespective of the causative agent, irritation at the site of application is a significant confounder in skin painting studies and its role in the tumour development of non-genotoxic chemicals has been well established (for examples see Nesselet al., 1998, 1999; Argyris, 1985).

The genotoxic potential of the long chain alcohols has been well investigated, bothin vitroandin vivoand no concerns were identified for genotoxicity. Furthermore they lack structural elements of concern for interaction with DNA (Ashby and Tenant, 1991). Together with the lack of response upon repeated application the skin painting studies long chained alcohols are regarded to be of little concern regarding carcinogenicty.

There are conclusive but not suffcient data for the classification of substance Alcohols, C12-14 with regard to carcinogenicity.

Carcinogenicity: IARC, NTP, ACGIH and OSHA do not classify this substance or its components as a carcinogen or suspect carcinogen.

 

 

Carcinogenicity: via oral route (target organ): other: all gross lesions and masses

Carcinogenicity: via inhalation route (target organ): respiratory: lung; other: all gross lesions and masses

Carcinogenicity: via dermal route (target organ): other: skin