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Administrative data

Description of key information

A reliable 13-week dietary study in rats using hexan-1-ol reported a NOAEL of 1127 mg/kg (Scientific Associates Inc., 1966a). No adverse effects were noted at any of the dose levels administered during the study. The results of this key study are supported by the reliable 3-week feeding study in rats which reported a NOAEL of approximately 1000 mg/kg bw/day (Moody and Reddy, 1978, 1982). In addition, a 13-week study in dogs reported a NOAEL for 370 mg/kg bw/day for male dogs and 435 mg/kg bw/day for female dogs (Scientific Associates, 1966b). Although this study had some methodology discrepancies, it is still considered to be reliable and can be used as supporting data. A reliability 4 six-month inhalation study to vapours of 118 mg/m3 (28.3 ppm) hexyl alcohol  in rabbits revealed ultrastructural  changes in the photoreceptor cells and Muller fibres. Based on the information provided, this study is considered to be of limited value. In addition, in a 90-day repeated dose dermal study (Wil Research, 1995) in rats, a multi-constituent solution containing circa 50% decan-1-ol and 45% octan-1-ol (semi-occluded conditions) reported no systemic effects at the highest dose tested. The study did however gave rise to marked dermal irritative effect. It is however important to take into account the different test protocol that was used, that is a 90-day repeated dose dermal study (6 hours/day for 5 days/week) compared to a standard 4-hour dermal irritation study and the different species (rats instead of rabbit) and test duration (90 days vs. 4 hours).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rats treated via the diet for 90 days with limited evaluation
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: no data but "young"
- Weight at study initiation: males 103.6 g, females 90.5 g
- Fasting period before study: no data
- Housing: individually in suspended wire-mesh cages
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data but "controlled within narrow limits"
- Humidity (%): no data but "controlled within narrow limits"
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): basal laboratory diet (Purina Laboratory Chow)
- Storage temperature of food: no data
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
continuous in diet
Dose / conc.:
0.25 other: %
Remarks:
nominal in diet
Dose / conc.:
0.5 other: %
Remarks:
nominal in diet
Dose / conc.:
1 other: %
Remarks:
nominal in diet
Dose / conc.:
2 other: %
Remarks:
nominal in diet
Dose / conc.:
4 other: %
Remarks:
nominal in diet
Dose / conc.:
6 other: %
Remarks:
nominal in diet
No. of animals per sex per dose:
10 (treated), 20 (controls)
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: no satellite groups
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 5 days/week
- Cage side observations included: general physical appearance, gross signs of systemic toxicity and/or pharmacological effect, behaviour, mortality

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as mg/kg bw/day: Yes

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: days 30 and 90
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5/sex per group
- Parameters examined: microhaematocrit, haemoglobin, total and differential leukocyte count

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: days 30 and 90
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- How many animals: 5/sex per group (samples pooled)
- Parameters examined: albumin, acetone, bilirubin, colour, occult blood, sugar, pH, appearance, microscopic examination of sediment

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: brain, thyroid, heart, liver, spleen, kidneys, adrenals, gonads (testes or ovaries)

HISTOPATHOLOGY: Yes
- brain, thyroid, parathyroid, heart, lung, liver, spleen, stomach, small intestine, large intestine, pancreas, kidney, urinary bladder, adrenal, gonad, lymph node, bone, bone marrow
- all listed tissues from 5/sex from high dose and controls examined
Other examinations:
none
Statistics:
Chi-squared test for comparing relative organ weights (but see 'Any other information on materials and methods')
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- one male in low dose group died during week 9; cause of death was said to be unrelated to treatment
- occasional bloody encrustations of the eyes and nose
- otherwise no effects

BODY WEIGHT
- no effects

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- food consumption 87.8% of controls in females in high dose group during week 13
- otherwise no effects

FOOD EFFICIENCY
- not examined

WATER CONSUMPTION
- not examined

OPHTHALMOSCOPIC EXAMINATION
- not examined

HAEMATOLOGY
- no effects other than "occasional aberrant value"

CLINICAL CHEMISTRY
- not examined

URINALYSIS
- high albumin, positive findings for occult blood; but no differences between treated and control groups

NEUROBEHAVIOUR
- not examined

ORGAN WEIGHTS
- some statistically significant effects (but see 'Remarks on results')

GROSS PATHOLOGY
- no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
- no effects

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- no effects

HISTORICAL CONTROL DATA (if applicable)
- no data
Key result
Dose descriptor:
NOAEL
Effect level:
1 127 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 243 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX (means calculated from individual weekly dietary intake data)
0.25% M 182 mg/kg/day; F 216 mg/kg/day
0.5% M 374 mg/kg/day; F 427 mg/kg/day
1% M 1127 mg/kg/day; F 1243 mg/kg/day

Organ weights: The original report indicates that there were significant differences in some relative organ weights from treated groups compared 

to controls. 


Conclusions:
In a reliable study, the NOAEL for Alfol 6 in rats following 13 weeks dietary exposure was 1127 mg/kg bw/day for males and 1243 mg/kg bw/day for females (highest doses tested).
Executive summary:

Rats exposed to hexan-1-ol via the diet for 13 weeks showed no signs of significant toxicity when administered at nominal concentrations up to 1% (with staged increases at concentrations up to 6% during the last phase of the exposure period). There were no microscopic alterations recorded in the animals receiving concentrations of 6% (equivalent to 1127 mg/kg/day). Examination of testes and the ovaries did not show any abnormalities.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 127 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 March to 15 June 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
no
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Inc., USA
- Age at study initiation: males approximately 43 days and females approximately 64 days
- Weight at study initiation: 225 - 299g males; 214 - 246g females
- Fasting period before study: no
- Housing: individually in wire mesh cages
- Diet (ad libitum): Purina Certified Rodent Chow #5002
- Water (ad libitum): municpal water supplied to Test Facility
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71.3 - 75.2
- Humidity (%): 41.6 - 77.7
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 15 March 1994 To: 15 June 1994
Type of coverage:
semiocclusive
Vehicle:
other: 0.9% Sodium chloride (this was dosed to the control group at a dose volume of 1.2 ml/kg.
Details on exposure:
TEST SITE
- Area of exposure: dorsal skin

- Type of wrap: gauze binder, secured with tape

REMOVAL OF TEST SUBSTANCE
- Washing: test article was removed from the application site with a wet paper towel

- Time after start of exposure: six hours

TEST MATERIAL - Control group
- Amount(s) applied: 1.2 ml/kg (Control and high dose), 0.12 ml/kg (low dose), 0.36 ml/kg (intermediate dose)

- Concentration (if solution): 0.9% saline

- Constant volume or concentration used: yes

TEST MATERIAL - Test groups(2-4)
- Amount applied: 100, 300 and 1000 mg/kg/day respectively
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
The application sites were wrapped for six hours with a gauze binder, secured with tape.

The range of areas exposed averaged approximately 8, 2, 4 or 9% of total body surface area for the Control, 100, 300 or 1000 mg/kg/day groups respectively.
Frequency of treatment:
Application for five days a week over thirteen consecutive weeks to the shaved intact dorsal skin of each rat for a minimum of 65 applications.
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
Control group: 20 rats (10 male and 10 female) which received 0.9% saline on a comparable regimen at a dose volume of 1.2 ml/kg.

Three test groups: 20 rats (10 males and 10 females) administered dosage levels of 100, 300 and 1000 mg/kg/day respectively.
Control animals:
yes
Details on study design:
- Dose selection rationale: not stated
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly

DERMAL IRRITATION: Yes
- Time schedule for examinations: once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to start of dosing and Week 12
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 13 at scheduled necropsy
- Anaesthetic used for blood collection: not stated
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table No.1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 13 at scheduled necropsy
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table No.2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
ORGAN WEIGHTS: Yes (see table 3)
GROSS PATHOLOGY: Yes (see table 4)
HISTOPATHOLOGY: Yes (see table 4)
Other examinations:
Selected organs were weighed and a microscopic examination was conducted on selected tissues from all animals at the scheduled necropsy.
Statistics:
All analyses were conducted using two-tailed tests for significance levels of 5% and 1% comapring the treated groups to the vehicle control group by sex. Body weight, body weight change, food consumption, clinical laboratory and absolute and relative organ weight data were subjected to a one-way analysis of variance follwoed by Dunnett's Test. Clinical laboratory values for cell types that occur at low incidence (i.e. monocytes, eosinophils, basophils and unsegmented neutrophils) were not subjected to statistical analysis.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Vocalisation, struggling during exposure and hypersensitivity to touch.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.
Mortality:
mortality observed, treatment-related
Description (incidence):
Vocalisation, struggling during exposure and hypersensitivity to touch.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean body weights were lower in the middle and high dose groups compared to the control group.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mean food consumption (evaluated as g/animal/day) was slightly but consistently decreased in the high dose group (males) during the first two thirds of the study period but was comparable with Controls thereafter.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No test related ophthalmic lesions were present at the week 12 opthalmologic examinations.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Mean white blood cell counts were increased in a non dose related manner in all the test groups (not the control). This was attributed to the acute dermal inflammation that was observed.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In the serum chemistry parameters albumin means were decreased and globulin means were increased (resulting in decreased A/G ratios). Again this was attributed to the acute dermal inflammation that was observed.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The adrenals, brain, kidneys, liver, ovaries and testes were weighed at necropsy. No remarkable statistically significant changes in organ weight were note for any of the organs, except increaed absolute and relative adrenal weights.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Scabbing and thickening of the skin was noted in all dose groups.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Squamous cell hyperplasia, hyperkeratosis and suppurative inflammation were noted at teh application site in all treated groups.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No effect of treatment.
Details on results:
CLINICAL SIGNS AND MORTALITY
Vocalisation (due to pain) was the predominant sign observed in the high dose group (females) generally on one to three days most often during the second week of test article administration. Excessive struggling was also reported during exposure on single occasions for one male in the low dose group and two female in the high dose group. Hypersensitivity to touch was also reported on two separate occasions for a single high dose male.
                                                                                                          
Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

BODY WEIGHT AND WEIGHT GAIN
Group mean body weights were lower than Control during the study for males at 300 mg/kg/day and both sexes at 1000 mg/kg/day by up to 19% at the end of the treatment period. A simialr, but less marked effect on body weight was recorded for both sexes at 100 mg/kg/day and 300 mg/kg/day females with group mean body weight up to 6% lower than Control at the end of the treatment period.

FOOD CONSUMPTION
Group mean food consumption was slightly lower than Control for males at 1000 mg/kg/day up to Week 9 of the treatment period. Slightly lower group mean food consumption was also noted for females at the same dose during the first week of treatment. For both males and females food consumption was comparable to Controls thereafter.

OPHTHALMOSCOPIC EXAMINATION
No effect of treatment.

HAEMATOLOGY
Group mean white blood cell count and neutrophil counts were increased in treated groups compared to Control. The magnitude of the increases was not dose-related. The effect on white cell counts was considered to be attributable to the acute dermal inflammatory response.

CLINICAL CHEMISTRY
Group mean albumin was increased and group mean globulin and A/G ratio were decreased in a non dose-related manner in all treatment groups. These changes were considered to be indicative of the acute dermal inflammatory response.

A dose-related decrease in group mean glucose levels was noted in all treated groups. Group mean calcium was decreased in 1000 mg/kg/day males and females. Increases in group mean urea nitrogen, alkaline phosphatase, aspartate aminotransferse and/or alanine aminotransferase were also noted at 1000 mg/kg/day.

ORGAN WEIGHTS
Group mean absolute and relative adrenal weights were increased in all treated groups.

GROSS PATHOLOGY
The only test article related gross lesions observed included scabbing and thickening of the skin at the test site. (Irritant related effects). There were no other test article related gross findings at the scheduled necropsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
Squamous cell hyperplasia, hyperkeratosis and suppurative inflammation in the skin of the application site was noted in males and females of all treated groups.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL for systemic effects
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL for local effects, based on severe dermal irritation recorded at all doses.
Critical effects observed:
not specified
Conclusions:
Based on the data that was reported the No-Observed-Effect-Level (NOEL) following dermal administration of fatty alcohol blend for a minimum of 90 days was stated to be less than 100 mg/kg/day. This is based primarily on the local irritation (and related) effects.

The local irritation effects are considered adverse and therefore the local, dermal Lowest-Observed-Adverse-Effect-Level (LOAEL) is 100 mg/kg/day (2.8 mg/cm3 based on test substance applied to 2% body surface area at this dose). It should be noted that the test substance was repeatedly applied to already damaged skin, which may have exacerbated the effects noted. Furthermore the dermal effects noted were variable in terms of the relationship of severity with duration of administration. The clinical signs and effects on body weight and food consumption are considered to be a consequence of the local irritant effect and the effects on white blood cell counts and albumin and globulin levels attributable to the acute dermal inflammatory response. The increased adrenal weights (with no associated pathological changes) were attributed to a stress response, also as a result of the dermal irritation. Therefore these effects are secondary to the local irritant effect of fatty alcohol blend.

There were also changes to some clinical chemistry parameters noted (decreased glucose and calcium, increased urea nitrogen, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase). The magnitude of change was generally not marked and/or was without pathological correlate in all cases and so they were considered not be adverse. Therefore, as there were no systemic effects noted that could not be attributed to the local irritant response, or were considered to be adverse, the systemic No-Observed-Adverse-Effect-Level following dermal administration of fatty alcohol blend for a minimum of 90 days was considered to be 1000 mg/kg/day (the highest dose tested).

Executive summary:

Intermediate (>C8 to C12) and higher (>C12) linear LCAAs are non-irritant at the site of first contact and are without a neurotoxic potential.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 March to 15 June 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
no
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Inc., USA
- Age at study initiation: males approximately 43 days and females approximately 64 days
- Weight at study initiation: 225 - 299g males; 214 - 246g females
- Fasting period before study: no
- Housing: individually in wire mesh cages
- Diet (ad libitum): Purina Certified Rodent Chow #5002
- Water (ad libitum): municpal water supplied to Test Facility
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71.3 - 75.2
- Humidity (%): 41.6 - 77.7
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 15 March 1994 To: 15 June 1994
Type of coverage:
semiocclusive
Vehicle:
other: 0.9% Sodium chloride (this was dosed to the control group at a dose volume of 1.2 ml/kg.
Details on exposure:
TEST SITE
- Area of exposure: dorsal skin

- Type of wrap: gauze binder, secured with tape

REMOVAL OF TEST SUBSTANCE
- Washing: test article was removed from the application site with a wet paper towel

- Time after start of exposure: six hours

TEST MATERIAL - Control group
- Amount(s) applied: 1.2 ml/kg (Control and high dose), 0.12 ml/kg (low dose), 0.36 ml/kg (intermediate dose)

- Concentration (if solution): 0.9% saline

- Constant volume or concentration used: yes

TEST MATERIAL - Test groups(2-4)
- Amount applied: 100, 300 and 1000 mg/kg/day respectively
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
The application sites were wrapped for six hours with a gauze binder, secured with tape.

The range of areas exposed averaged approximately 8, 2, 4 or 9% of total body surface area for the Control, 100, 300 or 1000 mg/kg/day groups respectively.
Frequency of treatment:
Application for five days a week over thirteen consecutive weeks to the shaved intact dorsal skin of each rat for a minimum of 65 applications.
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
Control group: 20 rats (10 male and 10 female) which received 0.9% saline on a comparable regimen at a dose volume of 1.2 ml/kg.

Three test groups: 20 rats (10 males and 10 females) administered dosage levels of 100, 300 and 1000 mg/kg/day respectively.
Control animals:
yes
Details on study design:
- Dose selection rationale: not stated
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly

DERMAL IRRITATION: Yes
- Time schedule for examinations: once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to start of dosing and Week 12
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 13 at scheduled necropsy
- Anaesthetic used for blood collection: not stated
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table No.1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 13 at scheduled necropsy
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table No.2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
ORGAN WEIGHTS: Yes (see table 3)
GROSS PATHOLOGY: Yes (see table 4)
HISTOPATHOLOGY: Yes (see table 4)
Other examinations:
Selected organs were weighed and a microscopic examination was conducted on selected tissues from all animals at the scheduled necropsy.
Statistics:
All analyses were conducted using two-tailed tests for significance levels of 5% and 1% comapring the treated groups to the vehicle control group by sex. Body weight, body weight change, food consumption, clinical laboratory and absolute and relative organ weight data were subjected to a one-way analysis of variance follwoed by Dunnett's Test. Clinical laboratory values for cell types that occur at low incidence (i.e. monocytes, eosinophils, basophils and unsegmented neutrophils) were not subjected to statistical analysis.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Vocalisation, struggling during exposure and hypersensitivity to touch.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.
Mortality:
mortality observed, treatment-related
Description (incidence):
Vocalisation, struggling during exposure and hypersensitivity to touch.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean body weights were lower in the middle and high dose groups compared to the control group.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mean food consumption (evaluated as g/animal/day) was slightly but consistently decreased in the high dose group (males) during the first two thirds of the study period but was comparable with Controls thereafter.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No test related ophthalmic lesions were present at the week 12 opthalmologic examinations.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Mean white blood cell counts were increased in a non dose related manner in all the test groups (not the control). This was attributed to the acute dermal inflammation that was observed.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In the serum chemistry parameters albumin means were decreased and globulin means were increased (resulting in decreased A/G ratios). Again this was attributed to the acute dermal inflammation that was observed.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The adrenals, brain, kidneys, liver, ovaries and testes were weighed at necropsy. No remarkable statistically significant changes in organ weight were note for any of the organs, except increaed absolute and relative adrenal weights.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Scabbing and thickening of the skin was noted in all dose groups.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Squamous cell hyperplasia, hyperkeratosis and suppurative inflammation were noted at teh application site in all treated groups.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No effect of treatment.
Details on results:
CLINICAL SIGNS AND MORTALITY
Vocalisation (due to pain) was the predominant sign observed in the high dose group (females) generally on one to three days most often during the second week of test article administration. Excessive struggling was also reported during exposure on single occasions for one male in the low dose group and two female in the high dose group. Hypersensitivity to touch was also reported on two separate occasions for a single high dose male.
                                                                                                          
Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

BODY WEIGHT AND WEIGHT GAIN
Group mean body weights were lower than Control during the study for males at 300 mg/kg/day and both sexes at 1000 mg/kg/day by up to 19% at the end of the treatment period. A simialr, but less marked effect on body weight was recorded for both sexes at 100 mg/kg/day and 300 mg/kg/day females with group mean body weight up to 6% lower than Control at the end of the treatment period.

FOOD CONSUMPTION
Group mean food consumption was slightly lower than Control for males at 1000 mg/kg/day up to Week 9 of the treatment period. Slightly lower group mean food consumption was also noted for females at the same dose during the first week of treatment. For both males and females food consumption was comparable to Controls thereafter.

OPHTHALMOSCOPIC EXAMINATION
No effect of treatment.

HAEMATOLOGY
Group mean white blood cell count and neutrophil counts were increased in treated groups compared to Control. The magnitude of the increases was not dose-related. The effect on white cell counts was considered to be attributable to the acute dermal inflammatory response.

CLINICAL CHEMISTRY
Group mean albumin was increased and group mean globulin and A/G ratio were decreased in a non dose-related manner in all treatment groups. These changes were considered to be indicative of the acute dermal inflammatory response.

A dose-related decrease in group mean glucose levels was noted in all treated groups. Group mean calcium was decreased in 1000 mg/kg/day males and females. Increases in group mean urea nitrogen, alkaline phosphatase, aspartate aminotransferse and/or alanine aminotransferase were also noted at 1000 mg/kg/day.

ORGAN WEIGHTS
Group mean absolute and relative adrenal weights were increased in all treated groups.

GROSS PATHOLOGY
The only test article related gross lesions observed included scabbing and thickening of the skin at the test site. (Irritant related effects). There were no other test article related gross findings at the scheduled necropsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
Squamous cell hyperplasia, hyperkeratosis and suppurative inflammation in the skin of the application site was noted in males and females of all treated groups.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL for systemic effects
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL for local effects, based on severe dermal irritation recorded at all doses.
Critical effects observed:
not specified
Conclusions:
Based on the data that was reported the No-Observed-Effect-Level (NOEL) following dermal administration of fatty alcohol blend for a minimum of 90 days was stated to be less than 100 mg/kg/day. This is based primarily on the local irritation (and related) effects.

The local irritation effects are considered adverse and therefore the local, dermal Lowest-Observed-Adverse-Effect-Level (LOAEL) is 100 mg/kg/day (2.8 mg/cm3 based on test substance applied to 2% body surface area at this dose). It should be noted that the test substance was repeatedly applied to already damaged skin, which may have exacerbated the effects noted. Furthermore the dermal effects noted were variable in terms of the relationship of severity with duration of administration. The clinical signs and effects on body weight and food consumption are considered to be a consequence of the local irritant effect and the effects on white blood cell counts and albumin and globulin levels attributable to the acute dermal inflammatory response. The increased adrenal weights (with no associated pathological changes) were attributed to a stress response, also as a result of the dermal irritation. Therefore these effects are secondary to the local irritant effect of fatty alcohol blend.

There were also changes to some clinical chemistry parameters noted (decreased glucose and calcium, increased urea nitrogen, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase). The magnitude of change was generally not marked and/or was without pathological correlate in all cases and so they were considered not be adverse. Therefore, as there were no systemic effects noted that could not be attributed to the local irritant response, or were considered to be adverse, the systemic No-Observed-Adverse-Effect-Level following dermal administration of fatty alcohol blend for a minimum of 90 days was considered to be 1000 mg/kg/day (the highest dose tested).

Executive summary:

Intermediate (>C8 to C12) and higher (>C12) linear LCAAs are non-irritant at the site of first contact and are without a neurotoxic potential.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
2.8 mg/cm²
Study duration:
subchronic
Species:
rat

Additional information

The findings of the key 13-week oral study (Scientific Associates Inc., 1966a) were supported by three reliability 2 supporting studies. However one of these had test duration of only three weeks and the other had some discrepancies in the methodology including toxicity at the highest dose. Therefore the 13-week study in the rats was selected as the key study. For inhalation exposure, there was only one reliability 4 study which studied the effect of 118 mg/m3 (28.3 ppm) hexyl alcohol vapours on the rabbit eye. However based on the information provided this study was considered to be of limited value.

The key 90-day dermal study (WIL Research, 1995), is the only repeated dose dermal study available. The data are read across from Fatty Alcohol Blend, which contains approximately 50% decan-1-ol and 45% octan-1-ol.

In the key 13-week study for repeated dose oral toxicity, rats were exposed to hexan-1-ol via the diet for 13 weeks showed no signs of significant toxicity when administered at nominal concentrations up to 1% (with staged increases at concentrations up to 6% during the last phase of the exposure period). There were no microscopic alterations recorded in the animals receiving concentrations of 6% (equivalent to 1127 mg/kg bw/day). Examination of testes and the ovaries did not show any abnormalities (Scientific Associates, 1966a).

Exposure of male rats to high dietary concentrations (up to 8%) of hexan-1-ol for 2 weeks did not produce evidence of peroxisome proliferation (Moody and Reddy, 1978, 1982).

Daily administration of capsules containing 1000 mg/kg bw/day hexan-1-ol to male and female dogs resulted in post-dose salivation, transient but marked CNS effects (ataxia, tremors and narcosis) and mortality. One animal died after the first dose (not examined microscopically); 3 of 5 animals after 3-5 weeks. In all decedents death was attributed to aspiration while the animals were under substance-induced narcosis . Macroscopic and microscopic examination of the decedents showed severe inflammation of the upper gastro-intestinal tract and testicular atrophy and decreased oogenesis. The single surviving female showed signs of gastro-intestinal irritation; however there were no adverse effects on the ovaries.

Other groups of 2 dogs/sex received hexan-1-ol incorporated in the daily ration at nominal concentrations of 0 (control), 0.5 or 1.0 %. Apart from local irritation of the gastro-intestinal tract in the 1.0% dose group, no adverse systemic effects were observed in these animals.

The testicular effects observed in the early decedents were attributed to the general ill health of these animals caused by the severe gastro-intestinal irritation. This likelihood is supported by the lack of gonadal effects in dogs exposed to 1% and 0.5% hexan-1-ol in the dietary portion of the study that showed greatly diminished or absence of the gastro-intestinal irritation, respectively. No other significant effects were noted at the 0.5% dietary level. The threshold for local irritative effects was 190 mg/kg bw/day (0.5%). The NOAEL for systemic effects was established at 1.0%, equivalent to 370 mg/kg bw/day (the highest dose tested in this portion of the study) (Scientific Associates, 1966b).

The key study for repeated dose dermal toxicity is a 90-day repeated dose dermal study (WIL Research, 1995) in rats where a multi-constituent solution containing circa 50% decan-1-ol and circa 45% octan-1-ol (semi-occluded conditions) there were no systemic effects at the highest dose tested. The study did however gave rise to marked dermal irritative effect. However, the test substance was repeatedly applied to already damaged skin, which may have exacerbated the effects noted. Furthermore the dermal effects noted were variable in terms of the relationship of severity with duration of administration. The clinical signs and reductions in body weight and food consumption noted are considered to be a consequence of the local irritant effect and the effects on white blood cell counts and albumin and globulin levels attributable to the acute dermal inflammatory response. The increased adrenal weights (with no associated pathological changes) were attributed to a stress response also as a result of the dermal irritation. Therefore these effects are secondary to the local irritant effect of fatty alcohol blend.

There were also changes to some clinical chemistry parameters noted (decreased glucose and calcium, increased urea nitrogen, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase). The magnitude of change was generally not marked and/or was without pathological correlate in all cases and so they were considered not be adverse. Therefore, as there were no systemic effects noted that could not be attributed to the local irritant response, or were considered to be adverse, the systemic No-Observed-Adverse-Effect-Level following dermal administration of fatty alcohol blend for a minimum of 90 days was considered to be 1000 mg/kg bw/day (the highest dose tested) and the LOAEL for local effects was 100 mg/kg bw/day (2.8 mg/cm²) (the lowest dose tested).

The available repeated dose toxicity data for long chain alcohols have been reviewed and discussed, with the conclusion that the long chain alcohols are of low systemic toxicity (Veenstra G, Webb C et al., 2009).

A full discussion of the Category and considerations of RAAF Assessment Entities can be found in the Human Health Alcohols C6-24 Category report (PFA, 2016).

Discussion of trends in the Category of C6-24 linear and essentially-linear aliphatic alcohols:

In summary, the sub-category of the linear LCAAs is of a low order of toxicity upon repeated exposure. The LCAAs at lower end of this group caused local irritation at the site of first contact and induced signs ofdepression and respiratory effects when administered at very high dose levels and only as a bolus dose (C6, C8 alcohol) in the dog (C6 alcohol) and the rat (C8 alcohol). Other routes of exposure induced no apparent neurotoxicity either centrally or peripherally. Intermediate (>C8 to C12) and higher (>C12) linear LCAAs are non-irritant at the site of first contact and are without a neurotoxic potential. At high dose levels some of the higher LCAAs showed changes in clinical chemistry and liver weight but without further evidence of systemic toxicity; this finding may be indicative of mild, sub-clinical effects in the liver. There are no species differences observed for this sub-category, based on a comparison of the results of parallel studies in the rat and the dog.

In summary, the data for the essentially linear LCAAs, including the data from supporting substances, indicate a low order of toxicity upon repeated exposure. A consistent finding for this group is the effect on the liver: mild organ weight increases and/or slight clinical chemical changes but without evidence of significant histopathological effects. The clinical chemistry changes were generally of a slight grade but showed some inconsistencies, some of which relating to decreases in transferase activity, a change not normally associated with adverse hepatic effects. The (small) degree of the liver weight increases, the pattern of the clinical chemical changes and the absence of markers support the conclusion that this sub-category of LCAAs lacks a potential for the induction of peroxisomal proliferation. There is evidence of irritation at the first site of contact for the lower members of this group.

Conclusion:

The repeat dose toxicity of the category of LCAAs with chain lengths ranging from C6 to C22 indicates a low order of toxicity upon repeated exposure. Typical NOAEL’s recorded for this category range between approx. 200 mg/kg/day to 1000 mg/kg/day in the rat upon sub-chronic administration via the diet. No adverse systemic effects have been seen in reliable studies with members of the Category of C6-24 Alcohols, therefore the NOAELs represent the highest dose tested. At the lower end, members of this category induce local irritation at the site of first contact. Other notable findings observed for several members within this group suggest mild changes consistent with low-grade liver effects with the changes in essentially linear LCAAs being slightly more pronounced than in linear alcohols. Typical findings include: slightly increased liver weight, in some cases accompanied by clinical chemical changes but generally without concurrent histopathological effects. Special studies demonstrated that this category does not have a potential for peroxisome proliferation. A potential for depression as observed for short chain aliphatic alcohols (C1 to C4; not included in this category) was also identified for 1-hexanol and 1-octanol, however this effect was only expressed upon repeated administration of a bolus dose;effects were absent upon inhalation or dietary administration. Similarly, 1-hexanol and 1-octanol induced respiratory distress upon repeated administration of a bolus dose. LCAAs do not have a potential for peripheral neuropathy. Furthermore, the data from the substances supporting this category (i.e. isoamyl alcohol), demonstrate that the toxicological profile of the repeated dose toxicity of 100% branched alcohols is qualitatively similar to that of the corresponding essentially linear alcohols.

Chronic and sub-chronic toxicity studies have shown that LCAAs are of low toxicity. Furthermore, combined repeated-dose studies with developmental endpoints, as well as reproductive and developmental studies showed no effects at the highest dose tested. Where data gaps exist, the gap is filled by read-across from reliable evidence within the C6 -24 Alcohols Category, where possible using interpolation between at least two reliable studies using higher and lower carbon number test substances.

Repeated dose toxicity data for the Category

 

 

CAS

CHEMICAL NAME

Species/ Study type/

Duration 1

Route

NOAEL

 

(Ref)

Rel.

C5

123-51-3

Isoamyl alcohol (supporting)

Rat 17 wk

Gavage

 500 mg/kg
(Carpanini, 1973)

2

C6

111-27-3

Hexan-1-ol

Dog 13 wk

Diet

370 mg/kg
(Sc.Assoc.1966b)

2

 

C6

111-27-3

Hexan-1-ol

Rat 13 wk

Diet

1127 mg/kg (Sc.Assoc.1966)

2

 

C6

111-27-3

Hexan-1-ol

Rat 3 wk

Diet

1000 mg/kg bw/day (Moody and Reddy, 1978-1982)

 

2

C6

111-27-3

Hexan-1-ol

Rat subchronic 30 wk

Intraperitoneal

No peripheral neuropathy (Perbellini et al., 1978)

2

C8

111-87-5

Octan-1-ol

 Rat
 Dev. Tox.

gavage 

130 mg/kg (Hellwig, 1997)

No systemic toxicity expected based on read across of a dermal study on Fatty Alcohol Blend of which octan-1-ol is a constituent, and on read-across from an oral study on hexan-1-ol. No adverse systemic effects were observed at the highest dose in either study.

2

C9

143-08-8

Nonan-1-ol

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

 

C10

112-30-1

Decan-1-ol

 

 

No systemic toxicity expected based on read across of a dermal study on Fatty Alcohol Blend of which decan-1-ol is a constituent, and on read-across from an oral study on hexan-1-ol. No adverse systemic effects were observed at the highest dose in either study.

 

C11

112-42-5

Undecan-1-ol

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

2

C12

112-53-8

Dodecan-1-ol

Rat 5wk

Diet

2000 mg/kg (Hansen,1992a)

2

C13

112-70-9

1-Tridecan-1-ol (supporting)

Rat 2 wk

Gavage

184 mg/kg (Rhodes, 1984)

2

C14

112-72-1

Tetradecan-1-ol

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

2

C15

629-76-5

Pentadecan-1-ol

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

2

C16

36653-82-4

Hexadecan-1-ol

Rat 4 wk

 

 

 

Diet

 

 

>1000 mg/kg (Henkel, 1985a)    

 

2

 

 

C16

36653-82-4

Hexadecan-1-ol

Dog 13 wk

 

Diet

 

>1054 mg/kg (Sc.Assoc, 1966b)

2

C16

36653-82-4

Hexadecan-1-ol

Rat 13 wk

Diet

 

>4257 mg/kg
(Sc.Assoc, 1966a)

2

C18

112-92-5

Octadecan-1-ol

Rat 4 wk

 

Rat 5 wk

Gavage

 

Diet

>1000 mg/kg (Henkel, 1986a)

2000 mg/kg (Hansen, 1992b)

1

 

2

C18

143-28-2

9-Octadecen-1-ol, (9Z)-

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

2

C20

629-96-9

Icosanan-1-ol

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

2

C22

661-19-8

Docosan-1-ol

 Rat 26 wk

Gavage

1000 mg/kg

(Iglesias,2002a)

1

 

C22

661-19-8

Docosan-1-ol

Dog 26 wk

Gavage

2000 mg/kg

(Iglesias,2002b)

1

C24

506-51-4

Tetracosan-1-ol

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

 

C8

60435-70-3

2-methylheptan-1-ol

 

 

 

 

C9

68515-81-1

Nonan-1-ol, branched and linear

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

 

C10

90342-32-8

Decan-1-ol, branched and linear

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

2

C11

128973-77-3

Undecan-1-ol, branched and linear

 

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

 

C13

90583-91-8

Tridecan-1-ol, branched and linear (supporting)

 

 

Low systemic toxicity expected

2

C15

90480-71-0

 

Pentadecan-1-ol, branched and linear

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

2

C7-9

 

Alcohols, C7-9

Rat 1-wk

 

Rat 1 wk

Gavage

 

Gavage

4175 mg/kg
(Brown, 1970)

128 mg/kg(Rhodes, 1984)

2

 

2

C8-10

 

Fatty Alcohol Blend

rat 90 day

dermal

1000 mg/kg bw/day

(WIL, 1995)

2

C9-11

 

Alcohols, C9-11

Rat 2 wk

Gavage

<4150 mg/kg(Brown, 1970)

2

C9-11

 

Alcohols, C9-11- branched and linear

Rat 9-day

Inhalation

<4150 mg/kg(Brown, 1970)

2

C11

 

Reaction mass of 2-methyldecan-1-ol and 2-propyloctan-1-ol and 2-ethylnonan-1-ol and 2-butylheptan-1-ol

 

 

No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.

 

C12-13

75782-86-4

Alcohols, C12-13

 

Rat 4wk

 

 

Gavage

 

300 mg/kg; (Sasol, 1999

 

1

C12-13

740817-83-8

Alcohols, C12-13-branched and linear

 

Rat 4wk (read-across)

 

 

Gavage

 

300 mg/kg; (Sasol, 1999

 

1

C12-13

90604-40-3

Alcohols, C12-13

Rat 2 wk

 

Gavage

 

209 mg/kg(Rhodes, 1984)

2

C14-15

75782-87-5

Alcohols, C14-15

Rat 90 day

Diet

167 mg/kg;
(Ito, 1978)

2

C14-15

 

Alcohols, C14-15-branched and linear

Rat 90 day (read-across)

Diet

167 mg/kg;
(Ito, 1978)

2

References:

Veenstra G, Webb C et al., (2009) Human health risk assessment of long chain alcohols. Ecotoxicology and environmental safety 71 1016-1030.

PFA (2016). C6-24 Alcohols Category Report: Human Health. Version number:01. Peter Fisk Associates Ltd. February 2016.


Justification for classification or non-classification

Based on the NOAEL of 1127 mg/kg bw, no classification is required under Regulation (EC) No 1272/2008.