Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Oral repeated dose toxicity 
The NOAEL for 13 week dietary feeding study in rats is ca 750 mg/kg/day (males 723, females 875) based on reduced weight gain and food consumption. The toxicological significance of observed changes in organ weights, all in the absence of histopathological change, is questionable. Increased liver weights at higher dose levels may be indicative of a mild adaptive effect on the liver.
In view of the structural and chemical similarities, it is considereed that the results of the study can be used for read-across to Alcohols, C12-14.
Dermal repeated dose toxicity
A 90-day dermal toxicity study in rats with fatty alcohol blend (56.7% decanol, 42.7% octanol) at dose levels of 0, 100, 300, or 1,000 mg/kg resulted in severe irritation at the application site. Severe irritation including fissuring of the skin occurred in 40% of the animals at 100 mg/kg/day and 80% of the animals at the limit dose. Slight changes in hematology, clinical chemistry, and organ weights were noted at the limit dose of 1,000 mg/kg/day.
NOAEL has been based on a local irritation effect rather than a systemic effect. Therefore it is proposed (by the author of the EPSR) that on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.
Inhalation repeated dose toxicity
Under the conditions of the test no treatment-related toxic effects were found in male and female Wistar rats which were exposed to 2-ethylhexanol vapor up to 120 ppm ie. 638.4 mg/m³ . (Klimisch HJ; Deckardt K; Gembardt C; Hildebrand B,1998).The substance Alcohols, C12-14, the subject of this dossier) is expected to exhibit very similar toxicity due to its close structural similarity to 2-ethylhexanol.Comparable metabolism would occur. Correcting for molecular weight, a conservative NOAEC of 980.6 mg/m3 can be derived (638.4 x 200) / 130.2 =980.6 mg/m3

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: published data
Adequacy of study:
key study
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:
Rats treated via the diet for 90 days with limited evaluation
GLP compliance:
not specified
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 104.1 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
Remarks:
Doses / Concentrations:
1%, 2.5%, 5-10%
Basis:
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. Original organ weight analyses using the Chi square test were supplemented by Tukey tests carried out by the Weinberg group (see 'Any other information on materials and methods')
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- all animals survived the 13 week treatment period.
- all surviving animals appeared normal

BODY WEIGHT AND WEIGHT GAIN
- significantly reduced (84.7 - 89.8% of controls) in top dose males for most study weeks, in mid dose females at weeks 4-13 and high dose females (81.7-89.7%) throughout the study
- changes were attributed at least in part to reduced food consumption and the high content of test material in the diet.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- significantly reduced (76.4 - 89.2% of controls) in top dose males at weeks 1 and 12, in mid dose males at week 13, in mid dose females at week 1 and high dose females weeks 1 and 12 (79.1 - 89.9% of controls).

FOOD EFFICIENCY
- no data

WATER CONSUMPTION
- not examined

OPHTHALMOSCOPIC EXAMINATION
- not examined

HAEMATOLOGY
- no effects

CLINICAL CHEMISTRY
- not examined

URINALYSIS
- no effects

NEUROBEHAVIOUR
- not examined

ORGAN WEIGHTS
- the original report indicated that there were significant differences in some relative organ weights from treated groups compared to controls. These were reanalysed by the Weinberg Group using the Tukey test (see 'Remarks on results' section)

GROSS PATHOLOGY
- unremarkable

HISTOPATHOLOGY: NON-NEOPLASTIC
- there were no treatment related histopathological changes in the control and top dose animals examined (including testes & ovaries).

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- not applicable

HISTORICAL CONTROL DATA (if applicable)
- no data
Dose descriptor:
NOAEL
Effect level:
> 4 257 mg/kg bw/day (nominal)
Based on:
other: based on highest dose tested.
Sex:
male
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
> 4 567 mg/kg bw/day (nominal)
Based on:
other: based on highest dose tested.
Sex:
female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
723 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: based on the reductions in body weight gain and food consumption
Dose descriptor:
NOAEL
Effect level:
875 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: based on the reductions in body weight gain and food consumption
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The NOAEL for this 13 week dietary feeding study in rats is ca 750 mg/kg/day (males 723, females 875) based on reduced weight gain and food consumption.
Critical effects observed:
not specified

In a 13-week study in rats1-hexadecanol was administered in the diet at concentrations of 0 (control), 1, 2.5 or 5%; the level in the highest dose group being increased stepwise to 10% during the last 3 weeks of the study. Reductions in body weight gain (82-90% of control values) and food consumption (76 – 90% of control values) in the highest dose group and, occasionally, at the 2.5% level were the main findings of this study. Relative liver weights were increased in males at the top dose level (124% of control values) but in the absence of any microscopic findings the significance of this change is uncertain. A NOAEL was established at a dietary concentration of 1% (equivalent toca.750 mg/kg/day) based on the reductions in body weight gain and food consumption

Conclusions:
The NOAEL for this 13 week dietary feeding study in rats is ca 750 mg/kg/day (males 723, females 875) based on reduced weight gain and food consumption. The toxicological significance of observed changes in organ weights, all in the absence of histopathological change, is questionable. Increased liver weights at higher dose levels may be indicative of a mild adaptive effect on the liver.
Hexadecan-1-ol (C16) is supporting substance for Alcohols,C12-C14 and the one of the component in Alcohols,C12-C14
In view of the structural and chemical similarities, it is considereed that the results of this study can be used for read-across to Alcohols, C12-14.

Executive summary:

The NOAEL for this 13 week dietary feeding study in rats is ca 750 mg/kg/day (males 723, females 875) based on reduced weight gain and food consumption. The toxicological significance of observed changes in organ weights, all in the absence of histopathological change, is questionable. Increased liver weights at higher dose levels may be indicative of a mild adaptive effect on the liver.

Hexadecan-1-ol (C16) is supporting substance for Alcohols,C12-C14 and the one of the component in Alcohols,C12-C14 .

In view of the structural and chemical similarities, it is considereed that the results of this study can be used for read-across to Alcohols, C12-14.

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: published data
Adequacy of study:
key study
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:
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
food available ad lib, dietary mixture prepared weekly
Remarks:
Doses / Concentrations:
0.25% & 0.50% for 13 weeks; 1.0% for 10 weeks then 2.0% (week 11), 4.0% (week 12) and 6.0% (week 13).
Basis:
nominal in diet
No. of animals per sex per dose:
10 (treated), 20 (controls)
Control animals:
yes, concurrent no treatment
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
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: see 'Remark'
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: see 'Remark'
Critical effects observed:
not specified

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX

                 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

 

 TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:

 - Mortality and time to death: One male at the lowest dose level (0.25%) died in the 9th week of the study. This was notattributed to treatment.

- Clinical signs: all surviving animals appeared normal.

- Body weight: comparable to controls.

 - Food consumption: with the exception of high dose females at week 13 food consumption was comparable with that of controls.At week 13 female food consumption was 87.8% of controlfemales at this time period. At this stage of the study thetop dose level had been increased incrementally from 1% atweek 10 to 6% in the diet at week 13.

- Clinical chemistry: not carried out.

- Haematology: No treatment related changes.

- Urinalysis: No treatment related changes.

- Organ weights: The original report indicates that there were significant differences in some relative organ weights from treated groups compared to controls. These were reanalysed by the Weinberg Group using the Tukey test which indicated thatonly the increased heart weight in mid dose males remained significant. The significant changes found in the original report together with the results of the Weinberg analysis aresummarised below.

 

                 OrganSex            Orig sig.                     Weinberg report

                 HeartM              mid-dose                   Significant

                 Spleen                M       high dose        Not significant

                      F                    high dose                   Not significant

                      F                    low dose                    Not significant

                 Gonads M           all levels                     Not significant

 

Additionally Weinberg reanalysed the organ weight data for the liver, kidney, adrenal, brain and thyroid none of which showed significant changes in the original statistical analysis.There were no significant changes except in the thyroid weightwhich showed a significant increase in top dose malesaccording to the Weinberg analysis.

 

Statistical results are not reported in detail, while  individual animal data are reported means are not given. Using this data to calculate the mean and SD for the organ weight changes originally reported as significant (see table above)  the magnitude of the changes is a follows:

 

                 Spleen weight mean relative:

                         Control Low    Mid    High

                 Males  0.185       0.175  0.19    0.199*

                 SD     0.044        0.008  0.028  0.047

 

                 Females 0.189      0.223*0.189  0.217*

                 SD        0.018     0.036  0.01    0.02

 

                 Gonad weight mean relative:

                         Control Low    Mid    High

                 Males  0.793       0.809*0.814*0.804*

                 SD      0.062       0.007  0.079  0.075

 

                 Heart weight mean relative:

                         Control Low    Mid           High

                 Males  0.296       0.268  0.331*+         0.328

                 SD      0.005       0.002  0.074             0.041

 

    *Significant using Chi square test as reported in original report. +Significant in Tukey test.

 

- Gross pathology: Unremarkable

- Histopathology: There were no treatment related histopathological changes in the control and top dose animals examined.

 

STATISTICAL RESULTS: Original organ weight analyses using theChi square test were supplemented by Tukey tests carried out by the Weinberg group.

 

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).
In view of the structural and chemical similarities, it is considereed that the results of this study can be used for read-across to Alcohols, C12-14.
Endpoint:
sub-chronic toxicity: oral
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Draft OECD 422 Combined Repeat dose and Reproductive/Developmental Toxicity Screening Test
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Moellegard breeding centre
- Age at study initiation: F 8 weeks, M 7 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 2/cage, steel wire cages type 3 (up to day 20 of gestation); macrolon cages type 3 (from day 20 of gestation)
- Diet (e.g. ad libitum): IT chow 101, presumably ad libitum
- Water (e.g. ad libitum): acidified tapwater, ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2
- Humidity (%): 55 +- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
ADMINISTRATION / EXPOSURE
- Duration of test/exposure: males: 41-44 days; females approx. 54 days
- Type of exposure: Dietary
- Post exposure period: None
- Vehicle: Diet. Diet preparation involved first mixing an aqueous dodecanol solution with the barley component, which varied for each dose level. The other components of the diet were then added.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Males 41-45 days; Females approx. 54 days
Frequency of treatment:
continuous in the diet
Remarks:
Doses / Concentrations:
0, 1500, 7500 & 30,000 ppm (approx 100, 500, 2000 mg/kg bw/day)
Basis:
nominal in diet
No. of animals per sex per dose:
12
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: preliminary test via a dermal route
- Rationale for animal assignment (if not random): 2 days prior to the start of dosing, animals randomised into four groups with same mean body weight
- Post-exposure recovery period: none
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Mortality, daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: males once per week; females premating once per week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Yes, once per week
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/week: Yes
- Compound intake calculated from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Food consumption in g body weight gain/kg food per week calculated from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: males after 37 days of dosing
- Anaesthetic used for blood collection: Yes (identity - no data)
- Animals fasted: No data
- How many animals: all males
- Parameters examined: haematocrit, heamoglobin, total erythrocyte and total leukocyte count, leukocyte differential count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: males after 37 days of dosing
- Animals fasted: No data
- How many animals: all males
- Parameters examined: protein, alkaline phosphatase, alanine aminotransferase, glucose, urea, creatinine, total and free cholesterol, triglycerides

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: animals mated for reproductive and developmental toxicity studies
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, full necropsy on all animals
ORGAN WEIGHT: males - liver, kidneys, thymus, testes, epididymides; females - liver, kidneys, thymus
ORGANS FIXED IN FORMALIN: males - liver, kidneys, adrenals, brain, heart, spleen, thymus, organs with pathological changes, testes and epididymides fixed in Bouin's solution; females - liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, other organs with observed pathological changes
HISTOPATHOLOGY: Yes, control and top dose group, all fixed organs except thymus
Other examinations:
Foetal examinations and reproductive parameters (reported elsewhere)
Statistics:
Using the SAS-stat program; analysis of variance; all statistically significant findings further evaluated by Dunnett's t-test
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:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
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
- Mortality and time to death: None
- Clinical signs: None reported

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: No differences between treated and controls of either sex.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
FOOD EFFICIENCY
- Food consumption/food efficiency: No differences between treated and controls of both sexes.
- Dietary concentrations of 1500, 7500 and 30000 ppm provided nominal dose levels of 100, 500 and 2000 mg/kg bw/day; measured dose levels were 82-122, 425-642 and 1616-2646 mg/kg bw/day respectively for males and 125-136, 639-676 and 2503-3058 mg/kg bw/day respectively for females premating.

HAEMATOLOGY (see table 1)
- Haematology: (males only investigated) A dose related reduction in total WBC was observed which reached statistical significance in top and mid
dose males, there were no differences in the differential white cell count that explained these observations.

CLINICAL CHEMISTRY (see table 1)
- Clinical chemistry (males only investigated): There was a significant reduction in plasma triglyceride (TG) at the top dose level and a significant
reduction in plasma free cholesterol (F-chol) at the intermediate dose level. The reduced cholesterol level was re-analysed after removing 2 outlying
values when the statistical significance was lost. These results may have been confounded by the difference in dietary composition between
groups.

ORGAN WEIGHTS (see table 2)
- Organ weights: There were no dose related changes in organ weights. In males only there was a reduction in relative and absolute liver weights at
the low dose level and a reduction in relative liver weight at the mid dose, the top dose was comparable to controls.

GROSS PATHOLOGY
- Gross pathology: There were no changes attributable to exposure to the test compound.

HISTOPATHOLOGY
- Histopathology: There were no treatment related histopathological changes.

HISTORICAL CONTROL DATA (if applicable): none

OTHER FINDINGS
- ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX
Males: 102.4, 530.8 and 2046.4 mg/kg bw/day (mean of values reported for 2 weeks prior to mating and 3 weeks after mating)
Females: 130.5, 657.5 and 2870.5 mg/kg bw/day (mean of values reported 2 weeks prior to mating)
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified

Table 1: Selected haematology and clinical chemistry findings

Doses (mg/kg bw/day (nominal))

0

100

500

2000

male (mean and standard deviation)

Number of animals/group

12

12

12

12

Haematology (day 37)

 

 

 

 

- WBC (mmol/l)

[sic, presumably x 109/l]

 7.0 ± 1.8

5.9 ± 1.3

4.3*** ± 1.4

4.7** ± 1.2 

Blood chemistry (day 37)

 

 

 

 

- total cholesterol (mmol/l)

 1.60 ± 0.27

1.74 ± 0.36 

1.64 ± 0.30 

1.75 ± 0.22 

- free cholesterol (mmol/l)

 0.18 ± 0.07

0.16 ± 0.05 

0.11* ± 0.06 

0.15 ± 0.05 

- triglyceride (mmol/l)

 0.58 ± 0.32

0.42 ± 0.11 

0.45 ± 0.17 

0.31** ± 0.06 

* p<0.05   ** p<0.01  *** p<0.001

Table 2: Absolute and relative organ weights

 

Males (mean and standard deviation)

DAILY DOSE
(mg/kg bw (nominal))

0

100

500

2000

NUMBER OF ANIMALS

12

12

12

12 

BODY WEIGHT (g)a

 370 ± 26.9

366 ± 20.4 

383 ± 20.6 

367 ± 16.7 

LIVER

 

 

 

 

AbsoluteWeighta

g

12.27 ± 1.2 

11.20* ± 0.8 

11.76 ± 1.0 

11.98 ± 0.9 

Per BodyWeighta

%

3.3 ± 0.19 

3.1* ± 0.21 

3.1* ± 0.24 

3.3 ± 0.21 

aGroup means at terminal necropsy are shown.

* p<0.05

Conclusions:
In a reliable study conducted to the draft OECD guideline 422, an NOAEL for systemic toxicity of 2000 mg/kg/day (highest dose tested) was determined in male rats in the absence of toxicologically significant effects at any dose level.Dodecan-1-ol (C12) is supporting substance for Alcohols,C12-C14 and the main component.
Executive summary:

The NOAEL for systemic toxicity in male rats is considered to be 2000 mg/kg/day (highest dose tested) in the absence of toxicologically significant effects at any dose level.

Endpoint:
chronic toxicity: oral
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
other: published data
Adequacy of study:
key 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 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
(no neurobehavioural testing; limited range of endpoints assessed in other examinations)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: M 84-98 g; F 81-93g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- no data

VEHICLE
- Justification for use and choice of vehicle (if other than water): not stated
- Concentration in vehicle: 0, 2, 10 or 20%
- Amount of vehicle (if gavage): 5 ml/kg bw
- Lot/batch no. (if required): no data
- Purity: no data
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily, 5 days/week
Remarks:
Doses / Concentrations:
100, 500, and 1000 mg/kg bw
Basis:
other: nominal conc.
No. of animals per sex per dose:
10 (main study) + 5 (satellite groups)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: reversibility
- Post-exposure recovery period in satellite groups: 28 days
- Section schedule rationale (if not random): no data
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: clinical signs and mortality

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: daily

FOOD EFFICIENCY: No data

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at end of study
- Dose groups that were examined: no data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 21/22 daily doses
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters examined.: Haematocrit, MCV, Hb, RBC, WBC, Thrombocytes, differential white count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 21/22 daily doses
- Animals fasted: No data
- How many animals: No data
- Parameters examined: Serum urea, creatinine, Na, K, calcium, alkaline phosphatase, ALAT, ASAT, GT, bilirubin, chloride, albumin, total protein, cholesterol

URINALYSIS: No

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

ORGAN WEIGHTS: thyroid, adrenals, thymus, kidney, spleen, heart, brain, testes, liver

HISTOPATHOLOGY: Yes, all organs from the control and top dose animals were examined plus the animals from the reversibility study.
Statistics:
T-test. U-test for organ weights
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 specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No effects on mortality
Unremarkable other than top dose females appearing rather defensive when handled

BODY WEIGHT AND WEIGHT GAIN
No effects

FOOD CONSUMPTION
No effects

FOOD EFFICIENCY
No data

WATER CONSUMPTION
No effects

OPHTHALMOSCOPIC EXAMINATION
No effects

HAEMATOLOGY
No differences between treated and control animals other than an increase in neutrophils containing rodlike bodies observed in top dose females (confidence level 95%*). Values obtained (% rod like cells) were controls 2.5, low dose 3.3, mid dose 2.9, high dose 5.3*

CLINICAL CHEMISTRY
Statistically significant changes (*95% ** 99% confidence) in some clinical chemistry parameters were noted as follows:
- 500 mg/kg bw/day males increased potassium*,
- 500 mg/kg/day females increased GGT*, cholesterol** and chloride*
- glucose was elevated in top dose males (mmol/l): Control 6.03, Low 6.20, Mid 6.25, High 7.28**
These changes were not dose and/or sex related and not correlated with any histopathological findings and are therefore not considered of toxicological significance.

URINALYSIS
No effects

NEUROBEHAVIOUR
No data

ORGAN WEIGHTS
Both absolute and relative organ weights were essentially comparable in treated and control animals.
Sporadic changes were observed as follows (*95% ** 99% confidence):
- increase in absolute male kidney weight at 500 mg/kg/day*
- increase in absolute testis weight at 1000 mg/kg/day*; mean relative (absolute) testis weight: Control 0.856 (3.207), Low 0.839 (3.186), Mid 0.908 (3.455), High 0.893 (3.474*)
- the only change in relative organ weight was an increase in male adrenal weight at 1000 mg/kg/day*; mean relative (absolute) adrenal weight: Control 0.013 (0.050), Low 0.014 (0.054), Mid 0.014 (0.055), High 0.015* (0.058)

GROSS PATHOLOGY
No effects

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment related histopathological changes in test, control or reversibility groups.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not applicable

HISTORICAL CONTROL DATA (if applicable)
No data
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified
Conclusions:
In a reliable study, performed according to a protocol similar to OECD guideline 407, a 28-day oral NOAEL of 1000 mg/kg bw/day was determined in the rat.
Hexadecan-1-ol (C16) is supporting substance for Alcohols,C12-C14 and the one of the component in Alcohols,C12-C14
In view of the structural and chemical similarities, it is considereed that the results of this study can be used for read-across to Alcohols, C12-14.
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS
- Supplier: Charles River Wiga GmbH, Sulzburg
- Age/Weight at study initiation: M64-97 g; F 62-99g
- Number of animals: 10M+10F per dose level plus 5M+5F per dose level for reversibility.

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
ADMINISTRATION / EXPOSURE
- Duration of test/exposure: 27-28 days exposure (5 days/week)
- Type of exposure: oral gavage
- Post exposure period: 28 days
- Vehicle: Olive oil
- Concentration in vehicle: 0, 2, 10 or 20%
- Total volume applied: 5 ml/kg
- Doses: 0, 100, 500 and 1000 mg/kg/day

SATELLITE GROUPS AND REASONS THEY WERE ADDED: 5M+5F per dose level for reversibility.

CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: Daily
- Mortality: Daily
- Body weight: Weekly
- Food consumption: Weekly
- Water consumption: Ad lib
- Ophthalmoscopic examination: At end of study
- Haematology: After 21/22 daily doses: Haematocrit, MCV, Hb, RBC, WBC, Thrombocytes, differential white count.
- Biochemistry: After 21/22 daily doses: Serum Urea, creatinine, Na, K, calcium, alkaline phosphatase, ALAT, ASAT, GT, bilirubin, chloride, Albumin, total protein, chloesterol.
- Urinalysis: Not done

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: Yes
- Organs weights: thyroid, adrenals, thymus, kidney, spleen, heart, brain, testes, liver.
- Microscopic: All organs from the control and top dose animals were examined plus the animals from the reversibility study.

STATISTICAL METHODS: T-test, organ weights U-test
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily, 5 days/week
Remarks:
Doses / Concentrations:
0, 100, 500, 1000 mg/kg in olive oil
Basis:
actual ingested
No. of animals per sex per dose:
10M+10F per dose level plus 5M+5F per dose level for reversibility.
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 28 days
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
NOAEL: 1000 mg/kg/day

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX
0, 100, 500 & 1000 mg/kg/day

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- Mortality and time to death: No mortalities.
- Clinical signs: Unremarkable.

- Body weight gain: Male bodyweight gain was reduced compared to controls, body weight gains were 95%, 91% and 82% of control values for low, mid and high dose levels respectively at the end of the study. This was attributed to a high mean control bodyweight in males and marked inhibition of bodyweight gain in one male in each of the high and mid dose levels.

- Food/water consumption: Water consumption was comparable in control and treated groups. Food consumption was slightly reduced in males (95% confidence).

- Ophthalmoscopic examination: No treatment related ocular lesions.

- Clinical chemistry: There were some statistically significant changes (p=0.05) in clinical chemical parameters in the top dose group. In males ASAT was increased (control mean 33 U/l; top dose 45.1); Na was also increased (control mean 143.1 mmol/l; top dose 144.4). Serum chloride was reduced (control mean 99.7 mmol/l; top dose 97.9). In females there was an increase in Na (control mean 142 mmol/l; top dose 143) and in phosphorous (control mean 1.99 mmol/l; top dose 21.9. These changes are not clearly dose related and apart from the slight increase in serum sodium do not appear in both sexes. There are no histopathological changes related to these changes which were considered chance observations and not indicative of a trend.

- Haematology: Treated and control groups were comparable. A slight increase (95% confidence *) in neutrophils with rod-like bodies (mid dose males), a marginal decrease in thrombocytes (top dose males) and eosinophils (top dose females) were not considered of biological significance.

Thrombocytes:
Control low mid high
male 633.9 619.9 583.9 511.9*

Eosinophils:
female 1.3 0.8 0.9 0.3**

- Urinalysis: Not done

- Organ weights: Sporadic changes in absolute or relative organ weights relative weights were not dose and/or sex related. There was no corresponding histopathological change. Relative heart weights were increased* in top dose males, Relative and absolute kidney weights were decreased* in mid-dose females, while other absolute organ weights were changed as follows:

Absolute mean spleen weight:
Control low mid high
male 0.706 0.651 0.585* 0,593*

Absolute mean thyroid weight:
Control low mid high
male 0.024 0.018** 0.02 0.018**

Absolute mean spleen weight:
Control low mid high
male 0.706 0.651 0.585* 0.593*

Relative mean heart weight:
Control low mid high
male 0.281 0.288 0.302 0.314*

- Pathology: There were no treatment related findings. Pathological changes observed were related to misdosing, respiratory infection or viral infection.

STATISTICAL RESULTS: T-test and U-test for organ weights.

The NOAEL for this study is considered to be >1000 mg/kg/day based on a lack of toxicologically significant effects. Statistically significant changes in some clinical chemical and haematological parameters and organ weights changes were not accompanied by histopathological changes and were either not dose related or appeared in only one sex. These effects are not considered of toxicological significance.

(1) valid without restriction
Guideline study
Henkel KGaA 1986a; Henkel 1999 (2-page English summary)
Hayes Consultancy Service Bromley, Kent
Critical study for SIDS endpoint
(13) (14)

rat
male/female
Wistar
oral feed
males 45 days; females ca 54 days
continuous in diet
none
0, 1500, 7500 or 30,000 ppm (ca 0, 100, 500, 2000 mg/kg/bw/day)
yes
= 2000 mg/kg bw
other: Draft OECD 422 combined repeated dose and reproductive/developmental toxicity screening test
1991
yes
as prescribed by 1.1 - 1.4

TEST ORGANISMS
- Age: 7 weeks
- Number of animals: 12M+12F/group

ADMINISTRATION / EXPOSURE
- Duration of test/exposure: males: 45 days; females approx. 54 days
- Type of exposure: Dietary
- Post exposure period: None
- Vehicle: Diet. Diet preparation involved first mixing the octadecanol with the barley component, the proportion of which varied for each dose level. The other components of the diet were then added.

CLINICAL OBSERVATIONS AND FREQUENCY:
- Mortality: Daily
- Body weight: weekly
- Food consumption: weekly (except during mating)
- Water consumption: ad lib
- Haematology: Males only at day 37; haematocrit, Hb, total RBC & WBC and differential WBC.
- Biochemistry: Males only at day 37; Plasma protein, alkaline phosphatase, AAT, glucose, urea, creatinine,total & free cholesterol and triglyceride.

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: Full necrospy on all animals.
- Organ weights: liver, kidneys, thymus (females) liver, kidney, thymus, testes, epididymes (males)
- Microscopic: Carried out on all control and top dose animals plus any obvious lesions observed at necrospy. Organs examined were liver, kidneys, adrenals, brain, heart, spleen, ovaries or testes and epididymes.

OTHER EXAMINATIONS: The results of foetal examinations and reproductive parameters are reported in the appropriate sections.

STATISTICAL METHODS: Using the SAS-stat program analysis of variance plus Dunnett's test if changes were significant.

NOAEL 2000 mg/kg/day, LOEL: 100 mg/kg/day

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX
Males: 99.25, 500.25 and 2146.5 mg/kg/day (mean of values reported for 2 weeks prior to mating and 3 weeks after mating)
Females:120, 625 and 2435.5 mg/kg/day (mean of values reported 2 weeks prior to mating)

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- Mortality and time to death: There were no mortalities.
- Clinical signs: None reported.

- Body weight gain: There were no significant changes in body weight or body weight gain in the 3 weeks prior to mating for both sexes. Or in males after mating.

- Food consumption/efficiency: Food consumption was significantly increased in top dose males (p<0.001) and in mid dose females (p<0.05) at week 3. There were no other differences in food consumption or food conversion efficiency.

- Clinical chemistry: (males only examined) There were significant (but non-dose related) differences in free cholesterol (increased) and triglycerides (decreased) at all dose levels. Total cholesterol levels were not significantly increased. Plasma glucose was elevated with statistical significance in the low and mid-dose groups.

Parameter Control 100 500 2000
(mM)
Free chol 0.29 0.38** 0.37** 0.36*
Total chol 1.30 1.56 1.56 1.40
Triglycerides 0.78 0.42** 0.49* 0.46**
Glucose 6.8 7.8* 7.9* 7.6

* p<0.05 ** P<0.01

- Haematology: No statistically significant differences between treated and control groups (males only examined).
- Organ weights: There were no significant differences in absolute or relative organ weights in males or females.

- Gross pathology: Unremarkable no changes attributable to treatment.
- Histopathology: Unremarkable no changes attributable to treatment.

- Other: The method of diet preparation resulted in different dietary content between the different treatment groups and controls.

STATISTICAL RESULTS: Reported above.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Statistically significant changes in some clinical chemical and haematological parameters and organ weights changes were not accompanied by histopathological changes and were either not dose related or appeared in only one sex.
Critical effects observed:
not specified

NOAEL: 1000 mg/kg/day

 

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX

0, 100, 500 & 1000 mg/kg/day 

 

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 

- Mortality and time to death: No mortalities.

- Clinical signs: Unremarkable.

 

- Body weight gain: Male bodyweight gain was reduced compared to controls, body weight gains were 95%, 91% and 82% of control values for low, mid and high dose levels respectively at the end of the study. This was attributed to a high mean control bodyweight in males and marked inhibition of bodyweight gain in one male in each of the high and mid dose levels.

 

- Food/water consumption: Water consumption was comparable in control and treated groups. Food consumption was slightly reduced in males (95% confidence).

 

- Ophthalmoscopic examination: No treatment related ocular lesions.

 

- Clinical chemistry: There were some statistically significant changes (p=0.05) in clinical chemical parameters in the top dose group. In males ASAT was increased (control mean 33 U/l; top dose 45.1); Na was also increased (control mean 143.1 mmol/l; top dose 144.4). Serum chloride was reduced (control mean 99.7 mmol/l; top dose 97.9). In females there was an increase in Na (control mean 142 mmol/l; top dose 143) and in phosphorous (control mean 1.99 mmol/l; top dose 21.9. These changes are not clearly dose related and apart from the slight increase in serum sodium do not appear in both sexes. There are no histopathological changes related to these changes which were considered chance observations and not indicative of a trend.

 

- Haematology: Treated and control groups were comparable. A slight increase (95% confidence *) in neutrophils with rod-like bodies (mid dose males), a marginal decrease in thrombocytes (top dose males) and eosinophils (top dose females) were not considered of biological significance.

 

Thrombocytes:

       Control  low   mid   high

male   633.9    619.9 583.9 511.9*

 

Eosinophils:

female 1.3      0.8   0.9   0.3**

 

- Urinalysis: Not done

 

- Organ weights: Sporadic changes in absolute or relative organ weights relative weights were not dose and/or sex related. There was no

corresponding histopathological change. Relative heart weights were increased* in top dose males, Relative and absolute kidney weights were

decreased* in mid-dose females, while other absolute organ weights were changed as follows:

 

Absolute mean spleen weight:

       Control   low   mid   high

male   0.706     0.651 0.585* 0,593*

 

Absolute mean thyroid weight:

       Control   low    mid   high

male   0.024     0.018** 0.02  0.018**

 

Absolute mean spleen weight:

       Control   low    mid   high

male   0.706     0.651  0.585* 0.593*

 

Relative mean heart weight:

       Control   low    mid   high

male   0.281     0.288  0.302 0.314*

 

- Pathology: There were no treatment related findings. Pathological changes observed were related to misdosing, respiratory infection or viral

infection. 

 

STATISTICAL RESULTS: T-test and U-test for organ weights.

Conclusions:
The NOAEL for this study is considered to be >1000 mg/kg/day based on a lack of toxicologically significant effects. Statistically significant changes in some clinical chemical and haematological parameters and organ weights changes were not accompanied by histopathological changes and were either not dose related or appeared in only one sex. These effects are not considered of toxicological significance.
Endpoint:
sub-chronic toxicity: oral
Type of information:
other: published data
Adequacy of study:
key 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 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
Method: other: An in-house protocol based on OECD Guide-line 407
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS
- Weight at study initiation: 142-153g
- Number of animals: 10M+10F/group
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
ADMINISTRATION / EXPOSURE
- Duration of test/exposure: 90 days
- Type of exposure: Oral gavage
- Post exposure period: None
- Vehicle: Olive oil
- Concentration in vehicle: Not reported
- Total volume applied: Not reported
- Doses: 1 ml/kg (840 mg/kg/day)

CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs/mortality: daily
- Body weight: weekly
- Food consumption:
- Water consumption:
- Ophthalmoscopic examination: not reported
- Haematology: At the end of study Hb, RBC, WBC, differential bloood count
- Biochemistry: At end of study serum glucose, calcium, urea, ALAT & ASAT,
- Urinalysis: At end of study following a water loading of 2 ml/100g/bw. pH, specific gravity, glucose, albumin, blood, bilirubin, ketones, urinary sediments.

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: An autopsy was carried out. Major organs were preserved. Organ weights were recorded (no further details of which organs were weighed).
- Microscopic: The liver was examined histologically following staining with both routine H&E and Sudan 111 to detect fatty degeneration.

STATISTICAL METHODS: Not reported
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily, 5 days/week
Remarks:
Doses / Concentrations:
1 ml/kg bw (840 mg/kg/day)
Basis:
actual ingested
No. of animals per sex per dose:
10M+10F/group
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
ADMINISTRATION / EXPOSURE
- Duration of test/exposure: 90 days
- Type of exposure: Oral gavage
- Post exposure period: None
- Vehicle: Olive oil
- Concentration in vehicle: Not reported
- Total volume applied: Not reported
- Doses: 1 ml/kg (840 mg/kg/day)

CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs/mortality: daily
- Body weight: weekly
- Food consumption:
- Water consumption:
- Ophthalmoscopic examination: not reported
- Haematology: At the end of study Hb, RBC, WBC, differential bloood count
- Biochemistry: At end of study serum glucose, calcium, urea, ALAT & ASAT,
- Urinalysis: At end of study following a water loading of 2 ml/100g/bw. pH, specific gravity, glucose, albumin, blood, bilirubin, ketones, urinary sediments.

Sacrifice and pathology:
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: An autopsy was carried out. Major organs were preserved. Organ weights were recorded (no further details of which organs were weighed).
- Microscopic: The liver was examined histologically following staining with both routine H&E and Sudan 111 to detect fatty degeneration.
Statistics:
STATISTICAL METHODS: Not reported
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
NOAEL: > 840 mg/kg bw

There was no mortality among the test animals and no adverse effects observed. Body weight gain appeared comparable between treated and control groups however there was no evidence that the results were analysed statistically. The haematological, as well as clinical-chemical parameters were comparable to the control group. The organ weights were within normal limits. No histopathological changes were reported. There was no detailed report of the measurements obtained from the various endpoints evaluated. There were no treatment related adverse effects on the liver sections examined histopathologically.

Dose descriptor:
NOAEL
Effect level:
> 840 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: There was no mortality among the test animals and no adverse effects observed. Body weight gain appeared comparable between treated and control groups however there was no evidence that the results were analysed statistically
Critical effects observed:
not specified

C16-18 and C18 unsaturated alcohols [CAS 68002-94-8]were without adverse effects in rats upon daily administration of 1 ml/kg/day (ca.840 mg/kg/day) for 4 weeks

Conclusions:
Repeated exposure for 13 weeks to 1 ml/kg/day (840 mg/kg) Eutanol HD appeared to have little adverse effect on the test animals. This dose level can be considered a NOAEL. The study is limited by lack of detailed reporting of the test results. The study is not in full accordance with OECD 407 but appears well conducted.
Endpoint:
sub-chronic toxicity: oral
Type of information:
other: published data
Adequacy of study:
key study
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:
Small groups of dogs treated via the diet for 90 days with limited evaluation
GLP compliance:
not specified
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5 months
- Weight at study initiation: M 4.77-8.63 kg; F 5.45-7.49 kg
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0.5, 1.0, and 3.0 % w/w
Basis:
nominal in diet
No. of animals per sex per dose:
2M+2F treated; 4M+5F controls
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 5 days/week; mortality daily

DETAILED CLINICAL OBSERVATIONS: Yes
- complete physical examination, body temperature, pulse rate, reflexes, mucous membranes, auscultation pretreatment at 3, 6 & 13 weeks
- ECG pretreatment, 3 and 13 weeks

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: weekly

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Parameters examined: total & differential leucocyte counts, Hb, haematocrit, erythrocyte sedimentation rate, prothrombin time measured pretreatmentand at 3, 6 and 13 weeks.

CLINICAL CHEMISTRY: Yes
- Parameters examined: plasma levels of glucose, total protein & albumin, albumin/globulin ratios, urea nitrogen measured pretreatment, 3, 6 and 13 weeks. Liver function assessed by BSP retention, alkaline phosphatase & SGOT at same time periods.

URINALYSIS: Yes
- Parameters examined: albumin, glucose, bilirubin, pH, vol., specific gravity, microscopic examination of sediment, total nitrogen. Carried out pretreatment & at 3, 6 & 13 weeks

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, complete, organ weights determined for brain, thyroid, heart, liver, kidneys, adrenals, spleen, gonads.
HISTOPATHOLOGY: Yes, brain, pituitary, sub-maxillary salivary gland, thyroid, parathyroid, heart, lung, liver, spleen, stomach (fundic & pyloric), small intestine (3 levels), large intestine, pancreas, gall bladder, kidney, urinary bladder, adrenal, gonads, lymph node (cervical & mesenteric), bone, bone
marrow, muscle (striated). All fixed. Tissues from controls & high dose animals examined microscopically. Stomach & intestinal tissues from mid
dose animals also examined plus any abnormal tissues identified at necropsy.
Statistics:
No statistical analysis reported in the original report. For the HPV program the results were analysed using Tukey's Test.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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:
no effects observed
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:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- No animals died.
- No specific clinical signs, all animals appeared normal and healthy throughout the study. This was suppported by the clinical examinations at weeks 3, 6 and 13 which were within normal limits.

BODY WEIGHT AND WEIGHT GAIN
- Comparable in test and control groups.

FOOD CONSUMPTION
- Comparable in test and control groups.

HAEMATOLOGY
- No adverse effects.

CLINICAL CHEMISTRY
- No treatment related adverse effects for most parameters. Plasma ALAT levels were increased at all dose levels at 13 weeks only.

URINALYSIS
- No adverse effects.

ORGAN WEIGHTS
- These were within normal limits and comparable to controls. Tukeys test did not indicate any statistical differences (however sample size was small).

GROSS PATHOLOGY
- Lymph node hyperplasia in both control and treated animals was considered due to roundworm infestation (despite routine deworming throughout the study). There were no treatment related findings.

HISTOPATHOLOGY: NON-NEOPLASTIC
- No treatment related changes.

OTHER
- ECG's showed no difference between the initial pattern recorded pretreatment and those seen at 3 and 13 weeks
Dose descriptor:
NOAEL
Effect level:
> 1 054 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: (Animals in the low, mid and high dose groups were administered dietary concentration of 0.5%, 1% and 3% respectively; average compound intake for females, calculated from weekly food consumption data, was 186, 374 and 1054 mg/kg bw/day respectively)
Dose descriptor:
NOAEL
Effect level:
>= 1 175 mg/kg bw/day (actual dose received)
Based on:
other: based on highest dose tested.
Sex:
male
Basis for effect level:
other: (Animals in the low, mid and high dose groups were administered dietary concentration of 0.5%, 1% and 3% respectively; average compound intake for males, calculated from weekly food consumption data, was 208, 502 and 1175 mg/kg bw/day respectively)
Critical effects observed:
not specified

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX 0.5% (M 208 mg/kg/day; F 186 mg/kd/day) 1% (M 502 mg/kg/day; F 374 mg/kg/day) 3% (M 1175 mg/kg/day; F 1054 mg/kg/day) STATISTICAL RESULTS: There was no statistical analysis of the study data in the original report. Subsequent analysis of organ weights using Tukeys test did not reveal any statistical differences between treated and control animals. This analysis was carried out by The Weinberg Group Inc.

Conclusions:
In a limited study, in which small groups of dogs were treated with Alfol 16 via the diet for 13 weeks, an NOAEL of 1175 mg/kg bw/day was determined for males and 1054 mg/kg bw/day for females (the highest doses tested).
Hexadecan-1-ol (C16) is supporting substance for Alcohols,C12-C14 and the one of the component in Alcohols,C12-C14
In view of the structural and chemical similarities, it is considereed that the results of this study can be used for read-across to Alcohols, C12-14.
Executive summary:

In a 13-week study groups of 2 dogs/sex/dose received dietary concentrations of 0 (control), 0.5, 1.0 or 3% 1-hexadecanol. There no were adverse effects reported except for elevations of AST at week 13 at all incorporation levels, without evidence of a clear dose response relationship. The small groups sizes used in this study preclude a definitive conclusion about the significance of these changed enzyme levels, especially in the absence of any further corroborating evidence of liver toxicity (liver weight and histology). A NOAEL of 1054 mg/kg (highest dose tested) is therefore proposed

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

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at delivery: 7 weeks
- Weight at study initiation: males 238 (+/- 2.3) g; females 238 (170 +/- 2.2) g
- Housing: singly in wire cages
- Diet: e.g. ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days acclimation to the inhalation chamber


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 hrs light/dark


IN-LIFE DATES: From: day1 To: day 93
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: whole-body inhalation chamber (glas/steel construction, volumes approx. 1.1 m³)
- Method of holding animals in test chamber: rats were kept individually in wire cages
- Test atmosphere generation: the test substance was delivered to heated evaporators by mean of metering pumps. The warmed air was mixed with compressed air and delivered to teh inhalation chamber.
- Source and rate of air: compressed air; variable rate
- Temperature, humidity, pressure in air chamber: 23.1 to 23.8°C; positive pressure 10.1 Pascal (ciontrol groups), negative pressure -10.2 Pascal (treated groups); 41.8 to 46.2% relative humidity
- Air flow rate: not reported in publication
- Air change rate: not reported in publication
- Treatment of exhaust air: not reported in publication
TEST ATMOSPHERE
- Brief description of analytical method used: samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day, 5 days/week (total of 65 exposures)
Remarks:
Doses / Concentrations:
0, 15, 40 and 120 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
15 (SD 0.67), 39.9 (SD 1.33), 120 (SD 4.8) ppm
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: none
Positive control:
not required
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS:
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: yes
- Time schedule: pre-treatment and at termination


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION:
- Food consumption: no data contained in the publication; not required


FOOD EFFICIENCY:
- Body weight gain: yes, but no data contained in the publication; not required
WATER CONSUMPTION: no data contained in the publication; not required


OPHTHALMOSCOPIC EXAMINATION: yes
- Time schedule for examinations: pre-treatment and at termination
- Dose groups that were examined: all animals


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination, day 94 of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals
- Parameters: white and red blood cells, hemoglobin, hematocrit, mean corpuscular volume. mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, differential blood count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination, day 94 of the study
- Animals fasted: No data
- How many animals: No data
- Parameters: sodium, potassium, chloride, glucose, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, clotting time


URINALYSIS: No data




OTHER:
- cyanide-insensitive palmitoyl-CoA oxidation in liver homogenates
- gross pathology of all animals at termination; determination of organ weights (lungs, liver, kidneys, adrenal glands, and testes)
- histopathology of organs/tissues required by guidelines, and all gross lesions
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
- Mean values +/- standard deviation: body weight, body weight gain, hematological and clinical biochemistry parameters, absolute and relative organ weights.
Dunnett's test: comparison of exposure groups with the control group.
Analysis of variance subsequent to Dunnett's test: body weight, body weight gain, hematological and clinical biochemistry parameters
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:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
1) Analysis of the daily inhalation chamber concentrations revealed that the values obtained closely fitted with the desired nominal level


2) There were no effects regarding the issues below noted at any dose level:

CLINICAL SIGNS AND MORTALITY


BODY WEIGHT AND WEIGHT GAIN


FOOD CONSUMPTION
FOOD EFFICIENCY


WATER CONSUMPTION


OPHTHALMOSCOPIC EXAMINATION


HAEMATOLOGY


CLINICAL CHEMISTRY


URINALYSIS


NEUROBEHAVIOUR
ORGAN WEIGHTS


GROSS PATHOLOGY


HISTOPATHOLOGY: NON-NEOPLASTIC


HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Dose descriptor:
NOAEC
Effect level:
120 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
NOAEC
Effect level:
638.4 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
NOAEC
Effect level:
980.6 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Correcting for molecular weight, a conservative NOAEC of 980.6 mg/m3 can be derived (638.4 x 200) / 130.2 =980.6 mg/m3
Critical effects observed:
not specified

Under the conditions of the test no treatment-related toxic
effects were found in male and female Wistar rats which were
exposed to 2-ethylhexanol vapor up to 120 ppm.

The concentration of 120 ppm corresponds to the calculated

saturated vapor concentration at 20°C.

Conclusions:
Under the conditions of the test no treatment-related toxic effects were found in male and female Wistar rats which were exposed to 2-ethylhexanol vapor up to 120 ppm ie. 638.4 mg/m³ .
Correcting for molecular weight, a conservative NOAEC of 980.6 mg/m3 can be derived
(638.4 x 200) / 130.2 =980.6 mg/m3
Executive summary:

No treatment-related effects were noted in a OECD Guideline 413 study (Subchronic Inhalation Toxicity: 90-Day) using male and female Wistar rats (10 rats per sex and dose). Exposure levels were 0, 15, 40, and 120 ppm (120 ppm is equivalent to saturation at 20°C). As there were no effects compared with the control groups in either sex on body weight or body weight gain, clinical signs of toxicity and mortality, hematological and clinical biochemistry parameters, ophthalmological parameters, absolute or relative organ weights including testes, or cyanide-insensitive palmitoyl-CoA oxidation as a parameter for hepatic peroxisome proliferation, the NOAEC was 120 ppm, ie. 638.4 mg/m³ (Klimisch, 1998).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
980.6 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
32.6 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Inhalation exposure:
There are no reliable Inhalation Repeated studies available for local effects.
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/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
750 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 32.6 mg/m3

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- 10 of each gender per test group and control group
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 if used: gauze binder, secured with tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): 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 (volume or weight with unit): 1.2 ml/kg

- Concentration (if solution): 0.9% saline

- Constant volume or concentration used: yes
TEST MATERIAL - Test groups(1-3)
- Amount(s) applied (volume or weight with unit): 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.
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.
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg/day
Basis:
other: volume or weight with unit
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, concurrent no treatment
Observations and examinations performed and frequency:
The animals were observed for signs of overt toxicity, dermal irritation, effects on body weight and consumption, haematology and serum chemistry parameters.
Sacrifice and pathology:
Complete necropsies were performed on all animals.
Other examinations:
Selected organs were weighed and a microscopic examination was conducted on selected tissues from all animals at the scheduled necropsy.
Clinical signs:
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.
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):
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 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. This was attributed to the test article.
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, and this was attributed to the test article.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Description (incidence and severity):
No information provided
Ophthalmological findings:
not specified
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 specified
Description (incidence and severity):
No information provided
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
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 for the adrenals.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No significant changes reported (except for the dermal application sites for all the dose groups)
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No significant changes reported (except for the dermal application sites for all the dose groups)
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.
Critical effects observed:
not specified

Clinical signs

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.

Organ weights

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 for the adrenals which was most likely related to stress resulting from severe dermal irritation that was observed in all dose groups.

Macroscopic examination

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.
Conclusions:
Based on the data that was reported a NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days was less than 100 mg/kg/day.
However the NOAEL has been based on a local irritation effect rather than a systemic effect. Therefore it is proposed (by the author of the EPSR) that on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.
Executive summary:

 A 90-day dermal toxicity study in rats with fatty alcohol blend (56.7% decanol, 42.7% octanol) at dose levels of 0, 100, 300, or 1,000 mg/kg resulted in severe irritation at the application site. Severe irritation including fissuring of the skin occurred in 40% of the animals at 100 mg/kg/day and 80% of the animals at the limit dose. Slight changes in hematology, clinical chemistry, and organ weights were noted at the limit dose of 1,000 mg/kg/day.

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

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- 10 of each gender per test group and control group
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 if used: gauze binder, secured with tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): 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 (volume or weight with unit): 1.2 ml/kg

- Concentration (if solution): 0.9% saline

- Constant volume or concentration used: yes
TEST MATERIAL - Test groups(1-3)
- Amount(s) applied (volume or weight with unit): 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.
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.
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg/day
Basis:
other: volume or weight with unit
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, concurrent no treatment
Observations and examinations performed and frequency:
The animals were observed for signs of overt toxicity, dermal irritation, effects on body weight and consumption, haematology and serum chemistry parameters.
Sacrifice and pathology:
Complete necropsies were performed on all animals.
Other examinations:
Selected organs were weighed and a microscopic examination was conducted on selected tissues from all animals at the scheduled necropsy.
Clinical signs:
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.
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):
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 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. This was attributed to the test article.
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, and this was attributed to the test article.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Description (incidence and severity):
No information provided
Ophthalmological findings:
not specified
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 specified
Description (incidence and severity):
No information provided
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
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 for the adrenals.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No significant changes reported (except for the dermal application sites for all the dose groups)
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No significant changes reported (except for the dermal application sites for all the dose groups)
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.
Critical effects observed:
not specified

Clinical signs

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.

Organ weights

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 for the adrenals which was most likely related to stress resulting from severe dermal irritation that was observed in all dose groups.

Macroscopic examination

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.
Conclusions:
Based on the data that was reported a NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days was less than 100 mg/kg/day.
However the NOAEL has been based on a local irritation effect rather than a systemic effect. Therefore it is proposed (by the author of the EPSR) that on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.
Executive summary:

 A 90-day dermal toxicity study in rats with fatty alcohol blend (56.7% decanol, 42.7% octanol) at dose levels of 0, 100, 300, or 1,000 mg/kg resulted in severe irritation at the application site. Severe irritation including fissuring of the skin occurred in 40% of the animals at 100 mg/kg/day and 80% of the animals at the limit dose. Slight changes in hematology, clinical chemistry, and organ weights were noted at the limit dose of 1,000 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5.62 mg/cm²
Study duration:
chronic
Species:
rat

Additional information

Oral repeated dose toxicity

1.1-Dodecanol[CAS 112-53-8](as a read across for Alcohols, C12-14) was tested in rats in a combined repeated-dose and reproductive / developmental toxicity screen. Animals received dietary concentrations of 1500, 7500 or 30,000 ppm during all phases in the production of a single generation; the composition of the diet was adjusted to take account of the caloric incorporation of the test material. Male animals were exposed for a total of 37 days including the mating period. Females were allowed to litter naturally and were terminated at day 5 post-natally. In males, there were no effects recorded other than a reduction in mean white blood cell count (15, 38 and 32% reduction for the low mid or high dose group, respectively) and changes in free cholesterol (38% reduction in the mid dose group) and triglycerides (46% reduction at the top dose level). In the absence of any changes in the differential white cell count, the observed reduction in total WBC is considered of uncertain significance. A reduction in plasma cholesterol was observed in the middle dose group; this was considered a chance finding associated with 2 outlying values. Although the reduction in plasma triglycerides and cholesterol levels may be indicative of marginal effects in the liver, the differences in composition of the test diets between control and the treatment groups may have confounded some of the parameters measured in this study. The NOEL was <1500ppm (<100 mg/kg/day) based on the haematological (WBC) changes; the NOAEL was 30,000 ppm (2000 mg/kg/day). 

2. In a 13-week study in rats 1-hexadecanol (as a read across for Alcohols, C12-14) was administered in the diet at concentrations of 0 (control), 1, 2.5 or 5%; the level in the highest dose group being increased stepwise to 10% during the last 3 weeks of the study. Reductions in body weight gain (82-90% of control values) and food consumption (76 – 90% of control values) in the highest dose group and, occasionally, at the 2.5% level were the main findings of this study. Relative liver weights were increased in males at the top dose level (124% of control values) but in the absence of any microscopic findings the significance of this change is uncertain. A NOAEL was established at a dietary concentration of 1% (equivalent to ca.750 mg/kg/day) based on the reductions in body weight gain and food consumption (Scientific Assoc., 1966).

3. 1-Hexadecanol [CAS 36653-82-4] (as a read across for Alcohols, C12-14).In a 13-week study groups of 2 dogs/sex/dose received dietary concentrations of 0 (control), 0.5, 1.0 or 3% 1-hexadecanol. There no were adverse effects reported except for elevations of AST at week 13 at all incorporation levels, without evidence of a clear dose response relationship. The small groups sizes used in this study preclude a definitive conclusion about the significance of these changed enzyme levels, especially in the absence of any further corroborating evidence of liver toxicity (liver weight and histology). A NOAEL of 1000 mg/kg (highest dose tested) is therefore proposed (Scientific Assoc., 1966).

4. 1-Hexanol [CAS 111-27-3] (as a read across for Alcohols, C12-14). Rats exposed to 1-hexanol 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 1-6% (equivalent to 1127 mg/kg/day). Examination of testes and the ovaries did not show any abnormalities (Scientific Associates, 1966).

5. 1-Hexadecanol [CAS 36653-82-4] (as a read across for Alcohols, C12-14) was without toxic effects in a 28-day study in rats receiving daily oral [gavage] doses of 0 (control), 100, 500 and 1000 mg/kg/day (Henkel, 1985).

6.In a 4-week oral study1-octadecanol (as a read across forAlcohols, C12-14) was administered daily (5 times/week) in olive oil to groups of 10 male and female Sprague-Dawley rats at levels of 0 (control), 100, 500 and 1000 mg/kg/day. There were no adverse effects reported in this study during all stages of the study (Henkel, 1986).

7. C16-18 and C18 unsaturated alcohols [CAS 68002-94-8] (as a read across for Alcohols, C12-14) were without adverse effects in rats upon daily administration of 1 ml/kg/day (ca.850 mg/kg/day) for 4 weeks (Henkel, 1973).

 

 

 NOAEL -750 mg/kg bw/day for male and female rats.

 

 

Dermal repeated dose toxicity

 

 A 90-day dermal toxicity study in rats with fatty alcohol blend (56.7% decanol, 42.7% octanol) at dose levels of 0, 100, 300, or 1,000 mg/kg resulted in severe irritation at the application site. Severe irritation including fissuring of the skin occurred in 40% of the animals at 100 mg/kg/day and 80% of the animals at the limit dose. Slight changes in hematology, clinical chemistry, and organ weights were noted at the limit dose of 1,000 mg/kg/day.

NOAEL has been based on a local irritation effect rather than a systemic effect. Therefore it is proposed (by the author of the EPSR) that on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.

 

 

Inhalation repeated dose toxicity

 

Under the conditions of the test no treatment-related toxic effects were found in male and female Wistar rats which were exposed to 2-ethylhexanol vapor up to 120 ppm ie. 638.4 mg/m³ . (Klimisch HJ; Deckardt K; Gembardt C; Hildebrand B,1998).The substanceAlcohols, C16-18, the subject of this dossier) is expected to exhibit very similar toxicity due to its close structural similarity to2-ethylhexanol.Comparable metabolism would occur.

 Correcting for molecular weight, a conservative NOAEC of 980.6 mg/m3 can be derived (638.4 x 200) / 130.2 =980.6 mg/m3 

 

 


Justification for selection of repeated dose toxicity dermal - local effects endpoint:
The generic modification from the NOAELtest (in mg/kg of body weight) to NOAELmodified (in mg/cm2/day) will be
NOAELin mg/cm2 = ((dose in mg/kg bw)x (average animal weight in kg)) / Treated surface in cm2)
NOAELtest* 0.25/44.5= NOAELmodified

The highest dose not causing irritation/corrosion was 1000 mg/kg bw in dermal toxicity study in rats of U.S.EPA.1996.
the modified dose descriptor would be
NOAELmodified =1000 mg/kg*0.25 kg/44.5cm2=5.62 mg/cm2

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; other: all gross lesions and masses

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: stomach; other: all gross lesions and masses

Repeated dose toxicity: dermal - systemic effects (target organ) other: all gross lesions and masses

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

Repeated dose toxicity

R33 Danger of cumulative effects.

T; R48/23 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation.

T; R48/23/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin.

T; R48/23/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

T; R48/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin.

T; R48/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed.

T; R48/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure if swallowed.

Xn; R48/20 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation.

Xn; R48/20/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin.

Xn; R48/20/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed.

Xn; R48/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin.

Xn; R48/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed.

Xn; R48/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure if swallowed.

 

CLP

Repeated dose toxicity

STOT Rep. Exp. 1

STOT Rep. Exp. 2

H372: Causes damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

H373: May cause damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

 

It is concluded that the substance Alcohols, C12-14 does not meet the criteria to be classified for human health hazards for Repeated dose toxicity