Dodecan-1-ol

Endpoint summary

Description of key information

There are no reliable long-term repeated dose toxicity data available on dodecan-1-ol (CAS 112-53-8). In the key study, no adverse effects were seen after dietary administration of Alcohols, C14-15-branched and linear for 90 days to rats (Ito et al., 1978) which reported a NOAEL value of >3548 mg/kg bw/day. This value is supported by data from a 13-week from a reliable oral feeding study in rats using hexadecan-1-ol. This study reports a NOAEL value of > 4400 mg/kg bw/day. (Scientific Associates 1966a). In addition a read across 28-day study using octadecan-1-ol (rat, oral gavage), reported a NOAEL >1000 mg/kg bw/day (Henkel, 1985a; rel. 2). A read-across from a reliable 13-week dietary study in rats using hexan-1-ol reported a NOAEL of 1127 mg/kg bw/day (Scientific Associates Inc., 1966). No adverse effects were noted at any of the dose levels administered during the study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats treated via the diet for 90 days with limited evaluation

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: no data but "young"
- Weight at study initiation: males 103.6 g, females 90.5 g
- Fasting period before study: no data
- Housing: individually in suspended wire-mesh cages
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

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

IN-LIFE DATES: no data

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): basal laboratory diet (Purina Laboratory Chow)
- Storage temperature of food: no data

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

continuous in diet

Dose / conc.:

0.25 other: %

Remarks:

nominal in diet

Dose / conc.:

0.5 other: %

Remarks:

nominal in diet

Dose / conc.:

1 other: %

Remarks:

nominal in diet

Dose / conc.:

2 other: %

Remarks:

nominal in diet

Dose / conc.:

4 other: %

Remarks:

nominal in diet

Dose / conc.:

6 other: %

Remarks:

nominal in diet

No. of animals per sex per dose:

10 (treated), 20 (controls)

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: no satellite groups

Positive control:

none

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 5 days/week
- Cage side observations included: general physical appearance, gross signs of systemic toxicity and/or pharmacological effect, behaviour, mortality

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

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

CLINICAL CHEMISTRY: No

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

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

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

HISTOPATHOLOGY: Yes
- brain, thyroid, parathyroid, heart, lung, liver, spleen, stomach, small intestine, large intestine, pancreas, kidney, urinary bladder, adrenal, gonad, lymph node, bone, bone marrow
- all listed tissues from 5/sex from high dose and controls examined

Other examinations:

none

Statistics:

Chi-squared test for comparing relative organ weights (but see 'Any other information on materials and methods')

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
- one male in low dose group died during week 9; cause of death was said to be unrelated to treatment
- occasional bloody encrustations of the eyes and nose
- otherwise no effects

BODY WEIGHT
- no effects

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

FOOD EFFICIENCY
- not examined

WATER CONSUMPTION
- not examined

OPHTHALMOSCOPIC EXAMINATION
- not examined

HAEMATOLOGY
- no effects other than "occasional aberrant value"

CLINICAL CHEMISTRY
- not examined

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

NEUROBEHAVIOUR
- not examined

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

GROSS PATHOLOGY
- no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
- no effects

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- no effects

HISTORICAL CONTROL DATA (if applicable)
- no data

Key result

Dose descriptor:

NOAEL

Effect level:

1 127 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No adverse effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

1 243 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effects observed

Critical effects observed:

no

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

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

to controls. 

Conclusions:

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

Executive summary:

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

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

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 (for males and for females up to day 20 of gestation); macrolon cages type 3 (for females 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:

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): IT chow 101
- Storage temperature of food:no data
- Preparation procedure: 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

Dose / conc.:

1 500 ppm

Remarks:

approx 100 mg/kg bw/day (nominal)

Dose / conc.:

7 500 ppm

Remarks:

approx 500 mg/kg bw/day (nominal)

Dose / conc.:

30 000 ppm

Remarks:

approx 2000 mg/kg bw/day (nominal)

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)

Key result

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

Key result

Dose descriptor:

NOEL

Effect level:

< 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No adverse effect observed

Critical effects observed:

no

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 10^9/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
AbsoluteWeight^a	g	12.27 ± 1.2	11.20* ± 0.8	11.76 ± 1.0	11.98 ± 0.9
Per BodyWeight^a	%	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 bw/day (highest dose tested) was determined in male rats in the absence of toxicologically significant effects at any dose level. . The study was performed in compliance with GLP.

Executive summary:

An oral NOAEL of 2000 mg/kg bw/day (the highest dose tested) was established in rats for dodecan-1-ol, in a combined repeat dose and reproductive/developmental toxicity screening test performed to draft OECD guideline 422 and to GLP (Hansen 1992a).

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

(no ophthalmology or neurobehavioural testing; slightly limited pathology examination; some details missing from report)

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Wistar-SLC

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: 5 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: "cages" (no further details given)
- Diet (e.g. ad libitum): CE-2, made by Nihon Kurea, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 2
- Humidity (%): 60 +/- 5
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): CE-2 solid food, made by Nihon Kurea
- Storage temperature of food: no data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

90 days

Frequency of treatment:

continuously

Dose / conc.:

0.2 other: %

Remarks:

Nominal in diet

Dose / conc.:

1 other: %

Remarks:

Nominal in diet

Dose / conc.:

5 other: %

Remarks:

Nominal in diet

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

3 548 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

11

Control animals:

yes, concurrent no treatment

Details on study design:

Post-exposure period: none

Positive control:

none

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: no data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):  Evaluated twice 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 time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY: Evaluated  twice weekly
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: Weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 90 days
- Anaesthetic used for blood collection: Yes (pentabarbital) (except blood sugar sample, which was taken from the tail vein, apparently without anaesthetic)
- Animals fasted: No data
- How many animals: all
- Parameters checked: sugar, RBC and WBC (by microcell counter), Hb (by cyanomethaemaglobin method), Haemocrit (by capillary centrifugal separation method), platelet count (by platelet counter) and differential  count (i.e. % of WBC; by ointment sample: GIEMSA dye).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 90 days
- Animals fasted: No data
- How many animals: all
- Parameters checked: Alkaline phosphatase activity, ALAT and ASAT (alanine and aspartate transaminase activities), total protein, albumin/globulin ratio, total cholesterol, urea nitrogen, sodium and potassium (using a Greiner electronic selective analyser II); glucose (using enzyme method: Tokyo Zoki Kagaku reagent).

URINALYSIS: Yes, in all animals
- Time schedule for collection of urine: at 90 days
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: pH, protein, sugar, ketone bodies, occult blood (using Labstix by Nihon Emusu)

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC)
Macroscopic: general examination
Organ weights: brain, hypophysis, thyroid, thymus, heart, liver,  kidney, spleen, adrenal, testes or ovaries.
Microscopic: the above mentioned organs plus stomach, pancreas, small &  large intestine, lymph gland, bone marrow.

Other examinations:

none

Statistics:

STATISTICAL METHODS: Student  t test.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Reduced at 1% and 5%

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Reduced at 1% and 5%

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

Increased at 1% and 5%

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Increased relative weight of several organs in males and females at 5%

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significant dose-related effects

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No animals died during the study and clinical signs were unremarkable.

BODY WEIGHT AND WEIGHT GAIN
Reduced at 1% and 5%

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Reduced at 1% and 5% (water consumption was also reduced at these dietary levels). Food loss due to spillage was frequently reported in these groups.

FOOD EFFICIENCY
Increased at 1% and 5%

HAEMATOLOGY
Haemoglobin was significantly reduced in top dose males (15.2 g/dl (SD +-0.5) compared to 15.9 g/dl (SD +-0.4) for controls). 
Eosinophils were significantly reduced at all dose levels in males but  this was not dose related (control 1.5%; low dose 0.6%; mid dose 0.2%;  high dose 0.6%).
White blood cell count was significantly increased in high-dose females (100/mm3: control 47 (SD +- 12.2); top dose 73.2 (SD +-16.2)). This was not accompanied by any significant changes in the  differential leucocyte count. There was no increase in WBC at the low and mid dose (mean values 45.2 and 45.5 respectively).

CLINICAL CHEMISTRY
See Table 1, below.
Alkaline phosophatase (AP) activity increased from 1%; Total protein increased at 1% and 5% in males and at 5% in females. At 5%, alanine aminotransferase activity increased (ALAT), albumin/globulin ratio (AG) increased, (in females) total cholesterol reduced and (in males) potassium increased.

URINALYSIS
No treatment-related changes

ORGAN WEIGHTS
See Table 2, below.
The most significant effects on organ weights were:
Increased relative weight of thyroid, liver and kidney in males and females at 5%.
Decreased absolute weight of brain in males and females at 5%.

At 5%:
Absolute brain & heart weights were decreased in males and females. 
Absolute lung, thymus and hypophysis weights were decreased in males. 
Absolute kidney and spleen  weights were decreased in males (this effect was seen in the mid-dose males as well). 
Absolute liver, kidney and thyroid weights were increased in females.
Relative lung and heart weights were increased in males. 
Relative liver, kidney, adrenal, thyroid and hypophysis weights increased in males (adrenal and thyroid effect also seen in mid-dose males).
Relative thyroid, kidney and liver weights increased in high-dose females (the liver and kidney were also significantly affected in mid-dose females).

No biologically signficant changes in either absolute or relative organ weights were observed at the low-dose level (0.2%).

GROSS PATHOLOGY
No treatment-related effects.
Blood was observed in the stomach of 1 female in each of the mid- and high-dose groups.  There were no other remarkable changes.

HISTOPATHOLOGY: NON-NEOPLASTIC
No significant treatment-related effects.  
Slight kidney changes such as hyaline casts, calculi and increased medullary connective  tissue were observed but these were not dose related. 
In the liver slight focal necrosis was observed in 1/5 low-dose females examined; there  were no histopathological changes in mid- or high-dose groups. 
No  abnormalites were observed in any other organs including the gonads.

Key result

Dose descriptor:

NOAEL

Effect level:

3 548 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Average dose. Effects observed on body weight, food consumption and food efficiency were considered to be attributable to lower food consumption as a result of lack of palatability. Effects noted on clinical chemistry were not considered adverse.

Critical effects observed:

no

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX: The dose levels were based on  the results of a 14 day preliminary study in which 

groups of rats  received 0.5, 1, 3 and 10% Dobanol 45 in the diet. As only the 10% level  showed any fatalities or signs of intoxiciation the 

dose levels for the  90 day study were set at 0.2, 1 and 5% in the diet. These are equivalent  to mean intakes (in mg/kg bw/day) of: 

males 171 (101 -317), females 167 108 -271 (0.2%); 

males 759  (488 -1301), females 736 (523 -1040) (1%); 

males 3626 (2660 -5659), females 3491 (2529 -4802) (5%)


Table 1 - Clinical chemistry: Significant changes from control are as shown below:

Dose          AP          ALAT          T-P          A/G         T-chol          K-
Males         (KA-U)       (K-U)          (g/dl)                    mg/dl          mEq l
Control         13.0         37.7          5.79          1.12          39.5          4.45
0.2%          13.7         46.0          5.93          1.09          40.5          4.66
1%           15.6**        36.5          5.94*          1.14          43.0          4.66
5%           16.4**        71.6**         5.52*          1.25**         42.2          4.93**
Females                                                
Control         12.9         35.3          5.78          1.12          52.1          4.45
0.2%          12.4         36.7          5.83         1.12         52.8           4.36
1%           15.5**        35.8          5.75          1.13        52.6           4.27
5%          19.8**        99.4**         5.55*          1.28**         42.7**          4.38

Table 2 - Organ weights: The more significant changes (either seen in both sexes or dose related) in relative organ weights

expressed in mg/100g (thyroid  & adrenal) or g/100g are shown in the table below. 

Dose         Brain         Thyroid     Testes     Liver       Kidney      Adrenal
Males        
Control        0.57         4.55         0.91         3.14         0.61         11.6
0.2%         0.57         4.72         0.90         3.09         0.59         12.3
1%         0.61**       5.07*       0.98*        3.30         0.62         13.0*
5%         0.71**       5.53**      1.12**      4.08**     0.71*        15.4**

Females                          Ovary                        
Control      0.93        6.05         31.8         2.89         0.61         26.1
0.2%         0.92        6.52         31.0         2.98         0.64         24.8
1%         0.96        6.79         32.0         3.12*        0.65**      26.0
5%         0.96        7.60**      36.8**      3.97**       0.70**      25.9

Conclusions:

In a reliable study, conducted using a protocol similar to OECD guideline 408, male and female rats were fed diets containing 0, 0.2%, 1% or 5% Dobanol-45 (providing average intakes of 169, 747 or 3548 mg/kg bw/day, respectively) for 90 days. Effects seen at doses higher than 0.2% included increased liver enzyme activity (alkaline phosphatase and alanine aminotransferase) and increased relative weights of a number of organs, which is attributable to the reduced body weight due to lower food consumption as a result of lack of palatability. It is considered that the increases in hepatic enzymes are not adverse as there was no associated pathology. It is therefore concluded that the NOAEL is 3548 mg/kg bw/day, the highest dose tested.

Executive summary:

The key study was performed using a protocol similar to OECD guideline 408 but prior to the introduction of GLP. The test material Alcohols, C14-15 branched and linear was administered to rats via the diet for 90 days at concentrations of 0, 0.2, 1 and 5% (providing average intakes of 169, 747 or 3548 mg/kg bw/day, respectively). The top and intermediate dose level (5 and 1%, respectively) had limited palatability and induced a considerable reduction in growth (>30% and approx. 15% reduction in body weight in high and mid dose males, respectively). Biochemistry showed increased liver enzyme activity (alkaline phosphatase and alanine aminotransferase) at the 1 and/or 5% level. It is considered that the increases in hepatic enzymes are not adverse as there was no associated pathology. The increase in relative weights of a number of organs is attributable to the reduced body weight due to lower food consumption as a result of lack of palatability. No treatment-related microscopic changes were observed, including both the testis and ovaries at this same dose level. Based on the effect on body weight a NOAEL was established at the 5% dietary incorporation level (approx. 3548 mg/kg/day) (Ito et al., 1978).

Reference 4

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Report in German language, English summary page.

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:

yes

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

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

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

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed

Critical effects observed:

no

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. The study was performed in compliance with GLP.

Executive summary:

Using a protocol similar to OECD guideline 407, a GLP study, in which male and female rats were administered hexadecan-1-ol by oral gavage on 5 days/week for 28 days, established an NOAEL of >1000 mg/kg bw/day, the highest dose tested (Henkel 1985a).

Reference 5

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Remarks:

Valid with restrictions including lack of biochemical investigations and limited reporting of statistical findings

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 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

Dose / conc.:

1 other: %

Remarks:

nominal in diet

Dose / conc.:

2.5 other: %

Remarks:

nominal in diet

Dose / conc.:

5 other: %

Remarks:

nominal in diet

Dose / conc.:

7.5 other: %

Remarks:

nominal in diet

Dose / conc.:

10 other: %

Remarks:

nominal in diet

No. of animals per sex per dose:

10 (treated), 20 (controls)

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: no satellite groups

Positive control:

none

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 5 days/week
- Cage side observations included: general physical appearance, gross signs of systemic toxicity and/or pharmacological effect, behaviour, mortality

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

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

CLINICAL CHEMISTRY: No

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

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

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

HISTOPATHOLOGY: Yes
- brain, thyroid, parathyroid, heart, lung, liver, spleen, stomach, small intestine, large intestine, pancreas, kidney, urinary bladder, adrenal, gonad, lymph node, bone, bone marrow
- all listed tissues from 5/sex from high dose and controls examined

Other examinations:

none

Statistics:

Chi-squared test for comparing relative organ weights. 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

Key result

Dose descriptor:

NOAEL

Effect level:

> 4 257 other: mg/kg (bw) based on highest dose tested.

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No adverse effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

> 4 567 other: mg/kg (bw) based on highest dose tested.

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effects observed

Critical effects observed:

no

Conclusions:

In a reliable study, in which rats were treated with Alfol 16 via the diet for 13 weeks, an NOAEL of >4400 mg/kg bw/day (highest dose tested) was determined. Reduced weight gain, food consumption and organ weight changes were deemed to be secondary to the high dose administered but not specific to the test substance.

Executive summary:

For hexadecan-1-ol, oral NOAELs were > 4257 and > 4567 mg/kg bw/day in male and female rats respectively in a 90-day repeated dose toxicity test in which a somewhat limited range of endpoints was evaluated (Scientific Associates 1966a).

Reference 6

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily, 5 days/week

Dose / conc.:

100 other: mg/kg in olive oil

Dose / conc.:

500 other: mg/kg in olive oil

Dose / conc.:

1 000 other: mg/kg in olive oil

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: 28 days

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effect observed

Critical effects observed:

no

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 bw/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.

Executive summary:

Data are available from a 28-day repeated dose oral toxicity study in which octadecan-1-ol was administered by oral gavage to male and female rats at 0, 100, 500, 1000 mg/kg bw/day. 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, so the NOAEL is concluded to be >1000 mg/kg/day, the highest dose tested.

Reference 7

Endpoint:

repeated dose toxicity: oral, other

Remarks:

sub-chronic; short-term

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

1. HYPOTHESIS FOR THE CATEGORY APPROACH
The hypothesis is that the category members have similar structures and properties (absence of repeated dose toxicity effects via the oral route), which are consistent across the category (Scenario 6 in the RAAF). The consistency of this property across the category is discussed in the endpoint summary.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to the test material identity information within each endpoint study record.

The long chain linear aliphatic alcohol Category has at its centre a homologous series of increasing carbon chain length alcohols. The category members are structurally very similar. They are all primary aliphatic alcohols with no other functional groups. The category members are linear or contain a single short-chain side-branch at the 2-position in the alkyl chain (usually an α-methyl or α-ethyl group), which does not significantly affect the properties (‘essentially linear’). The category members have saturated alkyl chains or contain a small proportion of naturally-occurring unsaturation(s) which does not significantly affect the properties. Linear, branched and unsaturated structures are considered to have such similar properties, including metabolic pathways and products, that their inclusion in the category is well justified.
Impurities: Linear and/or ‘essentially linear’ long chain aliphatic alcohols of other chain lengths may be present. These are not expected to contribute significantly to the properties in respect of this endpoint due to predictable trends (see point 3).
There are no impurities present at above 1% which are not category members or which would affect the properties of the substance.

3. CATEGORY JUSTIFICATION
The category members are structurally very similar (see point 2) and are biochemically very similar. The metabolic synthesis and degradation pathways are well established. This Category is associated with a consistency and predictability in the physicochemical, environmental, and toxicological property data across its members.

The consistency of observations in this property across the range of chain lengths covered by this Category is described in the Endpoint Summary and in the Category Report attached in Section 13.

In this registration, the information requirement is interpolated based on read-across from members of the category with shorter and longer chain length, providing evidence of consistency in effects irrespective of variation in physico-chemical properties of specific category member substances.

4. DATA MATRIX
A data matrix for the C6-24 alcohols Category is attached in Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

3 548 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Average dose. Effects observed on body weight, food consumption and food efficiency were considered to be attributable to lower food consumption as a result of lack of palatability. Effects noted on clinical chemistry were not considered adverse.

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

3 548 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A combined repeat dose and reproductive/developmental toxicity screening test is available for dodecan-1-ol. The key study was selected from data for substances with similar human health and physicochemical properties and therefore absorption properties to the registration substance. As no adverse systemic effects were observed for category members, the study using the highest dose from the available data was selected as key. The available repeated dose toxicity data for long chain alcohols have been reviewed and discussed, with the conclusion that the long chain alcohols are of low systemic toxicity (Veenstra G, Webb C et al., 2009). A full discussion of the Category and considerations of RAAF Assessment Entities can be found in the Human Health Alcohols C6-24 Category report (PFA, 2021).

The key study was performed using a protocol similar to OECD Test Guideline 408 but prior to the introduction of GLP. The test material Alcohols, C14-15 branched and linear was administered to rats via the diet for 90 days at concentrations of 0, 0.2, 1 and 5% (providing average intakes of 169, 747 or 3548 mg/kg bw/day, respectively). The top and intermediate dose level (5 and 1%, respectively) had limited palatability and induced a considerable reduction in growth (>30% and approx. 15% reduction in body weight in high and mid dose males, respectively). Biochemistry showed increased liver enzyme activity (alkaline phosphatase and alanine aminotransferase) at the 1 and/or 5% level. It is considered that the increases in hepatic enzymes are not adverse as there was no associated pathology. The increase in relative weights of a number of organs is attributable to the reduced body weight due to lower food consumption as a result of lack of palatability. No treatment-related microscopic changes were observed, including both the testis and ovaries at this same dose level. Based on the effect on body weight a NOAEL was established at the 5% dietary incorporation level (approx. 3548 mg/kg/day) (Ito et al., 1978).

The Category hypothesis is that the long chain linear aliphatic alcohol category has at its centre an homologous series of increasing carbon chain length, which is associated with a consistency and predictability in the property data across the group, for the physicochemical, environmental and toxicological property data sets. In view of the structural and chemical similarities, it is considered that the results from a number of reliable repeated dose toxicity studies on single- or multiple-constituent alcohols with appropriate chain lengths can be read across to dodecan-1-ol. A full discussion of the Category can be found in the Human Health Alcohols C6-24 Category report (PFA, 2021).

For hexan-1-ol, oral NOAELs were 1127 and 1243 mg/kg bw/day (the highest doses tested) in male and female rats respectively in a 90-day repeated dose toxicity test in which a somewhat limited range of endpoints was evaluated (Scientific Associates 1966a).

For hexadecan-1-ol, oral NOAELs were > 4257 and > 4567 mg/kg bw/day in male and female rats respectively in a 90-day repeated dose toxicity test in which a somewhat limited range of endpoints was evaluated (Scientific Associates 1966a). Using a protocol similar to OECD guideline 407, a GLP study, in which male and female rats were administered hexadecan-1-ol by oral gavage on 5 days/week for 28 days, established an NOAEL of >1000 mg/kg bw/day, the highest dose tested (Henkel 1985a).

An oral NOAEL of 2000 mg/kg bw/day (the highest dose tested) was established in rats for dodecan-1-ol, in a combined repeat dose and reproductive/developmental toxicity screening test performed to draft OECD guideline 422 and to GLP (Hansen 1992a). No maternal toxicity was seen in rats after oral gavage dosing with Alcohols C7-11 branched and linear at up to 1440 mg/kg bw/day on days 6 to 15 of gestation and this top dose was therefore the NOAEL (Hellwig & Jäckh 1997).

A sub-acute oral study is available for Alcohols, C12-13, branched and linear in which the test substance was administered by oral gavage. The study was conducted to OECD guideline 407 and in compliance with GLP (TNO, 1999). The study authors concluded a NOAEL of 300 mg/kg bw/day, however the reported liver findings were not accompanied by histopathological changes and it is concluded that the NOAEL is 1000 mg/kg bw/day.

For Alcohols, C12-16, data are available from a research publication in which the test material was dissolved in polyethylene glycol 300 and administered to male rats by oral gavage at 209 mg/kg bw/day for 14 days. There were no adverse effects on the small number of endpoints measured (liver and testis weight and histopathological examination of the liver). An NOAEL of 209 mg/kg bw/day was identified from this limited study (Central Toxicology Laboratory, 1984).

In a limited study, conducted prior to the introduction of GLP, Alcohols C16-18 and C18 unsaturated. was administered to male and female at a single dose level of 840 mg/kg bw/day by oral gavage and no toxicity was reported (Henkel 1973).

No repeated dose toxicity studies were available on any of the long chain linear aliphatic alcohol category by the dermal route. No reliable guideline repeated dose toxicity studies were available on any of the relevant members of the long chain linear aliphatic alcohol category by the inhalation route.

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

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

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

Conclusion:

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

Repeated dose toxicity data for the Category

	CAS	CHEMICAL NAME	Species/ Study type/ Duration 1	Route	NOAEL   (Ref)	Rel.
C5	123-51-3	Isoamyl alcohol (supporting)	Rat 17 wk	Gavage	500 mg/kg (Carpanini, 1973)	2
C6	111-27-3	Hexan-1-ol	Dog 13 wk	Diet	370 mg/kg (Sc.Assoc.1966b)	2
C6	111-27-3	Hexan-1-ol	Rat 13 wk	Diet	1127 mg/kg (Sc.Assoc.1966)	2
C6	111-27-3	Hexan-1-ol	Rat 3 wk	Diet	1000 mg/kg bw/day (Moody, 1978-1982)	2
C8	111-87-5	Octan-1-ol	Rat  Dev. Tox.	gavage	130 mg/kg (Hellwig, 1997) No systemic toxicity expected based on read across of a dermal study on Fatty Alcohol Blend of which octan-1-ol is a constituent, and on read-across from an oral study on hexan-1-ol. No adverse systemic effects were observed at the highest dose in either study.	2
C9	143-08-8	Nonan-1-ol			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.
C10	112-30-1	Decan-1-ol			No systemic toxicity expected based on read across of a dermal study on Fatty Alcohol Blend of which decan-1-ol is a constituent, and on read-across from an oral study on hexan-1-ol. No adverse systemic effects were observed at the highest dose in either study.
C11	112-42-5	Undecan-1-ol			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.	2
C12	112-53-8	Dodecan-1-ol	Rat 5wk	Diet	2000 mg/kg (Hansen,1992a)	2
C13	112-70-9	1-Tridecan-1-ol (supporting)	Rat 2 wk	Gavage	184 mg/kg (Rhodes, 1984)	2
C14	112-72-1	Tetradecan-1-ol			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.	2
C15	629-76-5	Pentadecan-1-ol			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.	2
C16	36653-82-4	Hexadecan-1-ol	Rat 4 wk	Diet	>1000 mg/kg (Henkel, 1985a)	2
C16	36653-82-4	Hexadecan-1-ol	Dog 13 wk	Diet	>1054 mg/kg (Sc.Assoc, 1966b)	2
C16	36653-82-4	Hexadecan-1-ol	Rat 13 wk	Diet	>4257 mg/kg (Sc.Assoc, 1966a)	2
C18	112-92-5	Octadecan-1-ol	Rat 4 wk   Rat 5 wk	Gavage   Diet	>1000 mg/kg (Henkel, 1986a) 2000 mg/kg (Hansen, 1992b)	1   2
C18	143-28-2	9-Octadecen-1-ol, (9Z)-			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.	2
C20	629-96-9	Icosanan-1-ol			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.	2
C22	661-19-8	Docosan-1-ol	Rat 26 wk	Gavage	1000 mg/kg (Iglesias,2002a)	1
C22	661-19-8	Docosan-1-ol	Dog 26 wk	Gavage	2000 mg/kg (Iglesias,2002b)	1
C24	506-51-4	Tetracosan-1-ol			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.
C8	60435-70-3	2-methylheptan-1-ol
C9	68515-81-1	Nonan-1-ol, branched and linear			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.
C10	90342-32-8	Decan-1-ol, branched and linear			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.	2
C11	128973-77-3	Undecan-1-ol, branched and linear			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.
C13	90583-91-8	Tridecan-1-ol, branched and linear (supporting)			Low systemic toxicity expected	2
C15	90480-71-0	Pentadecan-1-ol, branched and linear			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.	2
C7-9		Alcohols, C7-9	Rat 1-wk   Rat 1 wk	Gavage   Gavage	4175 mg/kg (Brown, 1970) 128 mg/kg(Rhodes, 1984)	2   2
C8-10		Fatty Alcohol Blend	rat 90 day	dermal	1000 mg/kg bw/day (WIL Research, 1995)	2
C9-11		Alcohols, C9-11	Rat 2 wk	Gavage	<4150 mg/kg(Brown, 1970)	2
C9-11		Alcohols, C9-11- branched and linear	Rat 9-day	Inhalation	<4150 mg/kg(Brown, 1970)	2
C11		Reaction mass of 2-methyldecan-1-ol and 2-propyloctan-1-ol and 2-ethylnonan-1-ol and 2-butylheptan-1-ol			No systemic toxicity expected based on data for category indicating no adverse systemic effects at highest dose tested.
C12-13	75782-86-4	Alcohols, C12-13	Rat 4wk	Gavage	300 mg/kg; (Sasol, 1999	1
C12-13	740817-83-8	Alcohols, C12-13-branched and linear	Rat 4wk (read-across)	Gavage	300 mg/kg; (Sasol, 1999	1
C12-15	90604-40-3	Alcohols, C12-15-branched and linear	Rat 2 wk	Gavage	209 mg/kg(Rhodes, 1984)	2
C14-15	75782-87-5	Alcohols, C14-15	Rat 90 day	Diet	167 mg/kg; (Ito, 1978)	2
C14-15		Alcohols, C14-15-branched and linear	Rat 90 day (read-across)	Diet	167 mg/kg; (Ito, 1978)	2

References

PFA (2021). C6-24 Alcohols Category Report: Human Health. Version number: 01. Peter Fisk Associates Ltd. 2021.

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

 

Justification for classification or non-classification

Based on the available data dodecan-1-ol would not be classified for specific target organ toxicity-repeated exposure according to Regulation (EC) No. 1272/2008 (CLP) since no adverse effects occurred at <100 mg/kg bw/day. Tests on similar substances included in this category are also supportive of these results, which do not warrant classification under GHS criteria.