Registration Dossier

Administrative data

Description of key information

In the key study, no adverse effects were seen after dietary administration of a reliable 13 week oral feeding study in rats using hexadecan-1-ol, resulting in a NOAEL value of >4400 mg/kg bw. (Scientific Assoc, 1966a; rel. 2) In addition read across from a reliable 28 day oral gavage study in rats using octadecan-1-ol reported a NOAEL value of >1000 mg/kg bw (Henkel, 1985a; rel. 2). A four week reliable oral study in rats using octadecan-1-ol reported a NOAEL value of >1000 mg/kg bw, the highest dose tested (Henkel, 1986a; rel. 1). A reliable 26 week oral gavage study in rats using docosan-1-ol reported no adverse effects at the highest dose tested, 1000 mg/kg bw (Iglesias et al., 2002a). Further supporting data come from a 90 day feeding study in rats with of Alcohols, C14-15-branched and linear (Ito et al., 1978) which reported a NOAEL value of >3548 mg/kg bw/day. Read across data from a reliable 13 week dietary study in rats using hexan-1-ol reported a NOAEL of 1127 mg/kg (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
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 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).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
4 400 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

Read across data from the reliable 13 week repeat dose/reproductive oral feeding study in rats using structurally analogous hexadecan-1-ol (Scientific Associates 1966a) will be considered as the basis for classification for docosan-1-ol. The key study was selected from data for substances with similar human health classification 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. A full discussion of the Category can be found in the Human Health Alcohols C6-24 Category report (PFA, 2016). 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).

In a 13-week study in rats hexadecan-1-ol (CAS 36653-82-4) was administered in the diet at concentrations of 0 (control), 1, 2.5 or 5- 10%; the level in the highest dose group being increased stepwise to 10% during the last 3 weeks of the study. Reductios 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 to be equivalent to 4400 mg/kg/day (Scientific Assoc., 1966a).

A read across from a reliable 13 week dietary study in rats using hexan-1-ol reported a NOAEL of 1127 mg/kg. No adverse effects were noted at any of the dose levels administered during the study.

Supporting data are available from a 28 day repeated dose oral 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 (Henkel, 1986). 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 considered to be >1000 mg/kg/day, the highest dose tested.

Further data for octadecan-1-ol comes from a combined repeated dose and reproductive/developmental screen feeding study in which octadecan-1-ol was tested in Wistar rats. Male animals were exposed for 37 days including the mating period, and no treatment-related histopathological changes were recorded. Clinical changes observed were without a dose response and are not considered to be adverse. The NOAEL was established to be 30 000ppm equivalent to 2000 mg/kg/day, the highest dose tested (Hansen, 1992b).

Docosan-1-ol (CAS 661-19-8) was administered daily to groups of rats at levels up to 1000 mg/kg for 26 weeks. Body weight and food consumption was not affected by treatment. Haematology, clinical chemistry and gross necropsy investigations showed no evidence of toxicity. There were no treatment related microscopic changes (Iglesias et al., 2002b).

In a 26-week oral gavage study docosan-1-ol (CAS 661-19-8; C22 alcohol) was administered daily to groups of dogs in levels up to 2000 mg/kg. Body weight and food consumption was not affected by treatment. Haematology, clinical chemistry and gross necropsy investigations showed no evidence of toxicity. There were no treatment related microscopic changes (Iglesias et al., 2002b).

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. NOAELs recorded for this category range between approx. 200 mg/kg/day to >4000 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.’66b)

2

 

C6

111-27-3

Hexan-1-ol

Rat 13 wk

Diet

1127 mg/kg (Sc.Assoc.’66)

2

 

C6

111-27-3

Hexan-1-ol

Rat 3 wk

Diet

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

 

2

C6

111-27-3

Hexan-1-ol

Rat subchronic 30 wk

Intraperit oneal

No peripheral neuropathy (Perbellini et al., 1978)

2

C8

111-87-5

Octan-1-ol

 Rat
 Dev. Tox.

gavage 

130 mg/kg (Hellwig, 1997)

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

2

C9

143-08-8

Nonan-1-ol

 

 

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

 

C10

112-30-1

Decan-1-ol

 

 

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

 

C11

112-42-5

Undecan-1-ol

 

 

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

2

C12

112-53-8

Dodecan-1-ol

Rat 5wk

Diet

2000 mg/kg (Hansen,1992a)

2

C13

112-70-9

1-Tridecan-1-ol (supporting)

Rat 2 wk

Gavage

184 mg/kg (Rhodes, 1984)

2

C14

112-72-1

Tetradecan-1-ol

 

 

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

2

C15

629-76-5

Pentadecan-1-ol

 

 

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

2

C16

36653-82-4

Hexadecan-1-ol

Rat 4 wk

 

 

 

Diet

 

 

>1000 mg/kg (Henkel, 1985a)    

 

2

 

 

C16

36653-82-4

Hexadecan-1-ol

Dog 13 wk

 

Diet

 

>1054 mg/kg (Sc.Assoc,

2

C16

36653-82-4

Hexadecan-1-ol

Rat 13 wk

Diet

 

1966b)          

>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, 2002b)

1

 

C22

661-19-8

Docosan-1-ol

Dog 26 wk

Gavage

2000 mg/kg

(Iglesias, 2002b)

1

C24

506-51-4

Tetracosan-1-ol

 

 

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

 

C8

60435-70-3

2-methylheptan-1-ol

 

 

 

 

C9

68515-81-1

Nonan-1-ol, branched and linear

 

 

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

 

C10

90342-32-8

Decan-1-ol, branched and linear

 

 

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

2

C11

128973-77-3

Undecan-1-ol, branched and linear

 

 

 

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

 

C13

90583-91-8

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

 

 

Low systemic toxicity expected

2

C15

90480-71-0

 

Pentadecan-1-ol, branched and linear

 

 

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

2

C7-9

 

Alcohols, C7-9

Rat 1-wk

 

Rat 1 wk

Gavage

 

Gavage

4175 mg/kg
(Brown, 1970)

128 mg/kg(Rhodes, 1984)

2

 

2

C8-10

 

Fatty Alcohol Blend

rat 90 day

dermal

1000 mg/kg bw/day

(WIL, 1995)

2

C9-11

 

Alcohols, C9-11- branched and linear

Rat 9-day

 

Rat 2 wk

Inhalation

 

Gavage

>0.158 mg/L.(Darmer, 1982)

<4150 mg/kg(Brown, 1970)

2

 

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

C16-17

 

Alcohols, C16-17;

Alcohols, C16-17 -branched and linear;

Alcohols, C16-17-monobranched

 

 

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

 

 

References:

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

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

Justification for classification or non-classification

Based on the data from the 13 week repeat dose studies together with the absence of any treatment related effects in the various types of repeated dose studies that have been conducted within the category, it is concluded that there is no basis for classification and labelling of docosan-1-ol according to Regulation (EC) No 1272/2008.