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Description of key information

In the key study, no adverse effects were seen after dietary administration of Alcohols, C14-15-branched and linear for 90 days to rats Alcohols, C12-15-branched and linear (Ito et al., 1978).  This is supported by a limited study in which no adverse effects were seen in the liver or testis after oral administration of Alcohols C12-15 branched and linear to male rats at 209 mg/kg bw/day for 14 days (Rhodes et al. 1984). A read-across from a reliable 13-week dietary study in rats using Hexanol reported a NOAEL of 1127 mg/kg bw/day and no adverse effects were noted at any of the dose levels administered during the study (Scientific Associates Inc. 1966).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

No repeated dose toxicity studies performed to international guidelines were available on Alcohols C12-15-branched and linear by any route, but one oral study with limitations has been reported.

 

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).

The Category hypothesis is that the long chain linear aliphatic alcohol family 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 Alcohols C12-15 branched and linear.

For Hexanol, 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 Hexadecanol, 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 Hexadecanol 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 Dodecanol, 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 & Jackh 1997).

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 (Rhodes et al. 1984).

 

In a limited study, conducted prior to the introduction of GLP, Alcohols C16-18 and C18 unsatd. 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 family 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 family 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 ofdepression and respiratory effects when administered at very high dose levels and only as a bolus dose (C6, C8 alcohol) in the dog (C6 alcohol) and the rat (C8 alcohol). Other routes of exposure induced no apparent neurotoxicity either centrally or peripherally. Intermediate (>C8 to C12) and higher (>C12) linear LCAAs are non-irritant at the site of first contact and are without a neurotoxic potential. At high dose levels some of the higher LCAAs showed changes in clinical chemistry and liver weight but without further evidence of systemic toxicity; this finding may be indicative of mild, sub-clinical effects in the liver. There are no species differences observed for this sub-category, based on a comparison of the results of parallel studies in the rat and the dog. In summary, the data for the essentially linear LCAAs, including the data from supporting substances, indicate a low order of toxicity upon repeated exposure. A consistent finding for this group is the effect on the liver: mild organ weight increases and/or slight clinical chemical changes but without evidence of significant histopathological effects. The clinical chemistry changes were generally of a slight grade but showed some inconsistencies, some of which relating to decreases in transferase activity, a change not normally associated with adverse hepatic effects. The (small) degree of the liver weight increases, the pattern of the clinical chemical changes and the absence of markers support the conclusion that this sub-category of LCAAs lacks a potential for the induction of peroxisomal proliferation. There is evidence of irritation at the first site of contact for the lower members of this group. Conclusion: The repeat dose toxicity of the category of LCAAs with chain lengths ranging from C6 to C22 indicates a low order of toxicity upon repeated exposure. Typical NOAEL’s recorded for this category range between approx. 200 mg/kg/day to 1000 mg/kg/day in the rat upon sub-chronic administration via the diet. No adverse systemic effects have been seen in reliable studies with members of the Category of C6-24 Alcohols, therefore the NOAELs represent the highest dose tested. At the lower end, members of this category induce local irritation at the site of first contact. Other notable findings observed for several members within this group suggest mild changes consistent with low-grade liver effects with the changes in essentially linear LCAAs being slightly more pronounced than in linear alcohols. Typical findings include: slightly increased liver weight, in some cases accompanied by clinical chemical changes but generally without concurrent histopathological effects. Special studies demonstrated that this category does not have a potential for peroxisome proliferation. A potential for depression as observed for short chain aliphatic alcohols (C1 to C4; not included in this category) was also identified for 1-hexanol and 1-octanol, however this effect was only expressed upon repeated administration of a bolus dose; effects were absent upon inhalation or dietary administration. Similarly, 1-hexanol and 1-octanol induced respiratory distress upon repeated administration of a bolus dose. LCAAs do not have a potential for peripheral neuropathy. Furthermore, the data from the substances supporting this category (i.e. isoamyl alcohol), demonstrate that the toxicological profile of the repeated dose toxicity of 100% branched alcohols is qualitatively similar to that of the corresponding essentially linear alcohols. Chronic and sub-chronic toxicity studies have shown that LCAAs are of low toxicity. Furthermore, combined repeated-dose studies with developmental endpoints, as well as reproductive and developmental studies showed no effects at the highest dose tested. Where data gaps exist, the gap is filled by read-across from reliable evidence within the C6-24 Alcohols Category, where possible using interpolation between at least two reliable studies using higher and lower carbon number test substances. Repeated dose toxicity data for the Category

Linear Alcohols

Essentially Linear Alcohols

 

CAS

CHEMICAL NAME

Species/ Study type/

Duration1

Route

NOAEL

 

(Ref)

Rel.

CAS

CHEMICAL NAME

Species/

Study type/ Duration1

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

 

 

 

 

 

 

 

Rat 13 wk

Diet

1127 mg/kg (Sc.Assoc.’66)

2

 

Rat 3 wk

Diet

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

 

2

Rat subchronic 30 wk

Intraperit oneal

No peripheral neuropathy (Perbelliniet al., 1978)

2

C7

 

 

 

 

 

 

 

Alcohols, C7-9

Rat 1-wk

Gavage

4175 mg/kg
(Brown, 1970)

128 mg/kg

2

Rat 1 wk

Gavage

128 mg/kg(Rhodes, 1984)

2

C8

60435-70-3

2-methylheptan-1-ol

 

 

 

 

 

 

 

 

 

 

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

 

 

 

 

 

 

C8

 

 

 

 

 

 

 

Fatty Alcohol Blend

rat 90 day

dermal

1000 mg/kg bw/day

(WIL, 1995)

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.

 

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.

 

C9

 

 

 

 

 

 

 

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

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.

 

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.

 

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

128973-77-3

Undecan-1-ol, branched and linear

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

112-53-8

Dodecan-1-ol

Rat 5wk

Diet

2000 mg/kg (Hansen,1992a)

2

75782-86-4

Alcohols, C12-13

 

Rat 4wk

 

 

Gavage

 

300 mg/kg; (Sasol, 1999

 

1

C12

 

 

 

 

 

 

740817-83-8

Alcohols, C12-13-branched and linear

 

Rat 4wk (read-across)

 

 

Gavage

 

300 mg/kg; (Sasol, 1999

 

1

C12

 

 

 

 

 

 

90604-40-3

Alcohols, C12-15-branched and linear

Rat 2 wk

 

Gavage

 

209 mg/kg(Rhodes, 1984)

2

C13

112-70-9

1-Tridecan-1-ol (supporting)

Rat 2 wk

Gavage

184 mg/kg (Rhodes, 1984)

2

90583-91-8

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

 

 

Low systemic toxicity expected

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

75782-87-5

Alcohols, C14-15

Rat 90 day

Diet

167 mg/kg;
(Ito, 1978)

2

C14

 

 

 

 

 

 

 

Alcohols, C14-15-branched and linear

Rat 90 day (read-across)

Diet

167 mg/kg;
(Ito, 1978)

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

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

C16

36653-82-4

Hexadecan-1-ol

Rat 4 wk

 

Dog 13 wk

 

Rat 13 wk

Diet

 

Diet

 

Diet

>1000 mg/kg (Henkel, 1985a)    

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

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

2

 

2

2

 

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.

 

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

 

 

 

 

 

 

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

 

 

 

 

 

 

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

 

Dog 26 wk

Gavage

 

Gavage

1000 mg/kg

(Iglesias,2002a)

2000 mg/kg

(Iglesias,2002a)

1

 

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.

 

 

 

 

 

 

 



Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The selected study was conducted according to a protocol similar to an appropriate OECD guideline using structural analogue Alcohols, C14-15, branched and linear.

Justification for classification or non-classification

Based on the available data, Alcohols C12-15 branched and linear would not be classified for specific target organ toxicity-repeated exposure under Regulation (EC) No. 1272/2008 (CLP) since no adverse effects occurred at <100 mg/kg bw/day, since no adverse effects occurred at <50 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.