Alcohols, C12-15-branched and linear

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

 

No studies on toxicity to reproduction performed to international guidelines were available on Alcohols C12-15 branched and linear by any route and the relevant data available from a repeated dose toxicity study are very limited.

The conclusion that the members of the aliphatic alcohol category (C6 to C22) are not expected to impair fertility is based on a weight of evidence approach using data from reproductive screening studies [C12 (dodecanol), C18 (octadecanol) ], a fertility study [C22 (docosanol) ], together with a lack of effect on the reproductive organs in repeat dose studies over the range of linear and essentially linear alcohols. In addition there have been no other treatment related effects reported in any of the other studies both using 1-octadecen-9-enol and other alcohols from the category. Based on this it is concluded that 1-octadecen-9-enol is not expected to impair fertility.

Dodecan-1-ol and octadecan-1-ol have been tested for potential reproductive toxicity in a combined repeat dose reproductive/developmental toxicity screening study in rats. The materials were administered to male and female rats via the diet at concentrations up to 30,000 ppm duringpre-mating, mating and gestation. Pregnancy rates, uterine parameters, time to pregnancy and gestation length indicated that fertility was not affected by exposure to dodecan-1-ol or octadecan-1-ol. There were no microscopic changes observed in the reproductive organs (Hansen, 1992 a,b). Docosan‑1‑ol (C22) did not affect reproductive parameters when administered orally at levels up to 1000 mg/kg/day to male and female rats during pre-mating (10 weeks for males and 2 weeks for females), mating and gestation (Iglesiaset al., 2002b).

 

In a research publication, the test material (Alcohols, C10-16) 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 testis weight relative to body weight; absolute testis weight data were not presented. An NOAEL of 209 mg/kg bw/day was identified from this very limited study (Rhodes et al. 1984).

 

A read-across feeding study reported a lack of effects on the reproductive organs of rats receiving Hexanol (NOAEL 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).

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

Chronic and sub-chronic toxicity studies have shown that long chain alcohols (LCA) are of low toxicity, with no indication of treatment-related systemic effects. Furthermore, combined repeated-dose studies with developmental endpoints, as well as reproductive toxicity screening studies and developmental studies showed no effects at the highest dose tested for any of the Category members for which data are available.

It is concluded that the members of the LCAAs (C6 to C22) are not expected to impair fertility based on the weight of evidence approach using data from reproductive screening studies (C12 - dodecanol, C18 - octadecanol) a fertility study (C22 - docosanol) together with a lack of effect on the reproductive organs in repeat dose studies over the range of linear and essentially linear LCAAs. In addition, weight of evidence from across the category suggests that members of the LCAAs (C6 to C22) are unlikely to cause developmental effects.

The relatively small amounts of absorption that may occur across all common physiological routes (dermal, oral, inhalation) will be rapidly and efficiently metabolised in vivo to the corresponding fatty acid; a substance family which is exempt under REACH. These metabolic products are subsequently rapidly eliminated or may be utilised by biochemical systems in vivo, meaning that bioaccumulation is very unlikely.

It is therefore considered that further reproductive toxicity testing of members of Category is not required.

Fertility data for the Category

Linear Alcohols						Essentially Linear Alcohols
	CAS	CHEMICAL NAME	NOAEL**	Study type* / Species / Effects	Rel.	CAS	CHEMICAL NAME	Study type / Species / Effects	Rel.
			(mg/kg)	(Reference)				(Reference)
C5						123-51-3	Isoamyl alcohol	RDT* Rat: None	2
							Supporting Substance	(Carpanini, 1973)
C6	111-27-3	1-Hexanol	370	RTD*: Dog: none (Sc. Ass. 1966b)	2
				RTD: Rat: none (Sc. Ass. 1966a)
			1127		2
C7	111-70-6	1-Heptanol		Supporting substance			Alcohols, C7-9- linear and branched	Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.
C8	60435-70-3	2-methyl-1-heptanol		Not expected to impair fertility based on read across from structurally analogous substances.
C8	111-87-5	1-Octanol		Not expected to impair fertility based on read across from structurally analogous substances.	2
C9	143-08-8	1-Nonanol		Not expected to impair fertility based on read across from structurally analogous substances.		68515-81-1	Nonanol, branched and linear	Not expected to impair fertility based on read across from structurally analogous substances.
C9							Alcohols, C9-11-branched and linear	Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.
C10	112-30-1	1-Decanol		Not expected to impair fertility, based on read across from structurally analogous substances.		90342-32-8	Decanol, branched and linear	Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.
C11	112-42-5	1-Undecanol		Not expected to impair fertility, based on read across from structurally analogous substances.		128973-77-3	Undecanol, branched and linear	Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.
							Reaction mass of 2-methyldecan-1-ol and 2-propyloctan-1-ol and 2-ethylnonan-1-ol and 2-butylheptan-1-ol
C12	112-53-8	1-Dodecanol	2000**	Fert* Rat: None (Hansen,1992a )	2	75782-86-4	Alcohols, C12-13	No data was available for the C12-13 alcohols for this endpoint. Data was therefore read across from hexanol, docosanol, dodecanol and octadecanol as weight of evidence.
						740817-83-8	Alcohols, C12-13-branched and linear
C12						90604-40-3	Alcohols, C12-15-branched and linear	Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.	2
C13	112-70-9	1-Tridecanol		RDT Rat: None	2	90583-91-8	Tridecanol, branched and linear	Not expected to impair fertility	2
		Supporting		(Rhodes, 1984)			Supporting
C14	112-72-1	1-Tetradecanol		Not expected to impair fertility, based on read across from structurally analogous substances.	2	75782-87-5	Alcohols. C14-15	RDT Rat: None	2
								(Ito, 1978)
C15	629-76-5	1-Pentadecanol		Not expected to impair fertility, based on read across from structurally analogous substances.	2	90480-71-0	Pentadecanol, branched and linear	Not expected to impair fertility, based on read across from structurally analogous substances.
C16	36653-82-4	1-Hexadecanol	1054	RDT Dog: None (Sc. Ass. 1966b)	2		Alcohols, C16-17;	Not expected to impair fertility based on read across from structurally analogous substances used as weight of evidence.
				RDT Rat: None (Sc. Ass. 1966a)			Alcohols, C16-17 -branched and linear;
			2000	RDT Rat: None (Henkel, 1985a)	2		Alcohols, C16-17-monobranched
			1000		2
C16	143-28-2	9-Octadecen-1-ol, (9Z)-		Not expected to impair fertility, based on category approach and read across from structurally analogous substances.	2
C18	112-92-5	1-Octadecanol	2000	Fert. Rat: None (Hansen, 1992b),	2
				RDT Rat None (Henkel, 1986a)
			1000		2
C20	629-96-9	1-Eicosanol		Not expected to impair fertility based on read across from structurally analogous substances.	2
C22	661-19-8	1-Docosanol	>1000	Repro Rat: None (Iglesias, 2002b)	2
				RDT Dog None (Iglesias, 2002a)
			>2000		2
C24	506-51-4	Tetracosanol		Not expected to impair fertility based on read across from structurally analogous substances.

Short description of key information:
No reproductive toxicity studies were available on Alcohols, C12-15-branched and linear. Reproductive screening tests with Dodecan-1-ol and Octadecan-1-ol were without effect on parental or F1 rats at 2000 mg/kg bw/day (Hansen 1992a, Hansen 1992b) and in a one-generation study with Docosanol the NOAEL was 1000 mg/kg bw/day (Iglesias 2002b). A read-across feeding study reported a lack of effects on the reproductive organs of rats receiving Hexanol (NOAEL 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).

Justification for selection of Effect on fertility via oral route:
The selected study was conducted according to an appropriate protocol.

Effects on developmental toxicity

Description of key information

No developmental toxicity studies were available on Alcohols C12-15 branched and linear by any route. In a guideline study with C7-11 branched and linear, the NOAEL for both maternal and developmental toxicity was 1440 mg/kg bw/day (Hellwig & Jackh 1997) and oral NOAELs of 2000 mg/kg bw/day were determined in developmental toxicity screening tests with Dodecanol and Octadecanol (Hansen 1992a, 1992b).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The selected study was conducted according to an appropriate protocol.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

                                      

No developmental toxicity/teratogenicity studies were available on Alcohols C12-15 branched and linear by any route.

 

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 developmental toxicity / teratogenicity studies on single- or multiple-constituent alcohols with appropriate chain lengths can be read across to Alcohols C12-15 branched and linear.

 

A prenatal developmental toxicity study, performed to OECD guideline 414 and to GLP, was performed in rats dosed orally by gavage on days 6 to 15 of gestation with Alcohols C7-11 branched and linear at up to 1440 mg/kg bw/day. No maternal or developmental toxicity was seen and the top dose was therefore the NOAEL (Hellwig & Jackh 1997).

 

In combined repeat dose and reproductive/developmental toxicity screening tests, performed to draft OECD guideline 422 and to GLP, NOAELs of 2000 mg/kg bw/day (the highest dose tested) were determined for Dodecanol and for Octadecanol for both maternal and developmental toxicity (Hansen 1992a, Hansen 1992b).

 

No reliable guideline studies on developmental toxicity/teratogenicity were available on any of the long chain linear aliphatic alcohol family by the dermal routes.

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

There has been no indication of treatment-related effects in any of the developmental toxicity studies conducted in rats or rabbits available for any members of the chemical category. Data are available for linear and methyl-branched essentially linear alcohols with carbon chain lengths from C5 to C34.

The relatively small amounts of absorption that may occur across all common physiological routes (dermal, oral, inhalation) will be rapidly and efficiently metabolised in vivo to the corresponding fatty acid; a substance family which is exempt under REACH and which is an integral component of the conserved metabolic pathways in cells of all living organisms. These metabolic products are subsequently rapidly eliminated or may be utilised by biochemical systems in vivo, meaning that bioaccumulation does not need to be considered.

The mammalian alcohol dehydrogenase system is a group of pathways which catalyse the conversion of alcohols and aldehydes, which includes different forms of the enzymes which vary in substrate specificity. The alcohol dehydrogenases (ADHs) are divided into six classes, denoted by ADH1-ADH6. Five of the six classes of alcohol dehydrogenase have been identified in humans. One of the classes, ADH3, is the ancestral form of all mammalian ADHs, and has been traced in all living species investigated. The alcohol dehydrogenase system is considered to be able to detoxify a wide range of alcohols and aldehydes without the generation of toxic radicals. Therefore the metabolism of all category members would be expected to follow the same pathway in rats and rabbits meaning a developmental toxicity study conducted in rabbits could be expected to have the same result as a rat study.

Three category members have been tested for developmental toxicity data in rabbits. Rabbits administered docosan-1-ol by the oral route and iso-amyl alcohol by the inhalation route showed no evidence of developmental effects. Docosan-1-ol (also known as behenyl alcohol) is a linear primary alcohol with a carbon chain length of twenty-two. Iso-amyl alcohol (also known as 3-methyl-1-butanol) is a single-branched five carbon alcohol. Iso-amyl alcohol has been tested in both rats and rabbits, and no developmental effects were observed in either species. A substance known as D-002 has also been tested in both rats and rabbits, by oral route, at doses of 100, 320 and 1000 mg/kg bw/day. The test substance is a multi-constituent substance comprising linear primary alcohols with carbon chain lengths of C24, C26, C28, C30, C32 and C34. No developmental effects were observed in either species.

It is therefore considered that there are no grounds for further developmental toxicity testing in either rodent or non-rodent species.

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

Developmental data for the Category

Linear Alcohols						Essentially Linear Alcohols
	CAS	CHEMICAL NAME	Study type / Species / Route / Effects	NOAEL	Rel.*	CAS	CHEMICAL NAME	Study type / Species Route / Effects	NOAEL	Rel.*
				(Ref)					(Ref)
C5						123-51-3	Isoamyl alcohol	Dev.Tox Rat Inhalation: None	Mat. 2.5 mg/L	2
							Supporting Substance		Dev. 10 mg/L
								Dev. Tox Rabbit Inhalation: None	(Klimischet al., 1995)
									Mat. 2.5 mg/L	2
									Dev. 10 mg/L
									(Klimischet al., 1995))
C6	111-27-3	1-Hexanol	Dev. Tox Rat Inhalation: None	Mat/Dev. 3.5 mg/L	2
				(Nelson, 1989)
			Dev. Tox rat oral; None	Dev 1000 mg/kg	4
				Mat 200 mg/kg
				(Rodwell, 1988)
							Alcohols, C7-9, branched and linear	Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances used as weight of evidence.
C8	60435-70-3	2-methyl-1-heptanol
C8	111-87-5	1-Octanol	Dev Tox Rat  Inhalat’n: None	Mat/Dev.>0.4 mg/L	2
				(Nelson, 1990, 1996)
				Mat 130 mg/kg       Dev 1300 mg/kg	2
			Dev. Tox Rat Ora: None	(Hellwig et al, 1997)
C9	143-08-8	1-Nonanol	Dev.Tox Rat Inhalat’n: None	Mat/Dev>0.15 mg/L	2	68515-81-1	Nonanol, branched and linear	Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from 1-octanol.
				(Nelson, 1990, 1996)
							Alcohols, C9-11-branched and linear	Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances as weight of evidence.
C10	112-30-1	1-Decanol	Dev.Tox Rat Inhalat’n: None	Mat/Dev >0.1mg/L	2
				(Nelson, 1990a, 1996)
C10						90342-32-8	Decanol, branched and linear	Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances as weight of evidence.
C11	112-42-5	1-Undecanol		Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from dodecanol.		128973-77-3	Undecanol, branched and linear	Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances as weight of evidence.
							Reaction mass of 2-methyldecan-1-ol and 2-propyloctan-1-ol and 2-ethylnonan-1-ol and 2-butylheptan-1-ol
C12	112-53-8	1-Dodecanol	Screen Rat Diet: None	Dev/Mat >2000 mg/kg	2
		Supporting Substance		(Hansen, 1992a)
C12						75782-86-4	Alcohols, C12-13	Not expected to be a developmental toxicant in the absence of maternal toxicity based on read across from structurally analogous substances.
							Alcohols, C12-13-branched and linear
						740817-83-8
C12						90604-40-3	Alcohols, C12-15-branched and linear	Not expected to be a developmental toxicant in the absence of maternal toxicity based on read across from structurally analogous substances as weight of evidence.
C13	112-70-9	1-Tridecanol Supporting Substance	Not expected to be a developmental toxicant in the absence of maternal toxicity			90583-91-8	Tridecanol, branched and linear Supporting Substance	Not expected to be a developmental toxicant in the absence of maternal toxicity
C14	112-72-1	1-Tetradecanol		Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances.		75782-87-5	Alcohols, C14-15	Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances as weight of evidence.
							Alcohols, C14-15-branched and linear
						n/a
C15	629-76-5	1-Pentadecanol		Not expected to be a developmental toxicant in the absence of maternal toxicity
C16	36653-82-4	1-Hexadecanol		Not expected to be a developmental toxicant in the absence of maternal toxicity			Alcohols, C16-17;	Not expected to be a developmental toxicant in the absence of maternal toxicity
							Alcohols, C16-17 -branched and linear;
							Alcohols, C16-17-monobranched
C16	143-28-2	9-Octadecen-1-ol, (9Z)-		Not expected to be a developmental toxicant in the absence of maternal toxicity, based on category approach and read across from structurally related substances.
C18	112-92-5	1-Octadecanol	Screen Rat Diet: None	Dev/Mat >2000 mg/kg	2
				(Hansen, 1992b)
C20	629-96-9	1-Eicosanol		Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances.
C22	661-19-8	1-Docosanol	Dev.Tox Rat gavage: None	Mat/Dev >1000 (Iglesias, 2002b)	2
			Dev. Tox Rabbit Gavage; None	Mat/Dev >2000 mg/kg (Iglesias, 2002b)	2
C24	506-51-4	Tetracosanol		Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances.

Justification for classification or non-classification

Based on the available data, Alcohols C12-15 branched and linear would not be classified as toxic to reproduction under Regulation (EC) No. 1272/2008 (CLP). Tests on similar substances included in this category are also supportive of these results, which do not warrant classification for toxicity to reproduction under GHS criteria.