Registration Dossier

Administrative data

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:
subchronic
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

Reproduction: 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.

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:
Read across from reliable oral study in rats with 1-octadecanol reported a parental NOAEL of 2000 mg/kg bw/day and the NOAEL for reproductive and developmental effects as 2000 mg/kg bw/day (highest dose level) (Hansen 1992, rel 2). A read across feeding studies reported a lack of effects on the reproductive organs of rats receiving 1 -hexanol (NOAEL 1127 mg/kg) (Scientific Associates Inc., 1966, rel; 2). No adverse effects were noted at any of the dose levels administered during the study.

In addition read across from a reliable one-generation reproduction study using 1-docosanol in rats reported a NOAEL of 1000 mg/kg. (Iglesias 2002b;rel 2)

Justification for selection of Effect on fertility via oral route:
The results for repeated oral exposure are based on read across data from a octadecan-1-ol and docosan-1-ol feeding study. These two studies report NOAEL values of > 2000 mg/kg bw (octadecan-1-ol) based on an OECD 422 study (Hansen 1992) and >1000 mg/kg bw/day based on a screening study for docosan-1-ol (Iglesias, 2002b).

Effects on developmental toxicity

Description of key information
Read across from  reliable oral study in rats with 1-octadecanol reported a  foetal NOAEL of 2000 mg/kg bw/day (the highest dose tested) and the NOAEL for developmental effects as 2000 mg/kg bw/day (highest dose level) (Hansen 1992, rel 2).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
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

Developmental effects: Based on the weight of evidence from other alcohols across the category and the combined repeat dose/reproductive/developmental study with octadecan-1-ol, (Hansen 1992, rel; 2) it is concluded that (z)-octadecen-9-enol is unlikely to be a developmental toxicant in the absence of maternal toxicity.

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 decan-1-ol 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 menbers 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

2

 

 

 

 

 

Dev. Tox Rabbit Gavage; None

(Iglesias, 2002b)

 

 

 

 

 

Mat/Dev >2000

2

 

mg/kg

 

 

(Iglesias, 2002b)

 

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 selection of Effect on developmental toxicity: via oral route:
The results for repeated oral exposure are based on read across data from a dodecan-1-ol (Hansen, 1992)

Justification for classification or non-classification

Based upon the above information, (Z)-octadecen-9-enol is not required to be classified in accordance with Regulation (EC) No. 1272/2008.