Docosan-1-ol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No key reproductive toxicity studies are available on docosan-1-ol. There is a testing proposal for an oral extended one-generation reproductive toxicity study on docosan-1-ol, to be performed according to OECD Test Guideline 443 and in compliance with GLP, after approval from ECHA.

A combined repeated dose toxicity study with the reproduction/ developmental toxicity screening test has been commissioned with the registered substance and will be conducted according to OECD Test Guideline 422 and in compliance with GLP.  

This new data will be used as dose-range finder for an extended one-generation reproductive toxicity study (EOGRTS) and bridging data to support reading across EOGRTS between Category members.

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Remarks:

Category data waiver as interim measure

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

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 C24) are not expected to impair fertility is based on a weight of evidence approach using data from reproductive screening studies [C12 (dodecan-1-ol), C18 (octadecan-1-ol)], together with a lack of effect on the reproductive organs in repeat dose studies over the range of linear and essentially linear alcohols. The available data have been reviewed and discussed (Veenstra G, Webb C et al., 2009). Based on this it is concluded that docosan-1-ol is not expected to impair fertility.

The read-across substances were chosen as representative of the lack of effects of the category. A full discussion of the Category can be found in the Human Health Alcohols C6-24 Category report (PFA, 2022).

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 during pre-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, Institute of Toxicology, 1992b). 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 (Iglesias et al., 2002a).

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 (Central Toxicology Laboratory, 1984).

A feeding study reported a lack of effects on the reproductive organs of rats receiving hexan-1-ol (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 studiesshowed 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 – dodecan-1-ol, C18 – octadecan-1-ol) 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 thatmay 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 systemsin vivo,meaning that bioaccumulation is very unlikely.

Effects on developmental toxicity

Description of key information

In a key study conducted according to a protocol similar to OECD Test Guideline 414 (in rats), with the registered substance docosan-1-ol, the NOAEL for developmental toxicity was at least 1000 mg/kg bw/day (highest dose tested) (Iglesias 2002).

No reliable developmental toxicity studies in rabbits are available on docosan-1-ol.

There is a testing proposal for an oral developmental toxicity study in second species (rabbits) on docosan-1-ol, to be performed according to OECD Test Guideline 414 and in compliance with GLP, after approval from ECHA.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

without detailed documentation

Principles of method if other than guideline:

Method: other

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

oral: gavage

Duration of treatment / exposure:

For 15 days prior to mating, during mating and up to Day 17 of gestation.

Frequency of treatment:

daily

Dose / conc.:

10 mg/kg bw/day

Dose / conc.:

100 mg/kg bw/day

Dose / conc.:

1 000 mg/kg bw/day

Control animals:

yes

Details on study design:

Sex: female
Duration of test: 20th day of gestation

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

no

All female rats survived to sacrifice and no maternal toxicity was  observed. The were no differences between treated and control animals in  any of the rerpoductive endpoints investigated (corpora lutea, pre & post  implantation sites, early & late resorption sites).  The litter size,  foetal weight and sex ratio observed in treated groups was comparable to  the control group.  There were no unusual macroscopic findings among  foetuses. Microscopic examination did not show any increased incidence of  anomalies in skeletal or soft tissues. See above chapter 5.8.1 for  further details.

Conclusions:

1000 mg/kg/day is the NOAEL for maternal toxicity, teratogenicity and foetotoxicity in rats receiving behenyl alcohol by gavage for 15 days premating, during mating and up until gestation day 17. This is based on the absence of adverse effects in any of the parental, reproductive or foetal parameters examined.

Reference 2

Endpoint:

developmental toxicity

Remarks:

Category data waiver as interim measure

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Species:

rabbit

Abnormalities:

not specified

Developmental effects observed:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

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:

The Category hypothesis is that the long chain linear aliphatic alcohol family is 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, in addition to data on docosan-1-ol itself, 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 docosan-1-ol. A full discussion of the Category can be found in the Human Health Alcohols C6-24 Category report (PFA, 2022).

Docosan-1-ol 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 (Iglesias et al., 2002b).

In combined repeat dose and reproductive/developmental toxicity screening tests, performed according to draft OECD guideline 422 and in compliance with GLP, NOAELs of 2000 mg/kg bw/day (the highest dose tested) were determined for dodecan-1-ol and for octadecan-1-ol for both maternal and developmental toxicity (Hansen, 1992a, Hansen,1992b).

Similarly, no maternal or developmental toxicity was observed in developmental toxicity studies in rabbits using with docosan-1-ol and in rats and rabbits with C24-C34 alcohols (Iglesias, 2002a; Rodriguez, 1998).

In a prenatal developmental toxicity study, performed according to OECD guideline 414 and in compliance with GLP, rats were 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 & Jäckh, 1997).

In a prenatal developmental toxicity study, performed according to OECD guideline 414 and in compliance with GLP, rats were dosed orally by gavage on days 6 to 15 of gestation with octan-1-ol at 130, 650, 975 or 1300 mg/kg bw/day. A dose-dependent increase in maternal toxicity was observed, with a LOAEL of 130 mg/kg bw/day. The NOAEL for foetal toxicity was determined to be 1300 mg/kg bw/day, the highest dose tested (Hellwig & Jäckh, 1997).

Developmental toxicity studies are available for several alcohols on both rats and rabbits, and no developmental effects have been observed in either species.

Whole body inhalation studies conducted in rats with octan-1-ol, decan-1-ol, nonan-1-ol (Nelson, 1990) and hexan-1-ol (Nelson, 1989) were also available, which confirmed that the alcohols of this category do not cause any developmental effects up to the maximum achievable concentrations.

Therefore, based on the weight of evidence from other alcohols across the category, it is concluded that docosan-1-ol is unlikely to cause developmental effects.

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 (Klimish, 1995) 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 (Rodriguez, 1998). 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.

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.

Justification for classification or non-classification

Based upon the above current available information, 1-docosan-1-olol is does not required to be classified classification for reproductive and developmental toxicity in accordance with EU guidelinesto Regulation (EC) No 1272/2008.