Tetradecanol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproductive toxicity studies are available on tetradecan-1-ol.

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test is 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

Reference 1

Endpoint:

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

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Reference 2

Endpoint:

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

Data waiving:

other justification

Justification for data waiving:

other:

Effect on fertility: via oral route

Endpoint conclusion:

no study available (further information necessary)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

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 tetradecan-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 and considerations of RAAF Assessment Entities can be found in the Human Health Alcohols C6-24 Category report (PFA, 2021).

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, 1992a and 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. A 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. No effects in reproductive organs have been observed in repeated dose studies with any category member (Scientific Associates Inc. 1966).

A 90-day dietary repeat dose study on alcohols, C14-15 showed an absence of effects on reproductive organs (Ito, 1978). In this study relative testes and ovary weights were increased at the 1% and/or 5% incorporation level, but at these levels a considerable reduction in bodyweight gain due to inanition was induced. The effects on relative organ weights were considered to be associated with the effects on body weight rather than a direct toxic effect. More importantly, there was no evidence of microscopic changes in the gonads (Ito, 1978).

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 – dodecan-1-ol, C18 – octadecan-1-ol) a fertility study (C22 – docosan-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 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.

Fertility data for the Category

 

 

	CAS	CHEMICAL NAME	NOAEL** (mg/kg)	Study type* / Species / Effects (Reference)	Rel.
C5	123-51-3	Isoamyl alcohol Supporting Substance		RDT* Rat: None (Carpanini, 1973)	2
C6	111-27-3	Hexan-1-ol	370	RDT*: Dog: none (Sc. Ass. 1966b)	2
C6	111-27-3	Hexan-1-ol	1127	RDT: Rat: none (Sc. Ass. 1966a)	2
C7	111-70-6	Heptan-1-ol		Supporting substance
C8	111-87-5	Octan-1-ol		Not expected to impair fertility based on read across from structurally analogous substances.	2
C9	143-08-8	Nonan-1-ol		Not expected to impair fertility based on read across from structurally analogous substances.
C10	112-30-1	Decan-1-ol		Not expected to impair fertility, based on read across from structurally analogous substances.
C11	112-42-5	Undecan-1-ol		Not expected to impair fertility, based on read across from structurally analogous substances.
C12	112-53-8	Dodecan-1-ol	2000	Fert* Rat: None (Hansen,1992a )	2
C13	112-70-9	Tridecan-1-ol Supporting		RDT Rat: None (Rhodes, 1984)	2
C8	60435-70-3	2-methylheptan-1-ol		Not expected to impair fertility based on read across from structurally analogous substances.
C9	68515-81-1	Nonan-1-ol, branched and linear		Not expected to impair fertility based on read across from structurally analogous substances.
C10	90342-32-8	Decan-1-ol, branched and linear		Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.
C11	128973-77-3	Undecan-1-ol, branched and linear		Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.
C13	90583-91-8	Tridecan-1-ol, branched and linear Supporting		Not expected to impair fertility	2
C18	112-92-5	Octadecan-1-ol	2000	Fert Rat: None (Hansen, 1992b)	2
C22	661-19-8	Docosan-1-ol	1000	Fert Rat: None (Iglesias, 2002a)	2
C7-9		Alcohols, C7-9- linear and branched		Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.
C9-11		Alcohols, C9-11-branched and linear		Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.
C11-13		Reaction mass of 2-methyldecan-1-ol and 2-propyloctan-1-ol and 2-ethylnonan-1-ol and 2-butylheptan-1-ol		Not expected to impair fertility, based on read across from structurally analogous substances as weight of evidence.
C12-13	75782-86-4	Alcohols, C12-13		No data was available for the C12-13 alcohols for this endpoint. Data was therefore read across from hexan-1-ol, docosan-1-ol, dodecan-1-ol and octadecan-1-ol as weight of evidence.
C12-13	740817-83-8	Alcohols, C12-13-branched and linear		No data was available for the C12-13 alcohols for this endpoint. Data was therefore read across from hexan-1-ol, docosan-1-ol, dodecan-1-ol and octadecan-1-ol as weight of evidence
C12-15	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

References:

PFA (2021). C6-24 Alcohols Category Report: Human Health. Version number:04. Peter Fisk Associates Ltd. October 2021.

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

Effects on developmental toxicity

Description of key information

No developmental toxicity studies in rats and rabbits were available on tetradecan-1-ol.

In a guideline study conducted in rats with C7-11 branched and linear, the NOAEL for both maternal and developmental toxicity was >1440 mg/kg bw/day (Hellwig & Jackh 1997) and in a similar study with octan-1-ol the NOAEL for developmental toxicity in rats was at least 1300 mg/kg bw/day, the highets dose tested (Hellwig & Jäckh 1997).

In a key study conducted according to a protocol similar to OECD Test Guideline 414 (in rats), with C22, the NOAEL for developmental toxicity was at least 1000 mg/kg bw/day, the highest dose tested (Iglesias 2002).

The key studies in rats will be reviewed once the new data from the testing strategy are available.

The developmental toxicity studies in second species will be generated as part of the category approach.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

group sizes are smaller than recommended 8-10 pregnant females rather than 20

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

group sizes are smaller than recommended; 8-10 pregnant females rather than 20

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Wistar outbred-strain Chbb/THOM

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Supplied by Dr K. Thomae, GmbH, Biberach, Germany.
- Age at study initiation: 68-85 days
- Weight at study initiation: 214-233 g
- Fasting period before study: no data
- Housing: DK III stainless steel wire-mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): "fully air conditioned rooms"
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: Doubly-distilled water containing about 0.005% Cremophor EL (as emulsifier)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Prepared daily in aqueous emulsions under rapid stirring


VEHICLE
- Justification for use and choice of vehicle: no data
- Concentration in vehicle: Adjusted to give constant volume
- Amount of vehicle: 5 ml/kg
- Lot/batch no.: no data
- Purity: no data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Gas chromatography

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: One to four untreated females were mated with one untreated fertile male
- Length of cohabitation: "overnight"
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

gestation days 6-15

Frequency of treatment:

daily

Duration of test:

20 days

Dose / conc.:

130 mg/kg bw/day

Dose / conc.:

650 mg/kg bw/day

Dose / conc.:

975 mg/kg bw/day

Dose / conc.:

1 300 mg/kg bw/day

No. of animals per sex per dose:

8-10 females

Control animals:

yes, concurrent vehicle

Details on study design:

no data

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: Daily


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Ovaries and uterus

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: half per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No

Statistics:

Dunnetts test for most reproductive parameters and Fischers exact test for evaluaton of conception rate and all foetal findings.

Indices:

Conception rates and pre & post implantation losses were calculated.

Historical control data:

Not presented

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
A dose-related increase in maternal toxicity with increasing severity of clinical signs (including lateral and abdominal position, unsteady gait, salivation, piloerection, nasal discharge and pneumonia) was observed in all treatment groups, compared to the controls. Two dams died in each of the groups (of ten rats) receiving the test material at 650, 975 and 1300 mg/kg bw/day, compared to no deaths in the dams receiving 130 mg n-octanol/kg bw/day or in the controls. A slight decrease in food consumption and body weight gain was observed in those female rats administered n-octanol at 650 mg/kg bw/day and above.

The number of pregnant dams per dose level was 10/10, 9/10, 8/10 and 8/10 in the dams administered the test material at 130, 650, 975, and 1300 mg/kg bw/day, respectively, compared to 9/10 in the water controls and 10/10 in the aqueous emulsifier. The number of resorptions, implantations, corpora lutea were comparable to controls (Number of resorptions (all)/dam (mean) 1.0, 1.4 (controls), and 1.2, 0.7, 0.8 and 1.3 in treated groups from low - high. Number of implantation sites/dam (mean) 14.7, 16.0 (controls), and 14.7, 15.4, 13.8 and 14.5 from treated groups low - high. Number of corpora lutea/dam (mean) 14.8, 16.3 (controls), and 15.0, 16.0, 14.9 and 14.5 in treated groups low - high.) Duration of pregnancy, and uterine and placental weights, were also comparable between treatment groups, and controls.

Key result

Dose descriptor:

NOAEL

Effect level:

130 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: Slight clinical signs seen at lowest tested dose, more marked at higher doses and associated with minor reductions in body weight gain and food consumption

Abnormalities:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No dead fetuses were observed and mean number of live foetuses/dam were unaffected by treatment ( 13.5, 14.7, 13.0 and 13.2 in treated groups receiving 130, 650, 975 or 1300 mg/kg bw/day, respectively, compared to 13.7 and 14.6 in controls). Litter size and weights were comparable in treated and control groups. Sex ratio was not reported. No treatment-related statistically significant and/or dose-related increases in the incidence of fetuses (or litters) with malformations, variations and retardations were observed, compared to controls. (Litters with malformations number 2 (22%), 3 (30%) (controls); 3 (30%), 3 (43%), 2 (25%) and 1 (17%) in treated groups low to high. Litters with variations number 8 (89%), 10 (100%) (controls); 10 (100%), 7 (100%); 7 (88%) and 5 (83%) in treated groups low to high. Litters with retardations number 8 (89%), 9 (90%) (controls);  9 (90%), 7 (100%), 8 (100%) and 5 (83%) in treated groups low to high. The authors note that "all foetal values were within the range of biological variation". A single cheiloschisis (cleft lip) and  one anophthalmy (eye loss) in the top-dose group was considered coincidental and not biologically relevant. 

Key result

Dose descriptor:

NOAEL

Effect level:

1 300 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

In a reliable study, performed to a protocol similar to OECD guideline 414, an NOAEL of 130 mg/kg bw/day (the lowest dose tested) was determined for maternal toxicity and an NOAEL of 1300 mg/kg bw/day for teratogenicity and foetotoxicity (the highest dose tested). The study was performed in compliance with GLP.

Executive summary:

Administration of octan-1-ol at daily gavage doses of 0, 130, 650, 975 or 1300 mg/kg resulted in significant, dose-related maternal toxicity, including clinical signs (depression, nasal discharge and pneumonia), and slight decreases in body weight gain and food consumption at 650, 975 or 1300 mg/kg/day. No adverse effects were recorded on foetal and developmental parameters.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

group sizes are smaller than recommended, 10 pregnant females rather than 20; some omissions in reporting

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

(only 10 animals per group instead of the 20 indicated in guideline; some omissions in reporting)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Wistar Chbb/THOM

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr K Thomae GmbH, Biberach, Germany
- Age at study initiation: 68-85 days (females)
- Weight at study initiation: 214-233 g (females)
- Fasting period before study: no data
- Housing: singly in stainless steel wire-mesh cages
- Diet (e.g. ad libitum): ground Kliba feed 343 rat/mouse/hamster, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): no data (air-conditioned)
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: no data

Route of administration:

oral: gavage

Vehicle:

other: double-distilled water with Cremophor EL as emulsifier

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: emulsified in double-distilled water containing 0.005% Cremophor EL. Prepared daily using a high-speed sonicator; a magnetic stirrer was used to keep the emulsion homogenous during dosing.

VEHICLE
- Justification for use and choice of vehicle (if other than water): to ensure even distribution of the test material
- Concentration in vehicle: 28.8, 144 or 288 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg bw/day

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentrations analysed by gas chromatography after homogenization by the addition of dioxane.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 male to 1-4 females
- Length of cohabitation: overnight
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no

Duration of treatment / exposure:

days 6-15 post coitum

Frequency of treatment:

daily

Duration of test:

20 days

Dose / conc.:

144 mg/kg bw/day

Dose / conc.:

720 mg/kg bw/day

Dose / conc.:

1 400 mg/kg bw/day

No. of animals per sex per dose:

8-10 females

Control animals:

yes, concurrent vehicle

other: double-distilled water

Details on study design:

- Dose selection rationale: based on equimolar dose levels as this was a study to compare toxicity of various C7-11 alcohols
- Rationale for animal assignment (if not random): random

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: yes

WATER CONSUMPTION: no

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: uterus

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: live foetuses, dead foetuses, numbers of implantations were shown as: live foetuses, dead implantations, early resorptions (stained), early & late resorptions (unnstained), dead foetuses; conception rates and pre & post implantation losses were calculated.

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: yes: half per litter

Statistics:

Dunnetts test for most reproductive parameters and Fishers exact test for evaluaton of conception rate and all foetal findings.

Indices:

no data

Historical control data:

none

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
No maternal toxicity or deaths occurred. There were no differences in body weight gain between the treated and control groups on days 0, 6, 15 or 20 and no differences in food consumption was evident. No differences were seen in the uterus, placental and foetal weights and the number of corpora lutea, implantation sites and live foetuses per dam were similar between the groups.

- Number pregnant per dose level: water control 9, aqueous emulsifier control 10, 144 mg/kg bw/day 9, 720 mg/kg bw/day 10, 1440 mg/kg bw/day 8.
- Number aborting: None
- Number of resorptions: comparable in treated and control groups. Resorptions/dam (mean) 1.2, 1.1 (control groups) 1.0, 1.2 and 1.1 for low, mid and high dose groups respectively.
- Number of implantations: comparable in treated and control groups. Implantation sites/dam (mean) 15.0, 15.7 (control groups) 14.8, 15.8 and 13.9 for low, mid and high dose groups.
- Post implantation loss: comparable in treated and control groups.
- Number of corpora lutea: comparable in treated and control groups. Corpora lutea/dam (mean) 16.1, 16.0 (control groups) 17.0, 17.0 and 15.6 for low, mid and high dose groups respectively.
- Duration of Pregnancy: comparable in treated and control groups.

No haematology, clinical chemistry, macro- or microscopic examinations were carried out and organs were not weighed (other than the uterus).

Key result

Dose descriptor:

NOAEL

Effect level:

1 440 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

1 440 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No embryotoxic effects were detected that were attributed to the treatment. Similar numbers of abnormalities occurred in the treated and control groups for the following parameters: bilateral renal pelvis, hydroureter, thoracic vertebral body dumbbell shaped, skeletal variations and skeletal retardations.

- Litter size and weights: comparable in treated and control groups. Foetal weights (mean) 3.8, 3.82 (controls) 3.88, 3.79 and 3.82 for low, mid and high dose groups respectively.
- Number viable: viability was comparable to controls. Live foetuses/dam (mean) 13.8, 14.6 (controls) 13.8, 14.6 and 12.8 for low, mid and high dose groups respectively.
- Sex ratio: Not reported.
- Total malformations, variations and retardations: the incidence was unaffected by treatment. Litters (%) with malformations (no. of litters) 11.1% (1), 20.0% (2)(controls) 11.1% (1), 40.0% (4) and 12.5% (1) for low, mid and high dose groups respectively.
- Litters (%) with variations (no. of litters) 88.9% (8), 100% (10) (controls) 100% (9), 100% (10) and 100% (8) for low, mid and high dose groups respectively.
- Litters (%) with retardations (no. of litters) 88.9% (8), 100% (10) (controls) 77.8% (7), 90.0% (9) and 87.5% (7) for low, mid and high dose groups respectively.

Key result

Dose descriptor:

NOAEL

Effect level:

1 440 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Abnormalities:

not specified

Developmental effects observed:

no

Conclusions:

In a reliable study, conducted to a protocol similar to OECD guideline 414, a mixture of mainly linear C7-9-11 alcohols exhibited no maternal or foetal toxicity after oral administration to rats on gestation days 6-15 at up to 1440 mg/kg bw/day. The study was performed to GLP.

Executive summary:

C7-11-branched and linear alcohols was administered at daily gavage doses of 0, 140, 720 and 1440 mg/kg bw/day to pregnant rats. No maternal toxicty was observed, and no adverse effects were recorded on foetal and developmental parameters.

Reference 3

Endpoint:

developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Species:

rabbit

Abnormalities:

not specified

Developmental effects observed:

not specified

Reference 4

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.

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

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 tetradecan-1-ol. A full discussion of the Category and considerations of RAAF Assessment Entities can be found in the Human Health Alcohols C6-24 Category report (PFA, 2021).

A prenatal developmental toxicity study, performed according to OECD Test 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).

A prenatal developmental toxicity study, performed according to OECD Test 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).

In combined repeat dose and reproductive/developmental toxicity screening tests, performed according to draft OECD Test 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).

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 available oral study and the weight of evidence from other alcohols across the category, and the combined repeated dose/reproductive/developmental toxicity screening study with dodecan-1-ol, it is concluded that tetradecan-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 (Iglesias, 2002) 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.

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

	CAS	CHEMICAL NAME	Study type / Species / Route / Effects	NOAEL (Ref)	Rel.*
C5	123-51-3	Isoamyl alcohol Supporting Substance	Dev.Tox Rat Inhalation: None	Mat. 2.5 mg/L Dev. 10 mg/L (Klimischet al., 1995)	2
C5	123-51-3	Isoamyl alcohol Supporting Substance	Dev. Tox Rabbit Inhalation: None	Mat. 2.5 mg/L Dev. 10 mg/L (Klimischet al., 1995)	2
C6	111-27-3	Hexan-1-ol	Dev. Tox Rat Inhalation: None	Mat/Dev. 3.5 mg/L (Nelson, 1989)	2
C6	111-27-3	Hexan-1-ol	Dev. Tox Rat Oral; None	Dev 1000 mg/kg Mat 200 mg/kg (Rodwell, 1988)	4
C8	111-87-5	Octan-1-ol	Dev Tox Rat  Inhalat’n: None	Mat/Dev.>0.4 mg/L (Nelson, 1990, 1996)	2
C8	111-87-5	Octan-1-ol	Dev. Tox Rat Oral: None	Mat 130 mg/kg       Dev 1300 mg/kg (Hellwig & Jackh, 1997)	2
C9	143-08-8	Nonan-1-ol	Dev.Tox Rat Inhalation: None	Mat/Dev>0.15 mg/L (Nelson, 1990, 1996)	2
C10	112-30-1	Decan-1-ol	Dev.Tox Rat Inhalation: None	Mat/Dev >0.1mg/L (Nelson, 1990, 1996)	2
C11	112-42-5	Undecan-1-ol		Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from dodecan-1-ol.
C12	112-53-8	Dodecan-1-ol Supporting Substance	Screen Rat Diet: None	Dev/Mat >2000 mg/kg (Hansen, 1992a)	2
C13	112-70-9	Tridecan-1-ol Supporting Substance		Not expected to be a developmental toxicant in the absence of maternal toxicity
C14	112-72-1	Tetradecan-1-ol		Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances.
C15	629-76-5	Pentadecan-1-ol		Not expected to be a developmental toxicant in the absence of maternal toxicity
C16	36653-82-4	Hexadecan-1-ol		Not expected to be a developmental toxicant in the absence of maternal toxicity
C18	112-92-5	Octadecan-1-ol	Screen Rat Diet: None	Dev/Mat >2000 mg/kg (Hansen, 1992b)	2
C18	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.
C20	629-96-9	Icosanan-1-ol		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	Docosan-1-ol	Dev.Tox Rat gavage: None	Mat/Dev >1000 (Iglesias, 2002b)	2
C22	661-19-8	Docosan-1-ol	Dev. Tox Rabbit Gavage; None	Mat/Dev >2000 mg/kg (Iglesias, 2002b)	2
C24	506-51-4	Tetracosan-1-ol		Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from structurally analogous substances.
C8	60435-70-3	2-methylheptan-1-ol
C9	68515-81-1	Nonan-1-ol, branched and linear		Not expected to be a developmental toxicant in the absence of maternal toxicity, based on read across from octan-1-ol.
C10	90342-32-8	Decan-1-ol, 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	128973-77-3	Undecan-1-ol, 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.
C14	90583-91-8	Tridecan-1-ol, branched and linear Supporting Substance		Not expected to be a developmental toxicant in the absence of maternal toxicity
C7-11	85566-14-9	Alcohols, C7-11-branched and linear	Dev.Tox Rat gavage: None	Mat/Dev >1440 (Hellwig & Jackh, 1997)	2
C9-11		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.
C11		Reaction mass of 2-methyldecan-1-ol and 2-propyloctan-1-ol and 2-ethylnonan-1-ol and 2-butylheptan-1-ol		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.
C12-13	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.
C12-13	740817-83-8	Alcohols, C12-13-branched and linear		Not expected to be a developmental toxicant in the absence of maternal toxicity based on read across from structurally analogous substances.
C12-15	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.
C14-15	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.
C14-15		Alcohols, C14-15-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.
C16-17		Alcohols, C16-17		Not expected to be a developmental toxicant in the absence of maternal toxicity

References:

PFA (2021). C6-24 Alcohols Category Report: Human Health. Version number: 04. Peter Fisk Associates Ltd. October 2021.

 

Justification for classification or non-classification

Based on the above information, tetradecan-1-ol does not require classification for reproductive and developmental toxicity according to Regulation (EC) No 1272/2008.