Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a reliable study conducted according to draft OECD guideline 422 with octadecan-1-ol, the parental NOAEL was 2000 mg/kg bw/day and the NOAEL for reproductive effects can be considered as 2000 mg/kg bw/day, the highest dose tested (Hansen, 1992b).

Data from a reliable study using dodecan-1-ol reported a parental NOAEL of 2000 mg/kg bw/day and a NOAEL for reproductive effects of 2000 mg/kg bw/day (highest dose level) (Hansen, 1992a).

Data from a reliable one-generation reproduction study using docosan-1-ol in rats reported a NOAEL of 1000 mg/kg (Iglesias, 2002a; rel 2).

A feeding study reported a lack of effects on the reproductive organs of rats receiving hexan-1-ol (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. No effects in reproductive organs have been observed in repeated dose studies with any category member.

Link to relevant study records

Referenceopen allclose all

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
without detailed documentation
Qualifier:
according to
Guideline:
other: ICH Harmonised Tripartite Guideline S5(R2) Detection of toxicity to reproduction for medicinal products and toxicity to male fertility
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
yes
Remarks:
(no postnatal observations of pups)
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: (P) males 6-7 wks, females 10-11 weeks
- Weight at study initiation: (P) males 193-240 g; females 208-262 g
- Fasting period before study: no
- Housing: according to the investigators "during the acclimation and premating periods, 10 rats (5 males and 5 females) were housed per TR18 stainless-steel cage..."; during mating, 1 male and 1 female housed in RB3-modified high-grade polypropylene cage with stainless-steel mesh lids and floors; during gestation, 5 females per RB3-modified cage; after mating, 5 males per TR18 cage
- Use of restrainers for preventing ingestion (if dermal): not applicable
- Diet (e.g. ad libitum): expanded rodent diet (Special Diet Services Ltd.), ad libitum
- Water (e.g. ad libitum): public supply, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18
- Humidity (%): 55
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data
Route of administration:
oral: gavage
Vehicle:
other: 1% w/w aqueous Tween 80
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- test material weighed into glass container and heated to ~80 deg C until molten
- vehicle heated to 75 deg C
- test material and vehicle combined using coninuous magnetic stirring, 20% behenyl alcohol
- suspension cooled slowly to <60 deg C
- further cooled to 30 deg C
- slowly homogenized <=2 min
- cooled to room temperature
- 20% suspension prepared weekly
- 20% suspension provided top dose
- mid and low dose prepared on day of use by dilution with vehicle; 20% suspension magnetically stirred prior to removal of aliquots for dilution; dilutions hand swirled prior to magnetic stirring

VEHICLE
- Justification for use and choice of vehicle (if other than water): not stated
- Concentration in vehicle: 20, 2 and 0.2%
- Amount of vehicle (if gavage): 5 ml/kg bw
- Lot/batch no. (if required): no data
- Purity: 1% aqueous
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: not stated
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of gestation
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: no data
- Further matings after two unsuccessful attempts: no data
- After successful mating each pregnant female was caged (how): 5/cage; RB3-modified cages
- Any other deviations from standard protocol: OECD guideline 415 recommends that: pregnant females are house individually, the mating period should be 3 weeks
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Males: from 71 days prior to mating, during mating and until females sacrificed
Females: from 15 days prior to mating, during mating, and up to day 17 of gestation; killed on day 20 of gestation
Frequency of treatment:
daily
Details on study schedule:
1-generation study
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
22
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: previous repeated dose toxicity study NOAEL was 1000 mg/kg bw/day
- Rationale for animal assignment (if not random): no data
Positive control:
no
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: evidence of reaction to treatment, moribund condition, mortality

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: males and females twice weekly prior to mating; males twice weekly after mating; females on gestation days 0, 3, 7, 10, 14, 18 and 20

FOOD CONSUMPTION :
- Food consumption: Yes
- Time schedule: males weekly prior to mating, females daily prior to mating, females on gestation days 0-2, 3-6, 7-9, 10-13, 14-17, 18-19

WATER CONSUMPTION: Yes
- Time schedule: males weekly prior to mating, females daily prior to mating, females on gestation days 0-2, 3-6, 7-9, 10-13, 14-17, 18-19
Oestrous cyclicity (parental animals):
10 days prior to mating, daily vaginal smears to assess regularity and duration of oestrus cycles
Sperm parameters (parental animals):
Parameters examined in male parental generations: testis weight, epididymis weight, sperm count in epididymides, sperm motility
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no, F1 generation examined as foetuses on day 20 of gestation

PARAMETERS EXAMINED
The following parameters were examined in parental females and F1 offspring: numbers of implantation sites, early and late resorptions and viable foetuses; distribution of foetuses in each uterine horn; placental weight; macroscopic examination of placentae; number and sex of foetuses

EXAMINATION OF PUPS: yes, for external and internal abnormalities (visceral and skeletal)
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals following necropsy of the females
- Maternal animals: All surviving animals on day 20 of gestation

GROSS NECROPSY
- Gross necropsy of females consisted of reproductive endpoints only
- Gross necropsy of males consisited of macroscopic examination externally and internally; sperm assessment

HISTOPATHOLOGY / ORGAN WEIGHTS
No tissues were prepared for microscopic examination
Reproductive organs were weighed
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were examined on day 20 of gestation
- These animals were subjected to examination as follows: each foetus weighed; detailed external examination; contents of cervical, thoracic and abdominal cavities removed from half the foetuses and examined and sex recorded; these foetuses stained for skeletal examination; remaining foetuses examined for visceral abnormalities

HISTOPATHOLOGY / ORGAN WEIGTHS
No tissues prepared for microscopic examination or weighed.
Statistics:
One-way analysis of variance, t-tests - body weight, body weight change, food and water consumption; Dunnetts' or Behren's-Fisher's tests - organ weights; nested analysis of variance, weighted t-tests - foetal and placental weights
Reproductive indices:
number of pregnant females, fertility
Offspring viability indices:
number of viable young (offspring evaluated as foetuses on day 20 of gestation)
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- females, no mortality
- males, one death in top dose group in week 6, not considered to be treatment related in the absence of toxic signs in any other animals

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- no effects

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
- no effects

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
- PREGNANCY RATE - no effects (22, 22, 22 and 21 in control, low, mid and high dose groups respectively)
- no effects

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- no effects

ORGAN WEIGHTS (PARENTAL ANIMALS)
- males, reproductive organs, no effects

GROSS PATHOLOGY (PARENTAL ANIMALS)
- no effects

HISTOPATHOLOGY (PARENTAL ANIMALS)
- not examined

OTHER
- REPRODUCTIVE PARAMETERS
- Number of corpora lutea - no effects (17.8, 18.4, 18.7 and 18.9 for controls, low, mid and high dose respectively)
- Number of implantations - no effects (means 17.2, 17.0, 18.1 and 18.0 for controls, low, mid and high dose respectively)
- Number of viable young - no effects (means 16.4, 15.9, 17.0 and 16.9 for controls, low, mid and high dose  respectively)
- Sex ratio - no effects
- Number of resorptions (early or late) - no effects
- Pre-implantation loss - no effects (3.3, 8.3, 3.2,  5.8% for controls, low, mid and high dose respectively)
- Post-implantation loss - no effects (4.7, 6.4, 6.3 and 5.8% for controls, low, mid and high dose respectively)
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Clinical signs:
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
VIABILITY (OFFSPRING)
- no effects

CLINICAL SIGNS (OFFSPRING)
- not applicable, foetuses examined at day 20 of gestation

BODY WEIGHT (OFFSPRING)
- no effects

SEXUAL MATURATION (OFFSPRING)
- not applicable, foetuses examined at day 20 of gestation

ORGAN WEIGHTS (OFFSPRING)
- not applicable, foetuses examined at day 20 of gestation

GROSS PATHOLOGY (OFFSPRING)
- not applicable, foetuses examined at day 20 of gestation

HISTOPATHOLOGY (OFFSPRING)
- not applicable, foetuses examined at day 20 of gestation

OTHER FINDINGS (OFFSPRING)
- MACROSCOPIC EXAMINATION (OFFSPRING)
- no variations were observed that were not comparable to historical control values
- SKELETAL EXAMINATION (OFFSPRING)
- no variations were observed that were not comparable to historical control values
- VISCERAL EXAMINATION (OFFSPRING)
- no variations were observed that were not comparable to historical control values
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Reproductive effects observed:
no
Conclusions:
In a reliable study, conducted to a protocol similar to OECD guideline 415, an NOAEL of 1000 mg/kg bw/day was determined in the rat for reproductive effects. The study was performed in compliance with GLP.
Executive summary:

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.

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Principles of method if other than guideline:
Conducted according to Draft OECD guideline 422 Combined repeated dose and reproductive/developmental toxicity screening test
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Moellegard Breeding Centre
- Age at study initiation: 8 (males) and 7 (females) weeks
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: 2 rats/cage for acclimatization period then individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±10
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): fluorescent light was on from 8 pm to 8 am

IN-LIFE DATES: no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Diet preparation involved first mixing the octadecanol with the barley component, the proportion of which varied for each dose level. The other components of the diet were then added.
- Rate of preparation of diet (frequency): not specified
- Mixing appropriate amounts with (Type of food): IT chow 101 diet
- Storage temperature of food: not specified
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 22 days
- Proof of pregnancy: vaginal plug referred to as day 0 or, if the plug was recorded during the morning, day 1 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged: individually in steel wire cages type 3 until day 20 in pregnancy where the pregnant females were placed in macrolon cages type 3.
- Any other deviations from standard protocol: none
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Exposure period: males 45 days, females up to 54 days
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: males 45 days, females up to 54 days
Frequency of treatment:
continuous in diet
Details on study schedule:
- Age at mating of the mated animals in the study: 10 (males) and 9 (females) weeks
Dose / conc.:
1 500 ppm (nominal)
Remarks:
100 mg/kg bw/day
Dose / conc.:
7 500 ppm (nominal)
Remarks:
500 mg/kg bw/day
Dose / conc.:
30 000 ppm (nominal)
Remarks:
2000 mg/kg bw/day
No. of animals per sex per dose:
12
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Doses chosen from the results of a preliminary test.
- Rationale for animal assignment (if not random): Randomized into 4 groups with the same mean body weight
Positive control:
none
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: not specified

BODY WEIGHT: Yes
- Time schedule for examinations: During the experiment the males were weighed once/week. The females were weighed during the premating period and during pregnancy once/week. Pup litter weight was determined on days 1 and 4 after birth.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OTHER: haematology and clinical biochemistry conducted in the males
Oestrous cyclicity (parental animals):
Exposure was for 14 days premating covering at least 2 oestrous cycles. Ovaries were weighed and examined histopathologically at section (5 days after birth).
Sperm parameters (parental animals):
Parameters examined in male parental generation: other: Exposure 14 days premating, no specific sperm analyses carried out, the testes & epididymes were weighed and examined histopathologically.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, postnatal mortality, presence of gross anomalies, weight gain, other: examined for internal malformations.

GROSS EXAMINATION OF DEAD PUPS:
no
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals sacrificed after 45 days of dosing
- Maternal animals: All surviving animals sacrificed on postnatal day 5

GROSS NECROPSY
Gross necropsy consisted of full macroscopic examination.

HISTOPATHOLOGY / ORGAN WEIGHTS
The liver, kidneys, thymus, testes and epididymides were weighed; the liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, testes, epididymides and any organs showing abnormality on macroscopic examination were fixed and the tissues from all controls and top dose treated rats (except the thymus) plus abnormalities were examined.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 5 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
Gross necropsy consisted of external malformations including the head (especially eyes and cleft palate). Animals were then opened to the abdomen and thoracic cavity for a study of malformations of the internal organs.

HISTOPATHOLOGY / ORGAN WEIGHTS
No histopathology or organ weights measured.
Statistics:
Analysis of variance followed if significant differences were established by Dunnetts t-test to assess possible intergroup differences. For pregnancy rate a Chi-squared test was carried out to confirm lack of significance.
Reproductive indices:
Pregnancy rate, length of gestation, implantations, corpora lutea and resorptions were recorded.
Offspring viability indices:
none
Clinical signs:
not examined
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): None reported

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): No treatment related effects

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): Not reported

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): Not reported

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): Not reported

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): There was no statistically significant difference in pregnancy rates (confirmed using a Chi-squared test) although they were reduced in treated groups C 92%, 100 & 500 mg/kg 75%, 2000 mg/kg/day 67% these were within the normal historical control range according to the authors (actual historical control data not presented).

ORGAN WEIGHTS (PARENTAL ANIMALS): There were no statistically significant dose related changes in organ weights including the testes, epididymides and ovaries.

GROSS PATHOLOGY (PARENTAL ANIMALS): There were no changes attributable to exposure to the test compound.

HISTOPATHOLOGY (PARENTAL ANIMALS): There were no treatment related histopathological changes including no effects in the testes and ovaries.

OTHER FINDINGS (PARENTAL ANIMALS): Duration of gestation was comparable in treated and control dams (mean 22 days for all groups) and no clinical biochemical findings, examined in the males only, were considered of biological significance. Haematological examination in the males only showed changes in plasma free cholesterol, triglycerides and glucose although the significance is unclear. The changes were observed at all doses levels but were not dose related and may be related to differences in dietary composition. There was no significant differences in the numbers of implantations between treated and control groups (Mean 13 in controls and low-dose, 15 in mid- and high-dose groups); resorptions mean for controls and low-dose 0, for mid- and high-dose 1; no significant differences between treated and control groups with respect to number of corpora lutea (mean controls 13, low and mid dose 14, high dose 15).
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
VIABILITY (OFFSPRING): Not examined

CLINICAL SIGNS (OFFSPRING): Not examined

BODY WEIGHT (OFFSPRING): Litter weights day 1 mean 69, 61, 75 and 75 g; Day 4 mean 96, 84, 101 and 101 g for controls, low, mid and high dose respectively

SEXUAL MATURATION (OFFSPRING): No treatment related effects.

ORGAN WEIGHTS (OFFSPRING): Not examined

GROSS PATHOLOGY (OFFSPRING): No treatment related effects

HISTOPATHOLOGY (OFFSPRING): Not examined

OTHER FINDINGS (OFFSPRING): No effect of treatment on litter size (mean litter size 11.73, 10.0, 13.6 and 13.38 for controls, low, mid and high dose respectively) and post natal survival until day 5 was similar in the treated and control groups.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Reproductive effects observed:
no
Conclusions:
In a reliable study conducted according to draft OECD guideline 422, parental NOAEL was 2000 mg/kg bw/day and the NOAEL for reproductive and developmental effects can be considered as 2000 mg/kg bw/day (highest dose level).
Executive summary:

Octadecan-1-ol has been tested for potential reproductive toxicity in a combined repeat dose reproductive/developmental toxicity screening study in rats conducted according to the draft OECD guideline 422 and in compliance with GLP. 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 octadecan-1-ol. There were no microscopic changes observed in the reproductive organs.

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Draft OECD 422 Combined Repeat dose and Reproductive/Developmental Toxicity Screening Test.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Moellegard breeding centre
- Age at study initiation: F 8 weeks, M 7 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 2/cage, steel wire cages type 3 (up to day 20 of gestation); macrolon cages type 3 (from day 20 of gestation)
- Diet (e.g. ad libitum): IT chow 101, presumably ad libitum
- Water (e.g. ad libitum): acidified tapwater, ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2
- Humidity (%): 55 +- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): IT chow 101
- Storage temperature of food:no data
- Preparation procedure: Diet preparation involved first mixing an aqueous dodecanol solution with the barley component, which varied for each dose level. The other components of the diet were then added.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug recorded during the morning referred to as day 1 of pregnancy; vaginal plug recorded at lunch time or during the afternoon referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male for up to 8 days
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): in steel wire cages type 3 until day 20 of pregnancy, placed in macrolon cages type 3 thereafter
- Any other deviations from standard protocol: none
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Exposure period: Males 41-44 days , females up to 54 days
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: Males 41-44 days, females up to 54 days
Frequency of treatment:
continuous in diet
Details on study schedule:
- One-generation study (only parental animals mated)
Dose / conc.:
1 500 ppm (nominal)
Remarks:
approx 100 mg/kg bw/day
Dose / conc.:
7 500 ppm (nominal)
Remarks:
approx 500 mg/kg bw/day
Dose / conc.:
30 000 ppm (nominal)
Remarks:
approx 2000 mg/kg bw/day
No. of animals per sex per dose:
12
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: preliminary test via a dermal route
- Rationale for animal assignment (if not random): 2 days prior to the start of dosing, animals randomised into four groups with same mean body weight
Positive control:
none
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: mortality

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: males once per week; females premating once per week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption in g body weight gain/kg food per week calculated from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
Oestrous cyclicity (parental animals):
no data (exposure was for 14 days premating covering at least 2 oestrous cycles; ovaries were weighed and examined histopathologically at necropsy)
Sperm parameters (parental animals):
Parameters examined in male parental generation: testis weight, epididymis weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no (one-generation screening study)

PARAMETERS EXAMINED
- The following parameters were examined in F1 offspring: number of pups on days 1, 4 and 5; sex of pups on day 5; postnatal mortality from day 1 to day 4; weight gain from day 1 to day 4; mean body weight of male and female pups on day 5; presence of gross abnormalities on day 5

GROSS EXAMINATION OF DEAD PUPS: yes, on day 5, for external abnormalities including the head (especially the eyes and cleft palate), abdomen and thoracic cavity examined internally for malformations; possible cause of death was not determined for pups born or found dead
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after 41-44 days of dosing
- Maternal animals: All surviving animals on day 5 after birth

ORGAN WEIGHT: males - liver, kidneys, thymus, testes, epididymides; females - liver, kidneys, thymus

ORGANS FIXED IN FORMALIN: males - liver, kidneys, adrenals, brain, heart, spleen, thymus, organs with pathological changes, testes and epididymides fixed in Bouin's solution; females - liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, other organs with observed pathological changes

HISTOPATHOLOGY: Yes, control and top dose group, all fixed organs except thymus
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age: not applicable (1-generation study)
Statistics:
Using the SAS-stat program; analysis of variance; all statistically significant findings further evaluated by Dunnett's t-test; chi-squared test for pregancy rate
Reproductive indices:
pregnancy rate; length of gestation; numbers of corpora lutea, implantations, resorptions and pups at birth
Offspring viability indices:
number of pups at birth and on days 4 and 5, number of pups per litter, pup deaths between days 1 and 4
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY
- Mortality and time to death: None
- Clinical signs: None reported

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: No differences between treated and controls of either sex.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Males: 102.4, 530.8 and 2046.4 mg/kg bw/day (mean of values reported for 2 weeks prior to mating and 3 weeks after mating)
Females: 130.5, 657.5 and 2870.5 mg/kg bw/day (mean of values reported 2 weeks prior to mating)

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
no data

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
no data

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- no statistically significant effects on pregnancy rate, length of gestation or numbers of corpora lutea, implantations, resorptions or pups at birth
- pregnancy rate was reduced in treated groups: 0 mg/kg bw/day 92%, 100 & 500 mg/kg bw/day 83%, 2000 mg/kg/day 75%; these were within the normal historical control range according to the investigators (actual historical control data not presented); lack of statistical significance confirmed using chi-squared test
- mean length of gestation: 23 days in all groups
- mean number of corpora lutea: 14 in all groups
- mean number of implantations: 13 in controls, 14 in all treated groups
- no resorptions in any group

ORGAN WEIGHTS (PARENTAL ANIMALS) (see table 2)
- There were no dose related changes in organ weights, including the testes, epididymides and ovaries; in males only there was a reduction in relative and absolute liver weights at the low dose level and a reduction in relative liver weight at mid doses, the top dose was comparable to controls.

GROSS PATHOLOGY (PARENTAL ANIMALS)
- There were no changes attributable to exposure to the test compound.

HISTOPATHOLOGY (PARENTAL ANIMALS)
- There were no treatment related histopathological changes.

OTHER (PARENTAL ANIMALS)
- Haematology and clinical chemistry data for parental males (reported elsewhere)
Key result
Dose descriptor:
NOAEL
Effect level:
> 2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Clinical signs:
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
VIABILITY (OFFSPRING)
- no statistically significant effect
- litter size mean on day 1: controls 13.25, low dose 13.27, mid dose 13.2, high dose 13.33. 

CLINICAL SIGNS (OFFSPRING)
- no effects

BODY WEIGHT (OFFSPRING)
- no statistically significant effects
- mean litter weights at day 1 were 75, 75, 71 and 77 g and at day 4 106, 107, 101 and 104 g for control, low, mid and high dose respectively

SEXUAL MATURATION (OFFSPRING)
- not applicable (1-generation screening study)

ORGAN WEIGHTS (OFFSPRING)
- not applicable (1-generation screening study)

GROSS PATHOLOGY (OFFSPRING)
- no effects

HISTOPATHOLOGY (OFFSPRING)
- no data

OTHER FINDINGS (OFFSPRING)
- no statistically significant effects on pup body weight on day 5
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Reproductive effects observed:
no
Conclusions:
In a reliable study conducted to the draft OECD guideline 422, a parental NOAEL of > 2000 mg/kg bw/day (highest dose tested) was determined for male and female rats. No adverse effects were observed on reproductive parameters and the NOAEL for reproductive and developmental effects was also > 2000 mg/kg bw/day. The study was performed in compliance with GLP.
Executive summary:

Dodecan-1-ol has been tested for potential reproductive toxicity in a combined repeat dose reproductive/developmental toxicity screening study in rats conducted according to the draft OECD guideline 422 and in compliance with GLP. The materials were administered to male and female rats via the diet at concentrations up to 30,000 ppm (2000 mg/kg bw/day) 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 octadecan-1-ol. There were no microscopic changes observed in the reproductive organs.

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

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)], 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 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, 2016).

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) 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 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.

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

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

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:

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

PFA (2016). C6-24 Alcohols Category Report: Human Health. Version number: 01. Peter Fisk Associates Ltd. February 2016.


Effects on developmental toxicity

Description of key information

Data from a reliable developmental toxicity study using 1docosan-1-ol in rabbits reported a NOAEL for developmental and maternal effects of > 2000 mg/kg. (Iglesias 2002b; rel 2)

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
without detailed documentation
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: ICH Harmonized Tripartite Guideline S5 (R2) for Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
(non standard examination of soft tissue and head of foetuses)
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Froxfield SPF Rabbits Ltd., UK
- Age at study initiation: 18-26 weeks on arrival
- Weight at study initiation: 3.29-4.98 kg at start of study
- Fasting period before study: no data
- Housing: individually in suspended stainless-steel cages (TR6)
- Diet (e.g. ad libitum): standard rabbit diet (Special Diets Services Ltd., UK), ad libitum
- Water (e.g. ad libitum): public supply, ad libitum
- Acclimation period: >=1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18
- Humidity (%): 55
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data
Route of administration:
oral: gavage
Vehicle:
other: 1% Tween 80
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- test material weighed into glass container and heated to ~80 deg C until molten
- vehicle heated to 75 deg C
- test material and vehicle combined using coninuous magnetic stirring, 20% behenyl alcohol
- suspension cooled slowly to <60 deg C
- further cooled to 30 deg C
- slowly homogenized <=2 min
- cooled to room temperature
- 20% suspension prepared weekly
- 20% suspension provided top dose
- mid and low dose prepared on day of use by dilution with vehicle; 20% suspension magnetically stirred prior to removal of aliquots for dilution; dilutions hand swirled prior to magnetic stirring

VEHICLE
- Justification for use and choice of vehicle (if other than water): not stated
- Concentration in vehicle: 20, 2 and 0.2%
- Amount of vehicle (if gavage): 10 ml/kg bw for vehicle control and top dose groups; 0.625 and 2.5 ml/kg bw for low and mid dose groups respectively
- Lot/batch no. (if required): no data
- Purity: 1%
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused with males of establised fertility
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: no data
- Further matings after two unsuccessful attempts: no data
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: not specified, but referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no data
Duration of treatment / exposure:
days 6-19 of gestation
Frequency of treatment:
daily
Duration of test:
females killed on day 29 of gestation
Dose / conc.:
125 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
22
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: female
Duration of test: 28 days
- Dose selection rationale: based on previous range-finding study
- Rationale for animal assignment (if not random): randomly allocated to the four treatment groups in order of mating "to evenly distribute the mated females among the groups"
- Other:
- approximately 2 weeks prior to arrival of females at testing facility, oestrus synchronised by supplier by intravenous injection of 25 IU luteinizing hormone
- following insemination, females injected intravenously with 25 IU luteinizing hormone to ensure successful ovulation
- examined on day 6 of gestation, prior to dosing, to determine suitability for use in study
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: evidence of reaction to treatment or moribund condition

DETAILED CLINICAL OBSERVATIONS: no data

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: Yes
- Time schedule for examinations: days 1-5, days 6-12, days 13-19, days 20-23, days 24-28

WATER CONSUMPTION: Yes
- Time schedule for examinations: daily

POST-MORTEM EXAMINATIONS: yes, macroscopic examination
- Sacrifice on gestation day 29
- Organs examined in addition to uterine contents and ovaries: no data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
- Number of viable young: males, females and total
- Distribution of foetusus in each uterine horn
- Uterus of any female presumed non-pregnant stained and examined for implantation sites
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter - cervical, thoracic and abdominal cavities dissected and contents examined microscopically
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: one third per litter
- Other: all per litter
- foetal body weight
- position of foetus in uterus
- placental weight
Statistics:
One-way analysis of variance, t-tests - body weight, body weight change, food and water consumption; Dunnett's or Behren's-Fisher's tests - organ weights; nested analysis of variance, weighted t-tests - foetal and placental weights
Indices:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
no effects other than pale faeces in animals of the top dose group
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
no effects
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
no

Table 1: Reproductive and developmental parameters

Observation

Dose (mg/kg bw/day)

0

125

500

2000

Animals Assigned (Mated)

22

22

22

22

Animals Pregnant

Pregnancy Rate (%)a

20

91%

19

86%

19

86%

20

91%

Nonpregnant

2

3

3

2

Total litter loss

(%)a

1

10.0%

1

5.3%

1

5.3%

0

0.0%

Corpora Lutea/Dam (mean±SD)

12.8±3.1

12.9±2.2

12.6±3.0

12.2±3.9

Implantations/Dam (mean±SD)

11.4±3.9

11.1±2.6

11.0±3.3

10.6±4.3

Live Fetuses/Dam (mean±SD)

Male (mean±SD)

Female (mean±SD)

10.1±3.7

4.6±2.6

5.5±2.4

9.8±2.1

4.8±1.5

4.9±1.7

9.3b±2.6

3.8±1.5

5.5±2.1

9.0±3.8

4.7±2.2

4.3±2.5

Resorptions/Dam (mean±SD)

Early (mean±SD)
Late (mean±SD)

1.4±1.2

0.4±0.6

1.0±1.0

1.3±1.2

0.3±0.5

1.1±1.0

1.7±1.3

0.4±0.6

1.2±1.1

1.6±1.2

0.7±0.8

0.9±0.9

Preimplantation Loss (%)

10.4

14.2

13.9

13.5

Postimplantation Loss (%)

12.1

12.0

15.2

14.7

aCalculated for this table

bIncludes one foetus not sexed at necropsy

Conclusions:
In a reliable study, conducted according to a protocol similar to OECD guideline 414, the NOAEL for maternal toxicity, teratogenicity and foetotoxicity in rabbits, was 2000 mg/kg/day (highest dose tested). The study was performed in compliance with GLP.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting 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
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
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
2 000 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
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 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, 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, 2016).

A prenatal developmental toxicity study, performedto 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 & Jäckh, 1997).

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 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 to draft OECD guideline 422 and to 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 rats and rabbits using with docosan-1-ol and C24-C34 alcohols (Iglesias, 2002a; Rodriguez, 1998).

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 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 eitherspecies.

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 et al, 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, 2002a)

2

C22

661-19-8

Docosan-1-ol

Dev. Tox Rabbit Gavage; None

 

 

Mat/Dev >2000

mg/kg

(Iglesias, 2002a)

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

 

C9-11

 

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.

 

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

 

 

C16-17

 

Alcohols, C16-17 -branched and linear

 

Not expected to be a developmental toxicant in the absence of maternal toxicity

 

C16-17

 

Alcohols, C16-17-monobranched

 

Not expected to be a developmental toxicant in the absence of maternal toxicity

References:

PFA (2016). C6-24 Alcohols Category Report: Human Health. Version number: 01. Peter Fisk Associates Ltd. February 2016.


Justification for classification or non-classification

Based upon the above information, 1-docosanol is not required to be classified in accordance with EU guidelines.