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REACH

Alcohols, C12-14

EC number: 279-420-3 | CAS number: 80206-82-2

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

It is concluded that the substance Alcohols, C12-14 does not meet the criteria to be classified for human health hazards for Reproductive toxicity

Link to relevant study records

Reference 1

Endpoint:: one-generation reproductive toxicity
Remarks:: based on generations indicated in Effect levels (migrated information)
Type of information:: other: published data
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: according to guideline
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
Limit test:: no
Species:: rat
Strain:: Wistar
Sex:: male/female
Details on test animals or test system 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)
Remarks:: Doses / Concentrations:
0, 1500, 7500 & 30,000 ppm (approx 100, 500, 2000 mg/kg bw/day)
Basis:
nominal in diet
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
Dose descriptor:: NOAEL
Effect level:: 2 000 mg/kg bw/day (nominal)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: Dietary concentrations of 1500, 7500 and 30000 ppm provided nominal dose levels of 100, 500 and 2000 mg/kg bw/day
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
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: Dietary concentrations of 1500, 7500 and 30000 ppm for parental animals provided nominal dose levels of 100, 500 and 2000 mg/kg bw/day
Reproductive effects observed:: not specified
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).
Dodecan-1-ol (C12) is supporting substance for Alcohols,C12-C14 and the main component.
Executive summary:: 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.

Reference 2

Endpoint:

two-generation reproductive toxicity

Remarks:

other: QSAR Estrogen Receptor Binding method

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction:Accepted Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.

Qualifier:

according to guideline

Guideline:

other: QSAR Toolbox Version 3.3.5.17

Principles of method if other than guideline:

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER binding and possible subsequent endocrine disruption.

The incorporated Toolbox ER binding profiling scheme is based on structural and parametric rules extracted from literature sources and supported by experimental data . The ER-binding profiler clasifies chemicals as non binders or binders depending on molecular weight (MW) and structural characteristics of the chemicals:
1. Very strong binders: Chemicals with MW between 200 and 500 Da and two rings with a hydroxyl group connected to each of them.
2.Strong binders: Chemicals with at least one 5-or 6-members carbon ring with an unhindered hydroxyl or amino group and MW between 200 and 500 Da;
3.Moderate binders: Chemicals with at least one 5-or 6-members carbon ring with an unhindered hydroxyl or amino group and MW between 170 and 200 Da;
4. Weak binders: Chemicals with at least one 5-or 6-members carbon ring with an unhindered hydroxyl or amino group and MW less than 170 Da;

If the target chemical does not meet some of the structural and parametric requirements listed above it is classified as Non binder:
Non binder with impaired hydroxyl or amino group;
Non binder, MW more than 500 Da;
Non binders without hydroxyl or amino group;
Non-binder, non-cyclic.

GLP compliance:

Remarks:

not applicable. QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.

Limit test:

Species:

other: fish (trout) and mammals.

Strain:

other: QSAR model

Sex:

not specified

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Details on exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Parental animals: Observations and examinations:

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

Non-ER binder due to non-cyclic molecular structure.Alcohols, C12-14 have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Alcohols, C12-14 does not cause reproductive toxicity.

1.1. CAS number: 80206-82-2
1.2. Chemical name(s):
Alcohols, C12-14
1.3. Structure codes:
a. SMILES: CCCCCCCCCCCCO
1.4. Profiling results:
-DNA binding by OECD -No alert found
-Estrogen Receptor Binding-Non binder, non cyclic structure
-OECD HPV Chemical Categories-Long chain alcohols
-Protein binding by OECD-No alert found
-US-EPA New Chemical Categories-Neutral Organics
-Toxic hazard classification by Cramer (original)-Low (Class I)

Dose descriptor:

other: Relative ERBA (Estrogen Receptor Binding Affinity)

Effect level:

< -3 other: Log RBA(Relative Binding Affinities )

Based on:

other: Estrogen receptor (ER) binding

Sex:

not specified

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Generation: QSAR model (migrated information)

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Remarks on result:

other: QSAR model

Reproductive effects observed:

not specified

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

Non-binder, impaired OH or NH2 group

Non-binder without OH or NH2 group

Non-binder, non-cyclic structure

Non-binder, MW > 500

Non-binder, non-cyclic structure– chemicals without cycles and MW =<500

Non-ER binder due to non-cyclic molecular structure.

Popular among these are the “four phase” assessment that includes Comparative Molecular Field Analysis (CoMFA) and the Common Reactivity Pattern Approach (COREPA)

Since the RE-binding is a receptor mediated event, particular organic functional groups, size and shape are critical to binding potency.

Alcohols, C12-14 have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Alcohols, C12-14 does not cause reproductive toxicity.

Conclusions:

Executive summary:

1.1. CAS number: 80206-82-2

1.2. Chemical name(s):

Alcohols, C12-14

1.3. Structure codes:

a. SMILES: CCCCCCCCCCCCO

1.4. Profiling results:

-DNA binding by OECD -No alert found

-Estrogen Receptor Binding-Non binder, non cyclic structure

-OECD HPV Chemical Categories-Long chain alcohols

-Protein binding by OECD-No alert found

-US-EPA New Chemical Categories-Neutral Organics

-Toxic hazard classification by Cramer (original)-Low (Class I)

Reference 3

Endpoint:: screening for reproductive / developmental toxicity
Remarks:: other: QSAR model
Type of information:: (Q)SAR
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:: QSAR prediction: Accepted Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Qualifier:: according to guideline
Guideline:: other: Estrogen Receptor Binding method
Principles of method if other than guideline:: This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.
GLP compliance:: no
Remarks:: not applicable. QSAR model
Limit test:: no
Species:: other: fish and mammals.
Strain:: other: QSAR model
Sex:: not specified
Route of administration:: other: QSAR model
Vehicle:: other: QSAR model
Details on exposure:: Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Analytical verification of doses or concentrations:: not specified
Duration of treatment / exposure:: Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Remarks:: Doses / Concentrations:

Basis:
other: QSAR model
Control animals:: not specified
Parental animals: Observations and examinations:: Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Clinical signs:: no effects observed
Description (incidence and severity):: QSAR model
Body weight and weight changes:: no effects observed
Description (incidence and severity):: QSAR model
Food consumption and compound intake (if feeding study):: no effects observed
Description (incidence and severity):: QSAR model
Organ weight findings including organ / body weight ratios:: no effects observed
Histopathological findings: non-neoplastic:: no effects observed
Description (incidence and severity):: QSAR model
Other effects:: no effects observed
Description (incidence and severity):: Test substance intake: QSAR model
Reproductive function: oestrous cycle:: no effects observed
Description (incidence and severity):: QSAR model
Reproductive function: sperm measures:: no effects observed
Description (incidence and severity):: QSAR model
Reproductive performance:: no effects observed
Description (incidence and severity):: QSAR model
Dose descriptor:: other: QSAR model
Effect level:: < -3 other: Log RBA
Based on:: other: Estrogen receptor (ER) binding
Sex:: not specified
Basis for effect level:: other: No binding to Estrogen Receptor Alpha (Log RBA <-3) for the Alcohols, C12-14) (CAS# 80206-82-2)
Remarks on result:: other: Generation: QSAR model (migrated information)
Clinical signs:: no effects observed
Description (incidence and severity):: QSAR model
Mortality / viability:: no mortality observed
Description (incidence and severity):: QSAR model
Body weight and weight changes:: no effects observed
Description (incidence and severity):: QSAR model
Sexual maturation:: no effects observed
Description (incidence and severity):: QSAR model
Organ weight findings including organ / body weight ratios:: no effects observed
Description (incidence and severity):: QSAR model
Gross pathological findings:: no effects observed
Description (incidence and severity):: QSAR model
Histopathological findings:: no effects observed
Description (incidence and severity):: QSAR model
Remarks on result:: other: QSAR model
Reproductive effects observed:: not specified
Conclusions:: No binding to Estrogen Receptor Alpha (Log RBA <-3) for the Alcohols, C12-14) (CAS# 80206-82-2) and therefore Alcohols, C12-14)does not cause reproductive toxicity.

Reference 4

Endpoint:: one-generation reproductive toxicity
Remarks:: based on test type (migrated information)
Type of information:: other: published data
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
Qualifier:: equivalent or similar to guideline
Guideline:: OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:: yes
Remarks:: (no postnatal observations of pups)
Qualifier:: according to guideline
Guideline:: other: ICH Harmonised Tripartite Guideline S5(R2) Detection of toxicity to reproduction for medicinal products and toxicity to male fertility
Deviations:: no
GLP compliance:: not specified
Limit test:: no
Species:: rat
Strain:: Sprague-Dawley
Sex:: male/female
Details on test animals or test system 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
Remarks:: Doses / Concentrations:
10, 100, 1000 mg/kg bw/day
Basis:
nominal conc.
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:: none
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
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
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:: not specified
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.

Reference 5

Endpoint:: screening for reproductive / developmental toxicity
Type of information:: other: published data
Adequacy of study:: key study
Study period:: not stated
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:: no guideline followed
Principles of method if other than guideline:: Rats treated via the diet for 90 days with limited evaluation, but including reproductive organs
GLP compliance:: no
Limit test:: no
Species:: rat
Strain:: other: albino
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: no data but "young"
- Weight at study initiation: males 103.6 g, females 90.5 g
- Fasting period before study: no data
- Housing: individually in suspended wire-mesh cages
- Use of restrainers for preventing ingestion (if dermal): not applicable
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data but "controlled within narrow limits"
- Humidity (%): no data but "controlled within narrow limits"
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
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): weekly
- Mixing appropriate amounts with (Type of food): basal laboratory diet (Purina Laboratory Chow)
- Storage temperature of food: no data
Details on mating procedure:: no mating - screening study
Analytical verification of doses or concentrations:: no
Duration of treatment / exposure:: 13 weeks
Frequency of treatment:: continuous in diet
Details on study schedule:: no mating - screening study
Remarks:: Doses / Concentrations:
0.25%, 0.50%, 1.0-6.0% w/w
Basis:
nominal in diet
No. of animals per sex per dose:: 10 (treated), 20 (controls)
Control animals:: yes, plain diet
Details on study design:: - Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
Positive control:: none
Parental animals: Observations and examinations:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 5 days/week
- Cage side observations included: general physical appearance, gross signs of systemic toxicity and/or pharmacological effect, behaviour, mortality

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as mg/kg bw/day: Yes

WATER CONSUMPTION: No

OTHER: Haematology and urinalysis (reported elsewhere)
Oestrous cyclicity (parental animals):: no data
Sperm parameters (parental animals):: Parameters examined in males: testis weight
Litter observations:: no litters - no mating - screening study
Postmortem examinations (parental animals):: SACRIFICE
- Males: All surviving animals, after 13 weeks of treatment
- Females: All surviving animals after 13 weeks of treatment

GROSS NECROPSY
- Gross necropsy included external and internal examinations of the cervical, thoracic, and abdominal viscera

ORGAN WEIGHTS: brain, thyroid, heart, liver, spleen, kidneys, adrenals, gonads (testes or ovaries)

HISTOPATHOLOGY: Yes
- brain, thyroid, parathyroid, heart, lung, liver, spleen, stomach, small intestine, large intestine, pancreas, kidney, urinary bladder, adrenal, gonads (testes or ovaries), lymph node, bone, bone marrow
- all listed tissues from 5/sex from high dose and controls examined
Postmortem examinations (offspring):: no offspring - no mating - screening study
Statistics:: Chi-squared test for comparing relative organ weights (but see 'Any other information on materials and methods')
Reproductive indices:: no mating - screening study
Offspring viability indices:: no offspring - no mating - screening study
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:: no effects observed
Reproductive function: oestrous cycle:: not examined
Reproductive function: sperm measures:: not examined
Reproductive performance:: not examined
Dose descriptor:: NOAEL
Effect level:: 1 127 mg/kg bw/day (actual dose received)
Based on:: test mat.
Sex:: male
Basis for effect level:: other: see 'Remark'
Dose descriptor:: NOAEL
Effect level:: 1 243 mg/kg bw/day (actual dose received)
Based on:: test mat.
Sex:: female
Basis for effect level:: other: see 'Remark'
Clinical signs:: not examined
Mortality / viability:: not examined
Body weight and weight changes:: not examined
Sexual maturation:: not examined
Organ weight findings including organ / body weight ratios:: not examined
Gross pathological findings:: not examined
Histopathological findings:: no effects observed
Remarks on result:: other: no mating - screening study
Reproductive effects observed:: not specified
Conclusions:: In a reliable screening study, a repeated oral dose NOAEL of 1243 mg/kg/day in females and 1127 mg/kg/day for males was determined for effects on reproductive organs in the rat.

Reference 6

Endpoint:: reproductive toxicity, other
Remarks:: other: repeat dose study with histopathology of reproductive organs.
Type of information:: other: published data
Adequacy of study:: weight of evidence
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: equivalent or similar to guideline
Guideline:: other: OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:: yes
Remarks:: (no neurobehavioural testing; limited range of endpoints assessed in other examinations)
Principles of method if other than guideline:: An in-house protocol based on OECD Guide-line 407, including evaluation of reproductive organs
GLP compliance:: no
Limit test:: no
Species:: rat
Strain:: Sprague-Dawley
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: M 84-98 g; F 81-93g
- Fasting period before study: no data
- Housing: no data
- Use of restrainers for preventing ingestion (if dermal): not applicable
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

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

IN-LIFE DATES: no data
Route of administration:: oral: gavage
Vehicle:: olive oil
Details on exposure:: PREPARATION OF DOSING SOLUTIONS:
- no data

VEHICLE
- Justification for use and choice of vehicle (if other than water): not stated
- Concentration in vehicle: 0, 2, 10 or 20%
- Amount of vehicle (if gavage): 5 ml/kg bw
- Lot/batch no. (if required): no data
- Purity: no data
Details on mating procedure:: no mating - screening study
Analytical verification of doses or concentrations:: no
Duration of treatment / exposure:: Exposure period: 28 days

Duration of test: 28 days
Frequency of treatment:: 5 days/week
Details on study schedule:: no mating - screening study
Remarks:: Doses / Concentrations:
100, 500, and 1000 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:: 10
Control animals:: yes, concurrent vehicle
Details on study design:: - Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
Positive control:: none
Parental animals: Observations and examinations:: CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

WATER CONSUMPTION: Yes

OTHER: ophthalmoscopic examination, haematology, clinical chemistry (reported elsewhere)
Oestrous cyclicity (parental animals):: no data
Sperm parameters (parental animals):: Parameters examined in males: testis weight
Litter observations:: no litters - no mating - screening study
Postmortem examinations (parental animals):: SACRIFICE
- Males: 28 days
- Females: 28 days

GROSS NECROPSY: Yes

HISTOPATHOLOGY: Yes, top dose and control animals only, including testes, prostate, ovaries, uterus, vagina

ORGAN WEIGHTS: Yes, including testes, ovaries
Postmortem examinations (offspring):: no offspring - no mating - screening study
Statistics:: no data
Reproductive indices:: no mating - screening study
Offspring viability indices:: no offspring - no mating - screening study
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:: no effects observed
Other effects:: not examined
Reproductive function: oestrous cycle:: not examined
Reproductive function: sperm measures:: not examined
Reproductive performance:: not examined
Dose descriptor:: NOAEL
Effect level:: 1 000 mg/kg bw/day
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: organ weights (ovaries, testes); histopathology (ovaries, uterus, vagina, testes, prostate)
Clinical signs:: not examined
Mortality / viability:: not examined
Body weight and weight changes:: not examined
Sexual maturation:: not examined
Organ weight findings including organ / body weight ratios:: not examined
Gross pathological findings:: not examined
Histopathological findings:: not examined
Remarks on result:: other: no litters - no mating - screening study
Reproductive effects observed:: not specified
Conclusions:: In a reliable screening study, performed using a protocol similar to OECD guideline 407, the 28-day oral NOAEL for effects on reproductive organs in rats was determined to be 1000 mg/kg bw/day.

Reference 7

Endpoint:: one-generation reproductive toxicity
Remarks:: based on generations indicated in Effect levels (migrated information)
Type of information:: other: published data
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: according to guideline
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
Limit test:: no
Species:: rat
Strain:: Wistar
Sex:: not specified
Details on test animals or test system 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
Remarks:: Doses / Concentrations:
0, 1500, 7500 or 30,000 ppm (ca 0, 100, 500, 2000 mg/kg/bw/day
Basis:
nominal in diet
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
Dose descriptor:: NOAEL
Effect level:: 2 000 mg/kg bw/day (nominal)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: mortality; body weight; food consumption and compound intake; gross pathology; organ weights; histopathology; number of implantation sites; duration of pregnancy; pregnancy index
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
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: litter size; litter weight; sex ratio; survival index
Reproductive effects observed:: not specified
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).

Reference 8

Endpoint:: screening for reproductive / developmental toxicity
Data waiving:: other justification
Justification for data waiving:: other:
Reproductive effects observed:: not specified

Reference 9

Endpoint:: reproductive toxicity, other
Remarks:: other: Repeat dose study with histopathology of reproductive organs.
Type of information:: other: published data
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: no guideline followed
Principles of method if other than guideline:: Rats treated via the diet for 90 days with limited evaluation, but including reproductive organs.
Groups of 20 rats (10 of each sex) were fed Alfol 16 in the diet for 13 weeks. The control group consisted of 20 males and 20 females at dose levels of 1, 2.5 and 5% with the top dose level increasing at week 11 to 7.5% and for weeks 12& 13 to 10% in the diet. At termination, all animals were necropsied and tissues from 5 males and 5 females (including gonads) of the high dose group and a similar number of controls were examined histopathologically. Testes and ovary weights were recorded together with other organ weights.
GLP compliance:: no
Limit test:: no
Species:: rat
Strain:: other: albino Charles river
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: no data but "young"
- Weight at study initiation: males 104.1 g, females 90.5 g
- Fasting period before study: no data
- Housing: individually in suspended wire-mesh cages
- Use of restrainers for preventing ingestion (if dermal): not applicable
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data but "controlled within narrow limits"
- Humidity (%): no data but "controlled within narrow limits"
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

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): weekly
- Mixing appropriate amounts with (Type of food): basal laboratory diet (Purina Laboratory Chow)
- Storage temperature of food: no data
Details on mating procedure:: no mating - screening study
Analytical verification of doses or concentrations:: no
Duration of treatment / exposure:: Exposure period: 13 weeks

Duration of test: 13 weeks
Frequency of treatment:: continuous in diet
Details on study schedule:: no mating - screening study
Remarks:: Doses / Concentrations:
1%, 2.5%, 5-10%
Basis:
nominal in diet
No. of animals per sex per dose:: 10 (treated), 20 (controls)
Control animals:: yes, plain diet
Details on study design:: - Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
Positive control:: none
Parental animals: Observations and examinations:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 5 days/week
- Cage side observations included: general physical appearance, gross signs of systemic toxicity and/or pharmacological effect, behaviour, mortality

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as mg/kg bw/day: Yes

WATER CONSUMPTION: No

OTHER: Haematology and urinalysis (reported elsewhere)
Oestrous cyclicity (parental animals):: no data
Sperm parameters (parental animals):: Parameters examined in males: testis weight
Litter observations:: no litters - no mating - screening study
Postmortem examinations (parental animals):: SACRIFICE
- Males: All surviving animals, after 13 weeks of treatment
- Females: All surviving animals after 13 weeks of treatment

GROSS NECROPSY
- Gross necropsy included external and internal examinations of the cervical, thoracic, and abdominal viscera

ORGAN WEIGHTS: brain, thyroid, heart, liver, spleen, kidneys, adrenals, gonads (testes or ovaries)

HISTOPATHOLOGY: Yes
- brain, thyroid, parathyroid, heart, lung, liver, spleen, stomach, small intestine, large intestine, pancreas, kidney, urinary bladder, adrenal, gonads (testes or ovaries), lymph node, bone, bone marrow
- all listed tissues from 5/sex from high dose and controls examined
Postmortem examinations (offspring):: no offspring - no mating - screening study
Statistics:: Chi-squared test for comparing relative organ weights. Original organ weight analyses using the Chi square test were supplemented by Tukey tests carried out by the Weinberg group (see 'Any other information on materials and methods')
Reproductive indices:: no mating - screening study
Offspring viability indices:: no offspring - no mating - screening study
Clinical signs:: no effects observed
Body weight and weight changes:: effects observed, treatment-related
Food consumption and compound intake (if feeding study):: effects observed, treatment-related
Organ weight findings including organ / body weight ratios:: effects observed, treatment-related
Histopathological findings: non-neoplastic:: no effects observed
Other effects:: effects observed, treatment-related
Reproductive function: oestrous cycle:: not examined
Reproductive function: sperm measures:: not examined
Reproductive performance:: not examined
Dose descriptor:: NOAEL
Effect level:: 1 822 mg/kg bw/day (actual dose received)
Based on:: test mat.
Sex:: male
Basis for effect level:: other: see 'Remark'
Dose descriptor:: NOAEL
Effect level:: 4 567 mg/kg bw/day (actual dose received)
Based on:: test mat.
Sex:: female
Basis for effect level:: other: see 'Remark'
Clinical signs:: not examined
Mortality / viability:: not examined
Body weight and weight changes:: not examined
Sexual maturation:: not examined
Organ weight findings including organ / body weight ratios:: not examined
Gross pathological findings:: not examined
Histopathological findings:: not examined
Remarks on result:: other: no mating - screening study
Reproductive effects observed:: not specified
Conclusions:: In a reliable screening study, a repeated oral dose NOAEL of 1822 mg/kg/day for males and 4567 mg/kg/day (the highest dose tested) in females was determined for effects on reproductive organs in the rat.

Reference 10

Endpoint:: reproductive toxicity, other
Remarks:: other: Repeat dose study with histopathology of reproductive organs.
Type of information:: other: published data
Adequacy of study:: supporting study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:: no guideline followed
Principles of method if other than guideline:: Small groups of dogs treated via the diet for 90 days with limited evaluation.
Groups of beagle dogs (2 of each sex/dose level) were exposed to hexadecan-1-ol at dose levels of 0.5, 1.0% and 3% w/w in the diet for 13 weeks. The control group contained 4 males and 5 females.Testes and ovaries were weighed and organs from top dose dogs examined histopathologically.
GLP compliance:: no
Limit test:: no
Species:: other: dog
Strain:: other: Beagle
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ORGANISMS
- Age: 5 months
- Weight at study initiation: M4.77-8.97 kg; F4.31-7.95 kg
- Number of animals: 2M+2F treated; 4M+5F controls
Route of administration:: oral: feed
Vehicle:: unchanged (no vehicle)
Details on exposure:: ADMINISTRATION / EXPOSURE
- Duration of test/exposure: 13 weeks
- Type of exposure: 0.5% and 1% in the diet (low and mid dose) daily, 1000 mg/kg/day as a gelatin capsule 6 days/week (high dose, dietary high dose was unpalatable).
- Post exposure period: None
- Vehicle: Diet, none for top dose level(gelatin capsule).
- Doses: 0.5 and 1% in diet, 1000 mg/kg by gelatin capsules.
Details on mating procedure:: no mating - screening study
Analytical verification of doses or concentrations:: no
Duration of treatment / exposure:: Exposure period: 13 weeks

Duration of test: 13 weeks
Frequency of treatment:: daily
Details on study schedule:: no mating - screening study
Remarks:: Doses / Concentrations:
0.5, 1.0 and 3.0% w/w
Basis:
nominal in diet
No. of animals per sex per dose:: Number of animals: 2M+2F treated; 4M+5F controls
Control animals:: yes
Positive control:: none
Parental animals: Observations and examinations:: CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: Daily 5 days/week. Complete physical examination, body temperature, pulse rate, reflexes, mucous membranes, auscultation pretreatment, 3, 6 & 13 weeks. ECG pretreatment, 3 and 13 weeks.
- Mortality: Daily (5 days/week?)
- Body weight: weekly
- Food consumption: weekly
- Water consumption: Not recorded.
- Ophthalmoscopic examination: Not recorded.
- Haematology: Total & differential leucocyte counts, Hb, haematocrit, erythrocyte sedimentation rate, prothrombin time measured pretreatment, 3, 6 and 13 weeks.
- Biochemistry: Plasma levels of glucose, total protein & albumin, albumin/globulin ratios, urea nitrogen measured pretreatment, 3, 6 and 13 weeks. Liver function assessed by BSP retention, alkaline phosphatase & ASAT at same time periods.
- Urinalysis: albumin, glucose, bilirubin, pH, vol. , specific gravity, microscopic examination of sediment, total nitrogen. Carried out pretreatemnt & at 3, 6 & 13 weeks.
Oestrous cyclicity (parental animals):: no data
Litter observations:: no litters - no mating - screening study
Postmortem examinations (offspring):: no offspring - no mating - screening study
Reproductive indices:: no mating - screening study
Offspring viability indices:: no offspring - no mating - screening study
Clinical signs:: no effects observed
Body weight and weight changes:: effects observed, treatment-related
Food consumption and compound intake (if feeding study):: effects observed, treatment-related
Organ weight findings including organ / body weight ratios:: effects observed, treatment-related
Histopathological findings: non-neoplastic:: no effects observed
Other effects:: effects observed, treatment-related
Reproductive function: oestrous cycle:: not examined
Reproductive function: sperm measures:: not examined
Reproductive performance:: not examined
Dose descriptor:: NOAEL
Effect level:: > 1 054 mg/kg bw/day
Based on:: test mat.
Sex:: male
Clinical signs:: not examined
Mortality / viability:: not examined
Body weight and weight changes:: not examined
Sexual maturation:: not examined
Organ weight findings including organ / body weight ratios:: not examined
Gross pathological findings:: not examined
Histopathological findings:: not examined
Reproductive effects observed:: not specified
Conclusions:: The NOAEL for effects on the reproductive organs of dogs is >1054 mg/kg/day (3% in the diet). There were no treatment related effects on reproductive organ weights and no histopathological changes in the gonads of top dose animals. This is also the NOAEL for systemic toxicity.

Reference 11

Endpoint:: screening for reproductive / developmental toxicity
Remarks:: based on test type (migrated information)
Type of information:: other: published data
Adequacy of study:: weight of evidence
Study period:: not stated
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:: no guideline required
Principles of method if other than guideline:: Repeated dose toxicity test in which rats were orally dosed daily for 26 weeks and reproductive organs assessed
GLP compliance:: not specified
Limit test:: no
Species:: rat
Strain:: other: CD
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: ~21-28 days at purchase
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5/cage in stainless steel cages, containing absorbent paper
- Diet (e.g. ad libitum): expanded rodent diet (Special Diets Services, UK), ad libitum
- Water (e.g. ad libitum): public supply (Suffolk Water Company, UK), ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- 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% aqueous Tween 80
Details on exposure:: PREPARATION OF DOSING SOLUTIONS:
- test material heated to approx. 80 deg C
- vehicle heated to approx. 75 deg C
- vehicle added to test material while being magnetically stirred at high speed
- resulting 20% (w/w) suspension homogenized and slowly cooled to below 60 deg C
- when cooled to 30 deg C, suspension slowly homogenized again for >=2 min
- cooled to room temp.
- stored at 13 deg C
- prepared once weekly
- 20% suspension used for top dose; for low and mid doses, suspension magnetically stirred and aliquots taken for dilution on day of use; constant dose volume of 5 ml/kg bw per dose
- dilutions mixed by hand swirling followed by magnetic stirring
VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 1%
- Amount of vehicle (if gavage): 5 ml/kg bw per dose
- Lot/batch no. (if required): no data
- Purity: no data
Details on mating procedure:: No mating - screening test
Analytical verification of doses or concentrations:: no
Duration of treatment / exposure:: 26 weeks
Frequency of treatment:: daily, 7 days/week
Details on study schedule:: No mating - screening test
Remarks:: Doses / Concentrations:
10, 100, 1000 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:: 20
Control animals:: yes, concurrent vehicle
Details on study design:: - Dose selection rationale: no data
- Rationale for animal assignment (if not random): random
- Other:
- Repeated dose toxicity (oral) study - acceptable as reproductive screen since reproductive organs were included in those evaluated
Positive control:: none
Parental animals: Observations and examinations:: CAGE SIDE OBSERVATIONS (including mortality): Yes
- Time schedule: >=twice daily
- Cage side observations included: evidence of reaction to treatment or moribund condition, evidence of ill health such as blood or loose faeces

DETAILED CLINICAL OBSERVATIONS: Yes, individual observations
- Time schedule: once daily during week 1, twice weekly during weeks 2 to 4, once weekly during weeks 5 to 13, once every 2 weeks from week 14 onwards

BODY WEIGHT: Yes
- Time schedule for examinations: pre-study, weekly during the study or more frequently if appropriate (for animals in moribund condition), at necropsy
FOOD CONSUMPTION:
- Food consumption for each cage determined: Yes

FOOD EFFICIENCY:
- Weekly group mean food conversion efficiencies calculated from the consumption and body weight gain data: Yes, for the first 14 weeks of treatment

WATER CONSUMPTION: No

OTHER: Ophthalmoscopic examination, haematology, clinical chemistry, urinalysis - reported elsewhere
Oestrous cyclicity (parental animals):: not examined; ovaries and uterus (with cervix) weighed and examined
Sperm parameters (parental animals):: not examined; testes and epididymides weighed and examined
Litter observations:: no litters - not mated - screening test
Postmortem examinations (parental animals):: SACRIFICE
- Male animals: after 26 weeks of treatment
- Maternal animals: after 26 weeks of treatment

GROSS NECROPSY
- Yes

ORGAN WEIGHTS: adrenals, brain, kidneys, liver, lungs (with main stem bronchi), ovaries, pituitary, prostate, spleen, testes, thymus, thyroid (with parathyroids), uterus, cervix

HISTOPATHOLOGY: Yes - adrenals, brain, eyes, optic nerve, femur, heart, kidneys, liver, lungs, seminal vesicles, spinal cord, stomach, thyroid, uterus
Postmortem examinations (offspring):: no offspring - not mated - screening test
Statistics:: Bartlett's test for homogeneity of variance (organ weights, body weight changes); if significant, Behrens-Fisher test, otherwise Dunnett's test.
Two-tailed Fisher's exact test (macroscopic/microscopic pathological findings).
Reproductive indices:: not mated - screening test
Offspring viability indices:: no offspring - not mated - screening test
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:: no effects observed
Other effects:: not examined
Reproductive function: oestrous cycle:: not examined
Reproductive function: sperm measures:: not examined
Reproductive performance:: not examined
Dose descriptor:: NOAEL
Effect level:: 1 000 mg/kg bw/day (nominal)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: overall effects
Remarks on result:: other: Generation: not mated - screening study (migrated information)
Clinical signs:: not examined
Mortality / viability:: not examined
Body weight and weight changes:: not examined
Sexual maturation:: not examined
Organ weight findings including organ / body weight ratios:: not examined
Gross pathological findings:: not examined
Histopathological findings:: not examined
Remarks on result:: other: no offspring - not mated - screening test
Reproductive effects observed:: not specified
Conclusions:: In a reliable screening study, a repeated oral dose NOAEL of 1000 mg/kg bw/day was determined for effects on reproductive organs in the rat.

Effect on fertility: via oral route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 2 000 mg/kg bw/day
Study duration:: subchronic
Species:: rat
Quality of whole database:

Effect on fertility: via inhalation route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEC
: 87 mg/m³
Study duration:: subchronic
Species:: rat
Quality of whole database:: Inhalation exposure:
There are no Inhalation reproduction studies available.
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat
2000 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 87 mg/m3

Effect on fertility: via dermal route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 50 mg/kg bw/day
Study duration:: chronic
Species:: rat
Quality of whole database:: There are no dermal reproduction studies available.
For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
corrected dermal NOAEL= oral NOAEL
2000 mg/kg bw/day x 0.025 kg =
NOAELrat = 50mg/kg bw/day

Additional information

Fertility studies

Dodecanol-1 and 1-octadecanol 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 dodecanol or octadecanol. There were no microscopic changes observed in the reproductive organs (Hansen, 1992 ). Docosanol (C22) did not affect reproductive parameters when administered orally at levels up to 1000 mg/kg/day to male and female rats during pre-mating (10 weeks for males and 2 weeks for females), mating and gestation (Iglesiaset al., 2002).

Absence of toxicity to reproductive organs at significant doses

As noted, testicular atrophy observed in dogs following a 13 week repeated dose exposure to 1000 mg/kg/day 1-hexanol administered via gelatin capsule was attributed to the general ill health, including severe gastrointestinal irritation, of the animals likely due to the manner in which the substance was administered. No effects on reproductive organs were observed in dogs that were exposed to the same test substance in the dietary portion of the study at both the 1% and 0.5% level of exposure (Sc. Assoc., 1966b). Similarly, rats receiving 1-hexanol in the diet at concentrations of 1% (with step-wise increases to 6%) showed no testicular weight changes or microscopic changes in the gonads (Sc. Assoc. 1966). Administration of high doses (up to 1000 mg/kg/day) of 1-hexadecanol, 1-octadecanol, 1-docosonol or C24 -34 alcohols to rats and/or dogs for periods up to one year was without adverse effects on the reproductive organs. Overall, these data justify the conclusion that linear alcohols have no potential for adverse effects on the reproductive organs.

Conclusion: Fertility assays did not reveal any adverse reproductive effects. Furthermore, examination of the reproductive organs in a number of repeated-dose studies did not show evidence indicative of adverse reproductive changes.Alcohols, C12-14 is from the category of Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22. Overall, there are no concerns that the category of Long Chain Aliphatic Alcohols might adversely affect fertility.

There are conclusive but not suffcient data for the classification of substance Alcohols, C12-14 with regard to reproduction.

It is concluded that the substance Alcohols, C12-14 does not meet the criteria to be classified for human health hazards for Reproductive toxicity.

Short description of key information:
There are conclusive but not suffcient data for the classification of substance Alcohols, C12-14 with regard to reproduction.
Non-ER binder due to non-cyclic molecular structure. Alcohols, C12-14 have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Alcohols, C12-14 does not cause reproductive toxicity.
It is concluded that the substance Alcohols, C12-14 does not meet the criteria to be classified for human health hazards for Reproductive toxicity.

Justification for selection of Effect on fertility via inhalation route:
Inhalation exposure:
There are no Inhalation reproduction studies available.
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat
2000 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 87 mg/m3

Effects on developmental toxicity

Description of key information

There are conclusive but not suffcient data for the classification of substance Alcohols, C12-14 with regard to Developmental toxicity / teratogenicity

Link to relevant study records

Referenceopen all close all

Reference 1

Endpoint:: developmental toxicity
Type of information:: other: published data
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: according to guideline
Guideline:: other: Draft 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 422 Combined repeat dose and reproductive/developmental toxicity screening test
GLP compliance:: yes
Limit test:: no
Species:: rat
Strain:: Wistar
Details on test animals or test system 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 (for males and for females up to day 20 of gestation); macrolon cages type 3 (for females 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.
Analytical verification of doses or concentrations:: no
Details on mating procedure:: - Impregnation procedure: cohoused with treated males
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- After 14 days of unsuccessful pairing replacement of first treated male by another treated male for up to 8 days
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- 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
- Any other deviations from standard protocol: none
Duration of treatment / exposure:: Females: up to 54 days (premating, mating and gestation until post natal day 5)
Males: 41-44 days (including 14 premating)
Frequency of treatment:: continuous in diet
Duration of test:: pups examined on postnatal day 5, following continuous treatment of male and female parents from 14 days prior to mating
No. of animals per sex per dose:: 12 male and 12 female parental animals per dose
Control animals:: yes, plain diet
Details on study design:: - Dose selection rationale: preliminary test apparently 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
Maternal 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: 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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on postnatal day (parental females): 5
- Organs examined (parental females): organ weights of liver, kidneys, thymus; organs fixed in formalin - liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, other organs with observed pathological changes; histopathology - control and top dose group, all fixed organs except thymus
Ovaries and uterine content:: The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
- Other:
- Total number of resorptions: Yes
Fetal examinations:: - On postnatal day 5, the pups were weighed and examined macroscopically for external malformations then sexed and examined for internal malformations, including:
- External examinations: Yes: all per litter
- Head examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
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
Indices:: numbers of corpora lutea, implantations, resorptions and pups at birth and on days 4 and 5
Historical control data:: none
Details on maternal toxic effects:: Maternal toxic effects:no effects

Details on maternal toxic effects:
- no mortality
- no statistically significant effects on body weight
- no statistically significant effects on organ weights or pathology
Dose descriptor:: NOAEL
Effect level:: 2 000 mg/kg bw/day (nominal)
Based on:: test mat.
Basis for effect level:: other: maternal toxicity
Dose descriptor:: NOAEL
Effect level:: 2 000 mg/kg bw/day (nominal)
Based on:: test mat.
Basis for effect level:: other: developmental toxicity
Fetal body weight changes:: no effects observed
Changes in litter size and weights:: not examined
Details on embryotoxic / teratogenic effects:: Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- no statistically significant effects on numbers of corpora lutea, implantations, resorptions or pups at birth; no statistically significant abnormalities in pups (see table 1)
Remarks on result:: other: no statistically significant effects on numbers of corpora lutea, implantations, resorptions or pups at birth; no statistically significant abnormalities in pups
Abnormalities:: not specified
Developmental effects observed:: not specified
Conclusions:: In a reliable study conducted to the draft OECD guideline 422, the NOAEL for maternal and developmental toxicity was 2000 mg/kg bw/day, the highest dose tested. The study was performed in compliance with GLP.Dodecan-1-ol (C12) is supporting substance for Alcohols,C12-C14 and the main component.
Executive summary:: Development was assessed as part of a combined repeat dose and reproductive/developmental toxicity study. There were no adverse effects on maternal toxicity or reproductive parameters and no adverse effect on the offspring which were examined on postnatal day 5. The NOAEL for maternal and foetotoxicity was 2000 mg/kg/day in rats receiving dodecanol in the diet for up to 54 days (premating, mating, gestation to postnatal day 5). There was no evidence of teratogenicity from the limited examinations of the pups which were carried out.

Reference 2

Endpoint:: developmental toxicity
Type of information:: other: published data
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:: no guideline followed
Principles of method if other than guideline:: Hexanol administered by inhalation to pregnant rats from day 1 to day 19 of gestation and uterine contents examined on day 20
GLP compliance:: not specified
Limit test:: no
Species:: rat
Strain:: Sprague-Dawley
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI, USA
- Age at study initiation: no data
- Weight at study initiation: 200-300 g
- Fasting period before study:
- Housing: shoebox cages with cleaned heat-treated sawdust bedding
- Diet (e.g. ad libitum): NIH-07 lab chow, ad libitum except during exposure
- Water (e.g. ad libitum): tap water, ad libitum except during exposure
- Acclimation period: 1-2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +- 2
- Humidity (%): 50 +- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data
Route of administration:: inhalation: vapour
Type of inhalation exposure (if applicable):: whole body
Vehicle:: unchanged (no vehicle)
Details on exposure:: GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 m3 Hinners type chambers
- Method of holding animals in test chamber: stainless steel wire mesh cages within the exposure chambers
- Source and rate of air: constant flow of alcohol mixed with known volume of heated compressed air causing instant vapourisation; mixture introduced into mainstream of chamber airflow upstream from an orifice; resulting turbulance produced uniform mixing
- Method of conditioning air: no data
- Temperature, humidity, pressure in air chamber: 25 +- 1 deg C, 50 +- 15%, no data on pressure
- Air flow rate: 0.5 m3/minute
- Air change rate: no data
- Treatment of exhaust air: no data

TEST ATMOSPHERE
- Brief description of analytical method used: Miran 1A infrared analyser, concentrations recorded every hour; charcoal tube samples 2 days/week and analyzed by gas chromatography
- Monitored continuously

VEHICLE (if applicable)
- not applicable
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Miran 1A infrared analyser, concentrations recorded every hour; charcoal tube samples 2 days/week and analyzed by gas chromatography
Details on mating procedure:: - Sperm positive females used, no other information
Duration of treatment / exposure:: days 1-19 of gestation
Frequency of treatment:: 7 hour/day
Duration of test:: 20 days
No. of animals per sex per dose:: 15 pregnant females
Control animals:: yes, sham-exposed
Details on study design:: Dose selection rationale: highest achievable concentration as a vapour at a temperature below 27 deg C (higher concentrations would have resulted in aerosol production)
- Rationale for animal assignment (if not random): "assigned without bias"
Maternal examinations:: CAGE SIDE OBSERVATIONS: Yes, no details (presumably daily) - "further, subjective observations of maternal animals did not provide evidence of toxicity"

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule: daily for the first week and weekly thereafter, means presented for days 0, 7, 14 and 20 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule: week 1, week 2, week 3 (days 7, 14 and 20 of gestation)

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule: week 1, week 3, week 3 (days 7, 14 and 20 of gestation)

POST-MORTEM EXAMINATIONS: No

OTHER:
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: No
- Number of late resorptions: No
- Other:
Total number of resorptions
Number of live foetuses
Fetal examinations:: - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: No
- Other:
foetal body weight and sex
Statistics:: Multivariate analysis of variance (MANOVA) and analysis of variance (ANOVA); statistical significance at p<=0.05; independent variable = exposure group; one-way MANOVA/ANOVA for litter data, with individual ANOVAs if significant MANOVA, with Bonferroni corrections for individual exposure groups if significant ANOVA; ANOVA for weight data using a litter per exposure group x day design; MANOVA/ANOVA for feed and water consumption data using a litter per exposure group x week design; for ANOVAs, Greenhouse-Geisser estimate of Box's epsilon used to correct within-litter main effects and interactions for ANOVAs
Indices:: no data
Historical control data:: resorption: up to 1.3 per litter
Details on maternal toxic effects:: Maternal toxic effects:no effects

Details on maternal toxic effects:
No clinical signs of toxicity; no effect on maternal body weight or water intake; food intake significantly higher than controls (127 +- 12 g vs. 117 +- 13 g); no effect on number of corpora lutea (17 +- 1, treated; 14 +- 4 controls); presumably no effect on number of implantations (no data presented, but endpoint measured according to methods); slight but statistically significant increase in total resorptions (1.3/litter in treated group, 0.4/litter in controls) but the frequency was within the historical control range
Dose descriptor:: NOAEC
Effect level:: 3 500 mg/m³ air (analytical)
Based on:: test mat.
Basis for effect level:: other: maternal toxicity
Dose descriptor:: NOAEC
Effect level:: 3 500 mg/m³ air (analytical)
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 effects on: litter size (mean, treated and control, 15), sex ratio (treated 8F,7M; controls 7F, 8M), grossly visible abnormalities, external or soft tissue abnormalities, male or female foetal weight (means, treated males 3.19 g, females 3.05g; control males 3.28 g, females 3.19 g); small, not statistically significant, effect on skeletal abnormalities - reversible delay in ossification of caudal vertebrae, sternum, metacarpals, and hindpaw phalanges (indicative of growth retardation but not accompanied by effects on foetal weight; data not presented).
Dose descriptor:: NOAEC
Effect level:: 3 500 mg/m³ air (analytical)
Based on:: test mat.
Basis for effect level:: other: teratogenicity
Abnormalities:: not specified
Developmental effects observed:: not specified
Conclusions:: In a reliable study, an NOAEC of 3500 mg/m3 (the highest achievable concentration in the test system) was determined in the rat for maternal toxicity and developmental toxicity after administration by inhalation for 7 hours/day on gestation days 1 to 19.

Reference 3

Endpoint:: developmental toxicity
Type of information:: other: published data
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: according to guideline
Guideline:: OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:: no
GLP compliance:: not specified
Limit test:: no
Species:: rat
Strain:: Fischer 344
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kinston, NY
- Age at study initiation: 84 (m) and 67 days (f)
- Weight at study initiation: 175-200 g (m) and 130-150 g (f) on arrival
- Fasting period before study: no data
- Housing: pregnant females were housed singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23
- Humidity (%): 42-65
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:: dermal
Vehicle:: unchanged (no vehicle)
Details on exposure:: TEST SITE
- Area of exposure: clipped dorsal skin, 1.5 x 1.5 inch, i.e. 9.7 cm²
- % coverage: no data
- Type of wrap if used: gauze patch, covered by a polyethylene patch. The application site was occluded with a Lycra-Spandex jacket
with Velcro closures.
- Time intervals for shavings or clipplings: no data

REMOVAL OF TEST SUBSTANCE
- Washing: no; th application site was gently wiped with moist gauze and blotted dry
- Time after start of exposure: 6 hours
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.3, 1, and 3 ml/kg bw/day
- Concentration (if solution): undiluted
- Constant volume or concentration used: yes; based on body weight on gestational day 6
- For solids, paste formed: n.a.

USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: The purit of the test material was examined by gas chromatography. The test material was dispensed from a 1.0 mL syringe
Details on mating procedure:: - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: no data
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug
Duration of treatment / exposure:: gestation day (GD) 6 through 15
Frequency of treatment:: daily; 6 hours/day
Duration of test:: 21 days
No. of animals per sex per dose:: 25 females per dose group in the main test;
8 females per dose group in the preliminary test
Control animals:: yes, sham-exposed
Details on study design:: - Dose selection rationale: based on the results of the preliminary test
Maternal examinations:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes / No / No data
- Time schedule for examinations:
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes / No / No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day #
- Organs examined:

OTHER:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before study initiation

BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 6, 9, 12, 15, and 21

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): n.a.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): n.a.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: weights of uterus, liver, spleen, adrenals, kidneys, and thymus were recorded. Ovaries, cervices, vaginas, and thoracic and abdominal cavities were examined grossly.
Ovaries and uterine content:: The ovaries and uterine content was examined after termination: Yes / No / No data
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:
Fetal examinations:: - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: cranofacial half per litter
Statistics:: Levene's test for equal variances, ANOVA, and t-tests with Bonferroni probabilities for pairwise comparaison were used. Nonparametrid data were evaluated using the Kruskal-Wallis test followed by Mann-Whitney test when appropriate. Incidences wre compared using Fisher's exact test
Historical control data:: Not required
Details on maternal toxic effects:: Maternal toxic effects:yes

Details on maternal toxic effects:
Administration of 2-ethylhexanol by occluded cutaneous application to time-pregnant Fischer 344 rats during organogenesis at 0, 0.3, 1.0, or 3.0 ml/kg bw/day (25 animals per dose) resulted in maternal toxicity at 1.0 and 3.0 ml/kg/day (clinical signs of toxicity at the dosing site for both doses and reduced weight gain in the treatment period at 3.0 ml/kg/day).
Dose descriptor:: NOAEL
Effect level:: 840 mg/kg bw/day
Based on:: test mat.
Basis for effect level:: other: maternal toxicity
Dose descriptor:: NOAEL
Effect level:: 2 520 mg/kg bw/day
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:
There was no developmental toxicity at any test dose. There was no treatment-related increased incidence of malformations
Dose descriptor:: NOAEL
Effect level:: 2 520 mg/kg bw/day
Based on:: test mat.
Basis for effect level:: other: teratogenicity
Abnormalities:: not specified
Developmental effects observed:: not specified
Conclusions:: No developmental toxicity by dermal route noted at and below dose levels producing maternal toxicity.
2-ethylhexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.
Executive summary:: The developmental toxicity of 2 -EH following dermal absorption was examined in a OECD TG 414 rat study that was conducted under GLP. 2 -EH was applied to the skin of 25 females at 252, 840, and 2520 mg/kg bw/day under an occlusive dressing during gestational days 6 -15 for 6 hours per day. The dose levels were selected based on the results of a preliminary study (Tyl et al., 1992).

The maternal toxicity was mild. There were no deaths or severe clinical signs of toxicity. A reduced body weight gain in high-dose rats was noted, and local skin irritation in rats at the intermediate and the high dose level.

2 -EH had no adverse effect on the maternal gestational parameters, or maternal organ weights, or on the fetal weight, sex ratio, viability, or the incidence of malformations and variations.

Therefore, the NOAEL for maternal systemic toxicity was 840 mg/kg bw/day, based on the effects on body weight gain; the NOAEL for skin irritation was 252 mg/kg bw/day. The NOAEL for developmental toxicity and teratogenicity was 2520 mg/kg bw/day.

2-ethylhexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.

Reference 4

Endpoint:

developmental toxicity

Type of information:

other: published data

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline followed

Principles of method if other than guideline:

Hexanol administered by gavage to pregnant rats from day 6 to day 15 of gestation and uterine contents examined on day

GLP compliance:

not specified

Limit test:

Species:

rat

Strain:

other: COBS CD

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

no data

Duration of treatment / exposure:

days 6-15 of gestation

Frequency of treatment:

daily

Duration of test:

to day 20 of gestation

No. of animals per sex per dose:

Control animals:

yes, concurrent vehicle

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes, appearance and behaviour
BODY WEIGHT: Yes

Fetal examinations:

- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Intrauterine survival
- Foetal body weight

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
There were no signs of maternal toxicity at 200 mg/kg/day.

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

In a briefly-reported study, an NOAEL of 200 mg/kg bw/day was determined for maternal toxicity and an NOAEL of 1000 mg/kg bw/day for developmental toxicity in the rat after oral administration on days 6 to 15 of gestation.

Executive summary:

The NOAEL for maternal toxicity in rats, following exposure by gavage to n-hexanol on gestation days 6-15, is considered to be 200 mg/kg/day based on clinical signs of toxicity and reduction in bodyweight at the higher dose level of 1000 mg/kg/day. The NOAEL for teratogenicity and foetotoxicity is considered to be 1000 mg/kg/day based on absence of adverse effects at this dose level (highest tested). A slight decrease in foetal weights was within historical control limits.

Reference 5

Endpoint:: developmental toxicity
Type of information:: other: published data
Adequacy of study:: weight of evidence
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: equivalent or similar to guideline
Guideline:: OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:: yes
Remarks:: (non standard examination of soft tissue and head of foetuses)
Qualifier:: according to guideline
Guideline:: other: ICH Harmonized Tripartite Guideline S5 (R2) for Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility
Deviations:: no
GLP compliance:: not specified
Limit test:: no
Species:: rabbit
Strain:: New Zealand White
Details on test animals or test system 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
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)
Based on:: test mat.
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)
Based on:: test mat.
Basis for effect level:: other: teratogenicity
Abnormalities:: not specified
Developmental effects observed:: not specified
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).

Reference 6

Endpoint:: developmental toxicity
Type of information:: other: published data
Adequacy of study:: supporting study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: equivalent or similar to guideline
Guideline:: OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:: yes
Remarks:: (non standard examination of soft tissue and head of foetuses)
Qualifier:: according to guideline
Guideline:: other: ICH Harmonized Tripartite Guideline S5 (R2) for Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility
Deviations:: no
GLP compliance:: not specified
Limit test:: no
Species:: rat
Strain:: Sprague-Dawley
Details on test animals or test system 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% 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
Duration of treatment / exposure:: For 15 days prior to mating, during mating and up to Day 17 of gestation.
Frequency of treatment:: daily
Duration of test:: females killed on day 29 of gestation
No. of animals per sex per dose:: 11
Control animals:: yes, concurrent vehicle
Details on study design:: Sex: female

Duration of test: 20th day of gestation
Maternal 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: daily

FOOD CONSUMPTION :
- Food consumption: Yes
- Time schedule: 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: females daily prior to mating, females on gestation days 0-2, 3-6, 7-9, 10-13, 14-17, 18-19
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:: 1 000 mg/kg bw/day
Based on:: test mat.
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:: 1 000 mg/kg bw/day
Based on:: test mat.
Basis for effect level:: other: teratogenicity
Abnormalities:: not specified
Developmental effects observed:: not specified
Conclusions:: 1000 mg/kg/day is the NOAEL for maternal toxicity, teratogenicity and foetotoxicity in rats receiving behenyl alcohol by gavage for 15 days premating, during mating and up until gestation day 17. This is based on the absence of adverse effects in any of the parental, reproductive or foetal parameters examined.

Reference 7

Endpoint:: developmental toxicity
Type of information:: other: published data
Adequacy of study:: supporting study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: according to guideline
Guideline:: OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:: no
GLP compliance:: not specified
Limit test:: no
Species:: mouse
Strain:: CD-1
Details on test animals or test system and environmental conditions:: - CD-1 Swiss mice
TEST ANIMALS
- Source: Charles River Laboratories Inc., Raleigh, NC
- Weight at study initiation: range 23.52-31.59 g
- Housing: individually in solid-bottom polycarbonate cage swith stainless steel wire lids
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 72°F
- Humidity (%): 48
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:: oral: feed
Vehicle:: other: microencapsulation
Details on exposure:: DIET PREPARATION
- Rate of preparation of diet (frequency): fed was prepared once. Fresh supplies of dosed feed were obtained from refrigerated stock every 3 days.
- Mixing appropriate amounts with (Type of food): Ground Purina Certified Rodnet Chow
- Storage temperature of food: refrigerated
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Concentration of 2-EH in the feed was analyzed by gas chromatography (GC) prior to use.
Details on mating procedure:: - Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:: Gestational days 0 to 17
Frequency of treatment:: 7/week
Duration of test:: 17 days
No. of animals per sex per dose:: 28
Control animals:: yes, plain diet
Details on study design:: Microencapsulated 2-EH (0%, 0.009%, 0.03%, or 0.09% in feed) was provided on gestational days (gd) 0 to 17 ad libitum to timed-mated CD-1® mice
(28/group).
Maternal examinations:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table [Appendis I-11] were included.

BODY WEIGHT: Yes
- Time schedule for examinations: gestational day 0, 3, 6. 9. 12, 15, 17

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- 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
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 17
- Organs examined: liver and uterus
Ovaries and uterine content:: At sacrifice (gd 17), the number of ovarian corpora lutea and uterine implantation sites, including resorptions, and dead or live fetuses, were recorded.
Fetal examinations:: Live and dead fetuses were weighed. Live fetuses were sexed and examined for external, visceral and skeletal malformations and variations.
Statistics:: General Linear Models (GLM) procedures were applied for the analysis of variance (ANOVA) of maternal and fetal parameters. Bartlett's test for homogeneity of variance was performed an all data to be analyzed by ANOVA. When ANOVA revealed a significant (p<0.05) dose effect, Dunnett’s Multiple Comparison Test was used to compare each of the treated groups with the control groups. Other analyses comprised chi square test and Fisher’s exact probability test.
Indices:: none
Historical control data:: not required
Details on maternal toxic effects:: Maternal toxic effects:no effects

Details on maternal toxic effects:
No dams died, delivered early or were removed from study. Pregnancy rate was high (93-96%) and equivalent across all groups. One litter at 0%
was fully resorbed; all other pregnant animals had live litters at scheduled necropsy. The numbers of live litters evaluated were 27 at 0.009 and
0.03% and 26 at 0 and 0.09% 2-EH.
There was no treatment-related maternal toxicity observed in this study. Maternal body weights, weight gains (absolute or corrected for gravid
uterine weight), gravid uterine weight and liver weight (absolute or relative to body weight) were unaffected. Food consumption (g/kg/day and g/day) was significantly increased for gd 0-3 at 0.09% and unaffected for all other time points evaluated. The calculated consumption of 2-EH, based on gestational food consumption was 0 (0 mmol/kg), 17 (0.13 mmol/kg), 59 (0.46 mmol/kg) and 191 mg/kg/day (1.49 mmol/kg), for the 0, 0.009, 0.03 and 0.090% groups, respectively.
Dose descriptor:: NOAEL
Effect level:: 191 mg/kg bw/day (actual dose received)
Based on:: test mat.
Basis for effect level:: other: maternal toxicity
Dose descriptor:: NOAEL
Effect level:: 191 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:
There were no effects of exposure to dietary 2-EH on any gestational parameters. The number of corpora lutea, uterine implantation sites (live, dead, resorbed), pre- and postimplantation loss, sex ratio (%, males) and live fetal body weight per litter (all fetuses or separately by sex) were all equivalent across all groups. There were also no treatment-related changes in the incidence of individual, external, visceral, skeletal or total malformations or variations.
Dose descriptor:: NOAEL
Effect level:: 191 mg/kg bw/day (actual dose received)
Based on:: test mat.
Basis for effect level:: other: teratogenicity
Abnormalities:: not specified
Developmental effects observed:: not specified
Conclusions:: No maternal or developmental toxicity was observed in a mouse oral feed study at (equivalent to OECD TG 414, dosing during gestation day 0-17) at any dose up to and including 191 mg/kg bw/day, the highest tested dose.
At equimolar doses, DEHP and and MEHP caused both maternal and developmental toxicity. It was therefore concluded that 2-EH does not play a in DEHP- or MEHP toxicity. 2-ethylhexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.
Executive summary:: 2-EH was examined in a mouse feed study for its potential for developmental toxicityequivalent toOECD TG 414 and under GLP conditions. Timed pregnant female CD-1 Swiss mice (28 animals/group, body weight range 32.5 to 31.6 g) received 2-EH in the diet at nominal concentrations of 0, 0.009, 0.03, and 0.09% during gestation days 0-17. The animals were housed singly and observations for clinical signs were made daily. Body weights were recorded on gestational day 0, 3, 6, 9, 12, 15, 17. Food consumption and test compound intake were calculated individually. Test substance purity and concentration in thediets wasverified using gas chromatography.Test substance purity was >99%. Concentration in the diets was within 99-108% of the nominal concentration.

Maternal effects:

Food intake and hence dose levels were higher than expected. Average intakes were 0, 17, 59, and 191 mg/kg bw/day, respectively. No dams died, delivered early or were removed from study. Pregnancy rates were high (93-96%) and equivalent across all groups. One litter at 0% was fully resorbed; all other pregnant animals had live litters at scheduled necropsy. The numbers of live litters evaluated were 27 at 0.009 and 0.03% and 26 at 0 and 0.09% 2-EH.

There was no treatment-related maternal toxicityobserved in this study. Maternal body weights, weight gains (absolute or corrected for gravid uterine weight), gravid uterine weight and liver weight (absolute or relative to body weight) were unaffected. Food consumption (g/kg/day and g/day) was significantly increased for GD 0-3 at 0.09% and unaffected for all other time points evaluated. The calculated consumption of 2-EH, based on gestational food consumption was 0 (0mmol/kg), 17 (0.13mmol/kg), 59 (0.46mmol/kg) and 191 mg/kg/day (1.49mmol/kg), for the 0, 0.009, 0.03 and 0.090% groups, respectively.

Fetal effects

There wereno effectsof exposure to dietary 2-EHon any gestational parameters.The number of corpora lutea, uterine implantation sites (live, dead, resorbed), pre- and postimplantation loss, sex ratio and live fetal body weight per litter (all fetuses or separately by sex) were all equivalent across all groups. There were also no treatment-related changes in the incidence of individual, external, visceral, skeletal or total malformations or variations.

In conclusion, there were no maternal or developmental toxic effects of 2-EH dietary exposure throughout gestation at any concentration tested, in contrast to the qualitatively similar maternal and developmental toxicity previously reported for DEHP (Tylet al., 1988) and MEHP (NTP, 1990) at approximately equimolar doses administered under comparable experimental conditions. The present study therefore indicates that2-EH plays essentially no role in the expression of DEHP-induced maternal and developmental toxicity. The NOAEL for maternal toxicity and for developmental toxicity and teratogenicity was therefore 191 mg/kg bw/day, the highest dose level tested.

Reference 8

Endpoint:: developmental toxicity
Type of information:: other: published data
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Qualifier:: according to guideline
Guideline:: other: Draft 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 422 Combined repeat dose and reproductive/developmental toxicity screening test
GLP compliance:: not specified
Limit test:: no
Species:: rat
Strain:: Wistar
Details on test animals or test system 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
Analytical verification of doses or concentrations:: no
Details on mating procedure:: - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 22 days
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- Proof of pregnancy: vaginal plug referred to as day 0 or, if the plug was recorded during the morning, day 1 of pregnancy
- Any other deviations from standard protocol: none
Duration of treatment / exposure:: Females up to 54 days, premating, mating and gestation until post natal day 5.
Males also treated.
Frequency of treatment:: continuous in diet
Duration of test:: From 14 days prior to mating then throughout mating and gestation until post natal day 5
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
Maternal 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): Yes
- 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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on postnatal day 5
- Organs examined: liver, kidney, adrenals, brain, heart, spleen, ovaries, thymus and other organs with observed pathological changes.

OTHER: Total gross pathological examinations were performed on each animal at necropsy and organ weights determined for the liver, kidneys and thymus.
Ovaries and uterine content:: The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
- Other: number of resorptions was examined but it is not specified whether these were early or late.
Fetal examinations:: - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: No
- Head examinations: Yes: all per litter
Statistics:: Statistical analysis made on all data using the SAS-stat program. All statistically significant findings were further evaluated by means of Dunnett¿s t-test to assess possible inter-group differences.
Indices:: Pregnancy rate
Historical control data:: none
Details on maternal toxic effects:: Maternal toxic effects:no effects

Details on maternal toxic effects:
- Body weight: No treatment related effects.
- Food/water consumption: No treatment related effects.
- Description, severity, time of onset and duration of clinical signs: None reported.
- Pregnancy rate: 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 investigators (actual historical control data not presented).
- Fertility index: Not reported
- Precoital interval: Not reported
- Duration of gestation: Comparable in treated and control dams.
- Gestation index: Not reported
- Changes in lactation: Not reported
- Changes in estrus cycles: Not reported
- Mortality: None
- Number of implantations: 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).
- Number of corpora lutea: No significant differences between treated and control groups (mean controls 13, low and mid dose 14, high dose 15).
- Ovarian primordial follicle counts: Not reported
Dose descriptor:: NOAEL
Effect level:: 2 000 mg/kg bw/day (nominal)
Based on:: test mat.
Basis for effect level:: other: maternal toxicity
Details on embryotoxic / teratogenic effects:: Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Litter size and weights: No effect of treatment (mean litter size 11.73, 10.0, 13.6 and 13.38 for controls, low, mid and high dose respectively). 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)
- Sex and sex ratios: No treatment related effects.
- Post natal survival until day 5: Similar in treated and control groups.
- Foetal anomalies: There were no treatment related changes in the incidence of external or visceral malformations visible on macroscopic examination.
Dose descriptor:: NOAEL
Effect level:: 2 000 mg/kg bw/day (nominal)
Based on:: test mat.
Basis for effect level:: other: teratogenicity
Abnormalities:: not specified
Developmental effects observed:: not specified
Conclusions:: In a reliable study, development was assessed as part of a combined repeat dose and reproductive/developmental toxicity study, conducted according to draft OECD guideline 422. The NOAEL for maternal and foetotoxicity in rats was 2000 mg/kg bw/day (highest dose level). There was no evidence of teratogenicity from the limited examination of the pups that was carried out.

Effect on developmental toxicity: via oral route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 2 000 mg/kg bw/day
Study duration:: subchronic
Species:: rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEC
: 3 500 mg/m³
Study duration:: subacute
Species:: rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 2 520 mg/kg bw/day
Study duration:: subacute
Species:: rat

Additional information

Oral exposure

In a reliable study(Hansen, E. 1992), development was assessed as part of a combined repeat dose and reproductive/developmental toxicity study, conducted according to draft OECD guideline 422. The NOAEL for maternal and foetotoxicity in rats was 2000 mg/kg bw/day (highest dose level). There was no evidence of teratogenicity from the limited examination of the pups that was carried out. Dodecan-1-ol (C12) is supporting substance for Alcohols,C12-C14 and the main component and it is considered that read-across is valid.

NOAELrat = 2000mg/kg bw/day

In a reliable study(Hansen, E. 1992), development was assessed as part of a combined repeat dose and reproductive/developmental toxicity study, conducted according to draft OECD guideline 422. The NOAEL for maternal and foetotoxicity in rats was 2000 mg/kg bw/day (highest dose level). There was no evidence of teratogenicity from the limited examination of the pups that was carried out. Octadecan-1-ol (C18) is closely related to the registered substance, Alcohols, C12-14 and it is considered that read-across is valid.

NOAELrat = 2000mg/kg bw/day

In a reliable study (Iglesias G, JJ Hlywka, JE Berg, MH Khalil, LE Pope and D Tamarkin,2002), 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. Docosan-1-ol (C22) ) is closely related to the registered substance, Alcohols, C12-14 and it is considered that read-across is valid.

NOAELrabbit = 2000mg/kg bw/day

In a reliable study (Iglesias G, JJ Hlywka, JE Berg, MH Khalil, LE Pope and D Tamarkin,2002), conducted according to a protocol similar to OECD guideline 414, the NOAEL was 1000 mg/kg/day 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. Docosan-1-ol (C22) ) is closely related to the registered substance, Alcohols, C12-14 and it is considered that read-across is valid.

NOAELrat = 1000mg/kg bw/day

In a briefly-reported study (Rodwell D E, Mercieca M D, Rusch G M, Tasker E J,1988), an NOAEL of 200 mg/kg bw/day was determined for maternal toxicity and an NOAEL of 1000 mg/kg bw/day for developmental toxicity in the rat after oral administration on days 6 to 15 of gestation. Hexan-1-ol (C6) is closely related to the registered substance, Alcohols, C12-14 and it is considered that read-across is valid.

NOAELrat = 1000mg/kg bw/day

Dermal exposure:

The developmental toxicity of 2 -EH following dermal absorption was examined in a OECD TG 414 rat study that was conducted under GLP. 2 -EH was applied to the skin of 25 females at 252, 840, and 2520 mg/kg bw/day under an occlusive dressing during gestational days 6 -15 for 6 hours per day. The dose levels were selected based on the results of a preliminary study (Tyl et al., 1992).

The maternal toxicity was mild. There were no deaths or severe clinical signs of toxicity. A reduced body weight gain in high-dose rats was noted, and local skin irritation in rats at the intermediate and the high dose level.

2 -EH had no adverse effect on the maternal gestational parameters, or maternal organ weights, or on the fetal weight, sex ratio, viability, or the incidence of malformations and variations.

Therefore, the NOAEL for maternal systemic toxicity was 840 mg/kg bw/day, based on the effects on body weight gain; the NOAEL for skin irritation was 252 mg/kg bw/day. The NOAEL for developmental toxicity and teratogenicity was 2520 mg/kg bw/day.

2-ethylhexan-1-ol is a substance supporting the category Long Chain aliphatic Alcohols within a carbon chain length range of C6-C22 and it is considered that read-across is valid.

NOAELMaternal: (840 mg/kg bw d)

NOAEL developmental toxicity and teratogenicity : (2520 mg/kg bw d)

Inhalation exposure:

Groups of approximately 15 sprague-dawley rats were exposed to 7 h/day on gestation days 1-19 to 3500 mg/m3 1-hexanol, which was the highest concentration which could be generated as a vapor. Dams were weighed daily for the first week of exposure and weekly thereafter and were sacrificed on day 20. Fetuses were serially removed, blotted dry, examined for external malformationa, sexed, weighed, fixed, and examined for visceral or skeletal defects.

In a reliable study (Nelson B K, Brightwell W S, Khan A, Krieg E F Jr, Hoberman A M,1989), an NOAEC of 3500 mg/m3 (the highest achievable concentration in the test system) was determined in the rat for maternal toxicity and developmental toxicity after administration by inhalation for 7 hours/day on gestation days 1 to 19.Hexan-1-ol (C6) is closely related to the registered substance, Alcohols, C12-14 and it is considered that read-across is valid.

NOAECrat = 3500mg/m3

Toxicity to reproduction: other studies

Link to relevant study records

Reference

Endpoint:: toxicity to reproduction: other studies
Type of information:: other: published data
Adequacy of study:: supporting study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:: no guideline followed
Principles of method if other than guideline:: Type: other: Effects on the rat prostate
GLP compliance:: not specified
Type of method:: in vivo
Species:: rat
Strain:: Wistar
Sex:: male
Route of administration:: oral: gavage
Vehicle:: unchanged (no vehicle)
Analytical verification of doses or concentrations:: not specified
Duration of treatment / exposure:: 28 days
Frequency of treatment:: daily
Duration of test:: Duration of test: 28 days
Remarks:: Doses / Concentrations:
1, 10, 100 mg/kg
Basis:
Control animals:: yes, concurrent vehicle
Details on study design:: Duration of test: 28 days
Dose descriptor:: NOAEC
Effect level:: 100 mg/kg bw/day (nominal)
Based on:: test mat.
Sex:: male
Basis for effect level:: other: Docosanol had no effect on the weight or histology of the prostate in intact rats but increased the RNA/DNA quotient in the ventral prostate.
Remarks on result:: not determinable
Remarks:: no NOAEC identified
Conclusions:: Docosanol had no effect on the weight or histology of the prostate in intact rats but increased the RNA/DNA quotient in the ventral prostate. Plasma LH and testosterone were reduced. In orchidectomised rats docosanol increased the prostate and adrenal weight but there was no increase in orchidectomised adn adrenalectomised rats, a weight reduction being observed. Also docosanol had a thymolytic effect in intact rats but not in adrenalectomised rats where the thymus weight was increased. These results suggest a stimulation of adrenal steroid secretion but this may not be the only effect of docosanol.
Docosanol is closely related to the registered substance, Alcohols, C16-18, and it is considered that read-across is valid.

Additional information

Docosanol administered by gavage to rats aged 6-7 months for 28 days did not affect bodyweight or the weights of any of the organs weighed other than a statistically significant increase in weight of

the seminal vesicles at the lower dose levels (1 and 10 mg/kg/day). There were no histological differences in the accessory sexual organs.

Docosanol had no effect on the weight or histology of the prostate in intact rats but increased the RNA/DNA quotient in the ventral prostate. Plasma LH and testosterone were reduced. In orchidectomised rats docosanol increased the prostate and adrenal weight but there was no increase in orchidectomised adn adrenalectomised rats, a weight reduction being observed. Also docosanol had a thymolytic effect in intact rats but not in adrenalectomised rats where the thymus weight was increased. These results suggest a stimulation of adrenal steroid secretion but this may not be the only effect of docosanol.

Docosanol is closely related to the registered substance, Alcohols, C12-14, and it is considered that read-across is valid.

no NOAEC identified : 100 mg/kg bw d)

Justification for classification or non-classification

Based on the hazard assessment of Alcohols, C12-14 in section 2.1 and 2.2. in IUCLID 6, available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health” andaccording to the criteria described in Directive 67/548 and in the CLP Regulation:

Directive 67/548

Toxicity to reproduction/development

Repr. Cat. 1; R61 May cause harm to the unborn child.

Repr. Cat. 2; R61 May cause harm to the unborn child.

Repr. Cat. 3; R63 Possible risk of harm to the unborn child.

Toxicity to reproduction/fertility

Repr. Cat. 1; R60 May impair fertility.

Repr. Cat. 2; R60 May impair fertility.

Repr. Cat. 3; R62 Possible risk of impaired fertility

CLP

Reproductive toxicity

Repr. 1A

Repr. 1B

Repr. 2

H360: May damage fertility or the unborn child <state specific effect if known > <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

H361: Suspected of damaging fertility or the unborn child <state specific effect if known> <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

It is concluded that the Alcohols, C12-14 does not meet the criteria to be classified for human health hazards for Reproductive toxicity

Additional information

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

	Control	Low	Mid	High
Males	0.793	0.768*	0.787	0.902*+
SD	0.062	0.003	0.084	0.052

Observation	Dose (mg/kg bw/day) (nominal via diet)
Observation	0	100	500	2000
Pregnancy rate (%)	92	83	83	75
Number of litters	12	11	10	9
Mean (±SD) number of corpora lutea	14±1.7	14±0.9	14±1.5	14±1.6
Mean (±SD) number of implantations	13±2.4	14±1.4	14±1.9	14±1.1
Total number of resorptions	0	0	0	0
Total number of pups (day 1)	159	146	132	120
Mean number of pups per litter (day 1)^b	13.25	13.27	13.20	13.33
Mean (±SD) litter weight (day 1) (g)	75±12.9	75±7.3	71±8.9	77±5.5
Total number of pups (day 4)	156	143^a	125	118
Total number of pup deaths (days 1-4)	3	3	7	2
Mean (±SD) litter weight (day 4) (g)	106±14.9	107±9.9	101±12.9	104±9.8
Mean (±SD) litter weight gain (day 4) (g)	31±8.5	32±4.5	30±6.3	27±7.8
Total number of pups (day 5) number of males number of females	156 70 86	144^a 55 89	125 61 63	118 62 56
Sex Ratio (% Male)^b	45	38	49	53
Mean (±SD) male pup body weight (day 5) (g)	9±0.7	9±0.5	9±1.2	9±1.1
Mean (±SD) female pup body weight (day 5) (g)	10±0.9	10±0.7	10±1.2	9±1.1
Postmortem findings - pups (day 5)	hydronephrosis (1 female), unilateral dil. renal pelvis (1 male), yellow spots on liver (1 male)	bilateral dil. renal pelvis (2 females), unilateral dil. renal pelvis (1 female)		aplasia testisuni. (1 male)

	Dose levels (mg/kg bw/day)
	0 (sham)	252	840	2520
No. pregnant dams	11.6(a)	10.4	11.3	10.8

Corpora lutea /dam	16.0	15.4	15.7	15.3
Total implants	5.9	6.7	8.3	7.4
Viable implants	4.24	4.36	3.96	3.2
Nonviable implants	0.4	0.2	0.1	0.1
Early resorptions	0.4	0.2	0.1	0.1
Late resorptions	0	0	0	0
Dead fetuses	0	0	0.1	0
Percentage of live fetuses	86	96.8	97.8	99
Sex ratio (% males)	62.8	41.8	43.7	53.4
Fetal body weight (g)	4.59	4.51	4.4	4.5

	Dose levels (mg/kg bw/day)
	0 (sham)	252	840	2520
External malformationsNumber with malformations/Number examined	0/110	0/124	0/185	0/147
%	0	0	0	0
Soft tissue malformationsNumber with malformations /Number examined	0/110	0/124	0/185	0/147
%	0	0	0	0
Skeletal malformationsNumber with malformations /Number examined	0/110	0/124	0/185	0/147
%	0	0	0	0

External variationsNumber with variations/Number examined	13/110	19/124	37/185	21/147
%	11.8	15.3	20	14.3
Soft tissue variationsNumber with variations/Number examined	30/63	36/66	57/97	42/79
%	47.6	54.5	58.8	53.2
Skeletal variationsNumber with variations/Number examined	53/53	88/88	68/68	31/31
%	100	100	100	100

Observation	Dose (mg/kg bw/day)
Observation	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	9.3^b±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

	Dose (mg/kg bw/d)
	0 (sham)	252	840	2520
Females in study	25	25	25	25
Delivered	2	2	0	0
Necropsied
- nonpregnant	3	4	2	5
- pregnant	20	19	23	20
- with only nonviable implants	2	0	0	0
- with viable fetuses	18	19	23	20
% pregnant

Registration Dossier

Registration Dossier

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Diss Factsheets

Alcohols, C12-14

Endpoint summary

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Link to relevant study records

Referenceopen allclose all

Effect on fertility: via oral route

Effect on fertility: via inhalation route

Effect on fertility: via dermal route

Additional information

Effects on developmental toxicity

Description of key information

Link to relevant study records

Referenceopen allclose all

Effect on developmental toxicity: via oral route

Effect on developmental toxicity: via inhalation route

Effect on developmental toxicity: via dermal route

Additional information

Toxicity to reproduction: other studies

Link to relevant study records

Reference

Additional information

Justification for classification or non-classification

Additional information

Referenceopen all close all

Referenceopen all close all