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EC number: 267-008-6 | CAS number: 67762-27-0 This substance is identified by SDA Substance Name: C16-C18 alkyl alcohol and SDA Reporting Number: 19-060-00.
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
It is concluded that the substance Alcohols, C16-18 does not meet the criteria to be classified for human health hazards for Reproductive toxicity
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- other: Repeat dose study with histopathology of reproductive organs.
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- Alcohols, C16-18 is a member and is from Long Chain Alcohols (C6-22 primary aliphatic alcohols) category.
The Long Chain Alcohols (C6-22 primary aliphatic alcohols) category is considered suitable as a source of data for Alcohols, C16-18.
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.
Long Chain Alcohols (C6-22 primary aliphatic alcohols) category covers a family of 30 primary aliphatic alcohols within a carbon chain length range of C6-C22. Commercial products generally include several aliphatic alcohol components, with a range of carbon chain lengths present. The family consists of alcohols with varying compositions and structures. Composition depends on the route to manufacture and the related feedstocks. Most of the alcohols have linear carbon chains but certain manufacturing processes create branched structures. Data are also available for eleven other similar substances, which support the category. Non-sponsored alcohols may not be HPV or may not be produced by members of the consortium, but have structures similar to sponsored linear alcohols.
Key points are that the members share:
• The same structural features
• Similar metabolic pathways
• Common mode of ecotoxicological action
• Common levels and mode of human health related effects. - Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- 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:
- not specified
- Remarks:
- Pre-dates widespread introduction of GLP
- 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
- Dose / conc.:
- 10 other: %
- Remarks:
- nominal in diet
- Dose / conc.:
- 5 other: %
- Remarks:
- nominal in diet
- Dose / conc.:
- 2.5 other: %
- Remarks:
- nominal in diet
- Dose / conc.:
- 1 other: %
- Remarks:
- 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
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: 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
- Key result
- 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'
- Key result
- 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
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- not examined
- Body weight and weight changes:
- not examined
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- 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
- Other effects:
- not examined
- Generation:
- F1
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: no offspring - 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
- none of the animals displayed overt signs of intoxication due to oral exposure to hexadecanol during the 13 weeks of the experiment.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- food consumption and body weights differed significantly for both males and females at various times in the intermediate and high dose levels.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
- animals in the low, mid and high dose groups were administered dietary concentration of 1%, 2.5% and 5-10% respectively
- average compound intake for males, calculated from weekly food consumption data, was 723, 1822 and 4257 mg/kg bw/day respectively
- average compound intake for females, calculated from weekly food consumption data, was 875, 2064 and 4567 mg/kg bw/day respectively
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
- not examined
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
- not examined
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- not examined
ORGAN WEIGHTS (PARENTAL ANIMALS)
- the relative testes weights were increased over control levels in all treatment groups reaching signficance in the low and high dose group according to the study report. The organ weight data were reanalysed by the Weinberg Associates using a Tukey test when significance was attained only at the high dose level (see 'Remarks on results' section)
- there were no significant changes in ovary weight
GROSS PATHOLOGY (PARENTAL ANIMALS)
- no effects
HISTOPATHOLOGY (PARENTAL ANIMALS)
- histopathological examination revealed no treatment-related changes in the ovaries or testes.
OTHER FINDINGS (PARENTAL ANIMALS)
Gonad weight mean relative:
|
Control |
Low |
Mid |
High |
Males |
0.793 |
0.768* |
0.787 |
0.902*+ |
SD |
0.062 |
0.003 |
0.084 |
0.052 |
*Significant using Chi square test as reported in original report. +Significant in Tukey test.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 822 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 79.2 mg/m³
- Study duration:
- chronic
- 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
1822 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 79.2 mg/m3
Effect on fertility: via dermal route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 45.55 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
1822 mg/kg bw/day x 0.025 kg =
NOAELrat = 45.55 mg/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, C16-18 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.
Short description of key information:
There are conclusive but not suffcient data for the classification of substance Alcohols, C16-18 with regard to reproduction.
It is concluded that the substance Alcohols, C16-18 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
1822 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 79.2 mg/m3
Effects on developmental toxicity
Description of key information
There are conclusive but not suffcient data for the classification of substance Alcohols, C16-18 with regard to Developmental toxicity / teratogenicity
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- 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.
Alcohols, C16-18 is a member and is from Long Chain Alcohols (C6-22 primary aliphatic alcohols) category.
The Long Chain Alcohols (C6-22 primary aliphatic alcohols) category is considered suitable as a source of data for Alcohols, C16-18.
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.
Long Chain Alcohols (C6-22 primary aliphatic alcohols) category covers a family of 30 primary aliphatic alcohols within a carbon chain length range of C6-C22. Commercial products generally include several aliphatic alcohol components, with a range of carbon chain lengths present. The family consists of alcohols with varying compositions and structures. Composition depends on the route to manufacture and the related feedstocks. Most of the alcohols have linear carbon chains but certain manufacturing processes create branched structures. Data are also available for eleven other similar substances, which support the category. Non-sponsored alcohols may not be HPV or may not be produced by members of the consortium, but have structures similar to sponsored linear alcohols.
Key points are that the members share:
• The same structural features
• Similar metabolic pathways
• Common mode of ecotoxicological action
• Common levels and mode of human health related effects. - Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Remarks:
- Pre-dates widespread introduction of GLP
- 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
- Dose / conc.:
- 2 520 mg/kg bw/day
- Dose / conc.:
- 840 mg/kg bw/day
- Dose / conc.:
- 252 mg/kg bw/day
- Dose / conc.:
- 0 mg/kg bw/day
- 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.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- 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
- Justification for type of information:
- Alcohols, C16-18 is a member and is from Long Chain Alcohols (C6-22 primary aliphatic alcohols) category.
The Long Chain Alcohols (C6-22 primary aliphatic alcohols) category is considered suitable as a source of data for Alcohols, C16-18.
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.
Long Chain Alcohols (C6-22 primary aliphatic alcohols) category covers a family of 30 primary aliphatic alcohols within a carbon chain length range of C6-C22. Commercial products generally include several aliphatic alcohol components, with a range of carbon chain lengths present. The family consists of alcohols with varying compositions and structures. Composition depends on the route to manufacture and the related feedstocks. Most of the alcohols have linear carbon chains but certain manufacturing processes create branched structures. Data are also available for eleven other similar substances, which support the category. Non-sponsored alcohols may not be HPV or may not be produced by members of the consortium, but have structures similar to sponsored linear alcohols.
Key points are that the members share:
• The same structural features
• Similar metabolic pathways
• Common mode of ecotoxicological action
• Common levels and mode of human health related effects. - Reason / purpose for cross-reference:
- read-across: supporting information
- 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
- Remarks on result:
- not determinable
- Dose descriptor:
- NOAEC
- Effect level:
- 3 500 mg/m³ air (analytical)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Remarks on result:
- not determinable
- 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.
- Sex:
- male/female
- Basis for effect level:
- other:
- Remarks on result:
- not determinable
- Dose descriptor:
- NOAEC
- Effect level:
- 3 500 mg/m³ air (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: teratogenicity
- Remarks on result:
- not determinable
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- 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.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- Alcohols, C16-18 is a member and is from Long Chain Alcohols (C6-22 primary aliphatic alcohols) category.
The Long Chain Alcohols (C6-22 primary aliphatic alcohols) category is considered suitable as a source of data for Alcohols, C16-18.
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.
Long Chain Alcohols (C6-22 primary aliphatic alcohols) category covers a family of 30 primary aliphatic alcohols within a carbon chain length range of C6-C22. Commercial products generally include several aliphatic alcohol components, with a range of carbon chain lengths present. The family consists of alcohols with varying compositions and structures. Composition depends on the route to manufacture and the related feedstocks. Most of the alcohols have linear carbon chains but certain manufacturing processes create branched structures. Data are also available for eleven other similar substances, which support the category. Non-sponsored alcohols may not be HPV or may not be produced by members of the consortium, but have structures similar to sponsored linear alcohols.
Key points are that the members share:
• The same structural features
• Similar metabolic pathways
• Common mode of ecotoxicological action
• Common levels and mode of human health related effects. - Reason / purpose for cross-reference:
- read-across: supporting information
- 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: 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
- Dose / conc.:
- 30 000 ppm (nominal)
- Remarks:
- 2000 mg/kg bw/day
- Dose / conc.:
- 7 500 ppm (nominal)
- Remarks:
- 500 mg/kg bw/day
- Dose / conc.:
- 1 500 ppm (nominal)
- Remarks:
- 100 mg/kg bw/day
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Doses chosen from the results of a preliminary test.
- Rationale for animal assignment (if not random): Randomized into 4 groups with the same mean body weight - 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:
- no
- 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.
- Executive summary:
Based on the weight of evidence from other alcohols across the category and the combined repeat dose/reproductive/developmental study with octadecan-1-ol, it is concluded that octadecan-1-ol is unlikely to be a developmental toxicant in the absence of maternal toxicity.
Referenceopen allclose all
Maternal data Fate: No females died, aborted or were removed from the study. Two sham control and two low dose rats delivered early, and their data were omitted (table 1). Of the treated rats thge pregnancy rates ranged between 88 to 92%; the viability was 100% at all dose levels (table 1):
|
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 |
|
|
|
|
Clinical findings for 2 -EH treated rats were limited to lower body weight changes at the beginning of the treatment (GD 6 -9; p<0.05 in the high dose group), skin irriation (exfoliation, encrustation, and erythema, but no edema). Erythema were seen at 840 mg/kg bw/day and above. Skin irritation was generally mild, max. Draize score was 0.3 on GD14 at 1680 mg/kg bw/day in the main study. Nasal and ocular effects (encrustation and discharge) were seen with 2 -EH and sham controls. This effect was therefore not regarded to be treatment-related. Necropsy findings: Residual exfoliation and crusting at the application site in mid- and high-dose 2 -EH groups were the only treatment-related findings; i.e. body weight, gravid uterus weight, and organ weights were all comparable to the controls. Gestational parameters: 2 -EH was without adverse effect, at any treatment level, compared with controls (table 2):
|
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 |
(a)n = 18 Fetal data Fetal body weight was not affected at any dose level (table 2).
The incidence and the pattern of malformations or variations was not changed in treated rats compared to controls (table 3):
|
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 |
The actual control value for total resorptions was at the lower end of the range of values found among 11 control groups used in a series of similar studies by these authors over a 5 year period (Nelson et al 1990b). The range of resorptions in these control groups was 0.2 -1.5 per litter (mean 0.9) further suggesting that this was not a treatment related effect.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- 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. Octadecan-1-ol (C18) is closely related to the registered substance, Alcohols, C16-18 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, C16-18 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, C16-18 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, C16-18 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, C16-18 and it is considered that read-across is valid.
NOAECrat = 3500mg/m3
Toxicity to reproduction: other studies
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, C16-18, 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, C16-18 in section 2.1 and 2.2. in IUCLID 5.4., 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
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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>.
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It is concluded that the Alcohols, C16-18 does not meet the criteria to be classified for human health hazards for Reproductive toxicity
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