Alcohols, C16-18

Endpoint summary

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

Reference

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

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- 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)

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

no offspring - no mating - screening study

Generation:

F1

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: no offspring - no mating - screening study

Reproductive effects observed:

not specified

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. 

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.

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

Reference

Reference 1

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

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

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 2

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

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.

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:

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.

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

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, C16-18 does not meet the criteria to be classified for human health hazards for Reproductive toxicity