Hexyl acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No data are available for the reproductive toxicity endpoint. A waiver is proposed for the 2-generation reproductive toxicity study, in line with Column 2 of Annex IX of the REACH Regulation and consistent with current guidance.  The 2-generation study is triggered at this tonnage band by alerts or concerns for reproductive toxicity from available data, QSAR or from related substances.  The key repeated dose toxicity study for hexyl acetate was a read-across 90-day inhalation study performed with the structurally related substance butyl acetate.  This study included assessment of testes weight, histopathology and sperm counts.  No clear effects of treatment were apparent on these parameters.  There is therefore no specific alert or concern over the reproductive toxicity of hexyl acetate.

Short description of key information:

No data are available for the reproductive toxicity endpoint.

Effects on developmental toxicity

Description of key information

Studies using gavage administration in the rat are available for octyl acetate and n-hexanol. Studies using inhalation exposure in the rat are available for n-butyl acetate and hexanol

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Abstract only available; suitable only as part of a WoE assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: COBS CD

Details on test animals or test system and environmental conditions:

25 mated female COBS CD rats per group..

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

N-hexanol was mixed with corn oil and administered by oral gavage at doses of 200 or 1000 mg/kg bw/day. Each group consisted of 25 mated female COBS CD rats. Ten consecutive daily doses were administered over gestation days 6-15, in a dose volume of 5 ml/kg bw.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No information

Details on mating procedure:

No data

Duration of treatment / exposure:

ten days GD 6-15

Frequency of treatment:

daily

Duration of test:

dams terminated on gestation day 20

Remarks:

Doses / Concentrations:
200 or 1000 mg/kg bw/day
Basis:
nominal conc.

No. of animals per sex per dose:

25 mated females per group

Control animals:

no

Details on study design:

No further details available

Maternal examinations:

Throughout gestation the rats were observed for appearance and behaviour, and bodyweights were recorded. On gestation day 20 intrauterine survival was evaluated following Caesarean section and foetal development indices – bodyweight, external, skeletal and visceral morphology – were assessed.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: intrauterine survival and foetal development indices

Fetal examinations:

On gestation day 20 intrauterine survival was evaluated following Caesarean section and foetal development indices – bodyweight, external, skeletal and visceral morphology – were assessed.

Statistics:

No data

Indices:

No information presented on how foetal development indices were determined

Historical control data:

No data

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: 1000 mg/kg bw/day

Details on maternal toxic effects:
Maternal toxicity was only evident at 1000 mg/kg bw/day – indicated by clinical signs and decreased maternal bodyweights during the treatment period.

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects. Remark: No embryotoxicity or teratologic effects were observed at either dose level.

Details on embryotoxic / teratogenic effects:
No embryotoxicity or teratologic effects were observed at either dose level.

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Mean foetal bodyweight was slightly decreased at 1000 mg/kg bw/day, but weights were within the laboratory historical range. An increase in the number of litters with the foetal variant ‘malaligned sternebrae’ occurred at the low dose level, 200 mg/kg bw/day. The incidence of this variation in the high dose group was similar to incidence in the controls.

Conclusions:

Maternal toxicity and developmental toxicity were evident at the highest dose level of 1000 mg/kg bw/d; there is no evidence for specific developmental toxicity.

Executive summary:

The potential maternal, embryotoxic and teratologic effects of N-hexanol were evaluated. N-hexanol was mixed with corn oil and administered by oral gavage at doses of 200 or 1000 mg/kg bw/day. Each group consisted of 25 mated female COBS CD rats. Ten consecutive daily doses were administered over gestation days 6-15, in a dose volume of 5 ml/kg bw. Throughout gestation the rats were observed for appearance and behaviour, and bodyweights were recorded. On gestation day 20 intrauterine survival was evaluated following Caesarean section and foetal development indices – bodyweight, external, skeletal and visceral morphology – were assessed. No embryotoxicity or teratologic effects were observed at either dose level. Maternal toxicity was only evident at 1000 mg/kg bw/day – indicated by clinical signs and decreased maternal bodyweights during the treatment period. Mean foetal bodyweight was slightly decreased at 1000 mg/kg bw/day, but weights were within the laboratory historical range.  An increase in the number of litters with the foetal variant ‘malaligned sternebrae’ occurred at the low dose level, 200 mg/kg bw/day. The incidence of this variation in the high dose group was similar to incidence in the controls. The 200 mg/kg bw/day dose level was considered a no-effect level. Maternal toxicity and developmental toxicity were evident at the highest dose level of 1000 mg/kg bw/d; there is no evidence for specific developmental toxicity.

Reference 2

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published summary of developmental toxicity for industrial alcohols, published review, peer reviewed and compliant with sound scientific principles

Qualifier:

no guideline followed

Principles of method if other than guideline:

Investigation of the developmental toxicology of 13 industrial alcohols (methanol, ethanol, I -propanol, isopropanol, I -butanol, 2-butanol, tertiary-butanol, I -pentanol, I-hexanol, 2-ethyl-1-hexanol, l-octanol, I-nonanol, and 1-decanol).

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

The mated females were exposed for 7 hours a day from gestation day 1 to 19. For behavioural tests the pups from the resultant litters were culled to 8 per litter and fostered to unexposed mothers. The offspring were then tested over days 10-90.

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Details on exposure:

The mated females were exposed from gestation days 1-19

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No information

Details on mating procedure:

No details

Duration of treatment / exposure:

males - 6 weeks. Females dosed from gestation day 1-19 .

Frequency of treatment:

daily - 7 hours inhalation exposure per day.

Duration of test:

Sacrifice on gestation day 20

No. of animals per sex per dose:

15 females per group.
Litters culled to 8 prior to observation/behavioural phase

Details on study design:

- Dose selection rationale: no details - tested at 840 ppm (3800 mg/m3; 3.8 mg/L)

Maternal examinations:

No details

Ovaries and uterine content:

No details

Fetal examinations:

Weights, incidence of external malformations, incidence of skeletal malformations, incidence of visceral malformations, resorptions - incidence of significantly increased resoprtions compared with controls

Statistics:

No data

Historical control data:

No data

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
No effects on maternal toxicity

Dose descriptor:

NOEC

Effect level:

3 800 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Slight increase in resorption rate compare with controls for rats dosed at 840 ppm (3800 mg/m3) with 1-hexanol

Dose descriptor:

LOAEC

Effect level:

3 800 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

The developmental toxicology of 13 industrial alcohols (methanol, ethanol, 1 -propanol, isopropanol, 1 -butanol, 2-butanol, tertiary-butanol, 1 -pentanol, 1 -hexanol, 2 -ethyl-1 -hexanol, l-octanol, 1 -nonanol, and 1-decanol) was assessed in a series of experiments (Nelson et al, 1990); results for 1 -pentanol, 1 -hexanol and 2 -ethyl-1 -hexanol are also reported separately (Nelson et al, 1989). The alcohols were administered by inhalation for 7 hours per day on gestation Days 1-19 to groups of approximately 15 pregnant Sprague-Dawley rats. For developmental toxicology evaluations, dams were sacrificed on gestation Day 20.  Foetuses were serially removed, weighed, sexed, and examined for external malformations.  The frequency of visceral malformations and variations was determined in one-half of the foetuses and the frequency of skeletal deviations was determined in the other half. For hexanol, exposure to 3500 mg/m3 (840 ppm) resulted in a slightly (but significantly) increased resorption rate compared to the group control but no apparent maternal toxicity.

Parameter	Group Control	1-hexanol	Control range
			Nelson et al (1990)
Corpora lutea (#)	13	17	14-16
Resorptions (#)	0.4	1.3*	0.2-1.5
Males/litter (#)	7	8	5.9-7.3
Females/litter (#)	8	7	6.5-7.8
Foetal weight M (g)	3.28	3.19	3.17-3.45
Foetal weight F (g)	3.19	3.05	3.02-3.29

However it can be seen that the slightly increased resorption rate seen in the hexanol-treated group was associated with a higher number of corpora lutea (which exceeded the control range), was within the range for all control groups and did not result in any significant effect on litter size. A clear association with treatment is therefore not demonstrated.

Conclusions:

The results of this study do not show any clear evidence for the developmental toxicity of hexanol.

Executive summary:

The developmental toxicology of 13 industrial alcohols (methanol, ethanol, 1 -propanol, isopropanol, 1 -butanol, 2-butanol, tertiary-butanol, 1 -pentanol, 1 -hexanol, 2 -ethyl-1 -hexanol, l-octanol, 1 -nonanol, and 1-decanol) was assessed in a series of experiments (Nelson et al, 1990); results for 1 -pentanol, 1 -hexanol and 2 -ethyl-1 -hexanol are also reported separately (Nelson et al, 1989). The alcohols were administered by inhalation for 7 hours per day on gestation Days 1-19 to groups of approximately 15 pregnant Sprague-Dawley rats. For developmental toxicology evaluations, dams were sacrificed on gestation Day 20.  Foetuses were serially removed, weighed, sexed, and examined for external malformations.  The frequency of visceral malformations and variations was determined in one-half of the foetuses and the frequency of skeletal deviations was determined in the other half. For hexanol, exposure to 3800 mg/m3 (840 ppm) resulted in a slightly (but significantly) increased resorption rate but no apparent maternal toxicity.

The slightly increased resorption rate seen in the hexanol-treated group was associated with a higher number of corpora lutea (which exceeded the control range) and did not result in any significant effect on litter size. A clear association with treatment is therefore not demonstrated.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Studies using gavage administration in the rat are available for octyl acetate and n-hexanol. Both studies indicate possible mild developmental toxicity at the limit dose of 1000 mg/kg bw/d, however the resulting NOAEL is lower for the n-hexanol study as a consequence of dose spacing

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

3 800 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Studies using inhalation exposure in the rat are available for n-butyl acetate and hexanol..

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

A weight of evidence approach is used for developmental toxicity, using studies in the rat performed with a number of read-across substances using oral (gavage) dosing and inhalation exposure.

A gavage study performed with octyl acetate (Daughtrey et al, 1989) reported maternal toxicity at dose levels of 500 and 1000 mg/kg bw/d; toxicity at the highest dose level included maternal mortality. Developmental toxicity in this study was limited to a possible slight increase in the incidence of vertebral variations/malformations at the highest dose level only.

A gavage study performed with n-hexanol (Rodwell et al, 1988) reports maternal toxicity (clinical signs and reduced weight gain) and a slight reduction in foetal weight at the highest dose level of 1000 mg/kg bw/d. No effects were seen at the next dose level of 200 mg/kg bw/d.

An inhalation study performed using n-butyl acetate (Saillenfait et al, 2007) reported maternal toxicity (reduced weight gain and/or food consumption at exposure levels of 1000, 2000 and 3000 ppm); developmental toxicity was limited to reduced foetal weight at the highest concentration.

An inhalation study performed using hexanol (Nelson et al, 1989; 1990) showed no maternal toxicity at an exposure level of 3800 mg/m3. A slight increase in resorption rate seen at this exposure level was within the control range.

The results of developmental toxicity studies with read-across substances (analogues, metabolites) indicate possible mild developmental toxicity only at very high and maternally toxic dose levels. There is no evidence for selective developmental toxicity.

Justification for selection of Effect on developmental toxicity: via oral route:

A weight of evidence approach is followed for this endpoint.  

Justification for selection of Effect on developmental toxicity: via inhalation route:

Studies using inhalation exposure in the rat are available for n-butyl acetate and hexanol.  The lower endpoint is from the hexanol study

Justification for classification or non-classification

There is no evidence for reproductive toxicity or for specific developmental toxicity in studies performed with read-across substances; developmental toxicity was mild and seen only at very high and maternally toxic dose levels. No classification for reproductive toxicity is therefore proposed according to the CLP Regulation.