2-ethylhexane-1,3-diol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Remarks:

other: Teratology study with information on fertility

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published in a peer-reviewed journal

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD 414

Principles of method if other than guideline:

GLP teratology study with information on fertility

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc. Portage, MI, USA
- Age at study initiation:
- Weight at study initiation: 250-300 g (males) and 175-200 g (females)
- Housing: two per cage, in stainless steel wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad liitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-75 F.
- Humidity (%): 42-65
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: 1.5 x 1.5 inches
- % coverage:
- Type of wrap if used: occlusive, polyvinyl film over sterilized gauze square. A Lycra-Spandex jacket with Velcro closure covered the dosing site.
- Time intervals for shavings or clipplings: no data, but skin was clipped

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, warm water-dampened gauze
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):1.0-4.0 ml/day
- Concentration (if solution): 100%
- Constant volume or concentration used: no

USE OF RESTRAINERS FOR PREVENTING INGESTION: no; applied to dorsal trunk not accessible to mouth

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Proof of mating: The presence of a dropped copulation plug was considered evidence of successful mating, and designated as gestation day (gd) 0

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

not required for undiluted material

Duration of treatment / exposure:

10 days during gestation

Frequency of treatment:

once daily

Details on study schedule:

Days 6-15 (inclusive) during gestation

Remarks:

Doses / Concentrations:
4.0 ml/kg bw/d
Basis:
other: undiluted test article based on maternal body weight on GD 6. Equivalent to 3768 mg/kg bw/d.

Remarks:

Doses / Concentrations:
2.0 ml/kg bw/d
Basis:
other: undiluted test article based on maternal body weight on GD 6. Equivalent to 1884 mg/kg bw/d.

Remarks:

Doses / Concentrations:
1.0 ml/kg bw/d
Basis:
other: undiluted test article based on maternal body weight on GD 6. Equivalent to 942 mg/kg bw/d.

No. of animals per sex per dose:

25 successfully-mated females per dose group

Control animals:

yes

Details on study design:

Controls were animals where 4.0 ml of water was applied under identical occlusive patches
- Dose selection rationale: Doses were those found to include the NOAEL for repeated dose exposure (see Section 7.5.2, Van Miller, 1994)
- Rationale for animal assignment (if not random): randomly assigned by computer-generated procedure.

Positive control:

none

Parental animals: Observations and examinations:

Assessments made on females only.
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily, twice daily during the treatment period

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily, twice daily during the treatment period for clinical signs of toxicity or pharmacologic effects and local skin irritation

BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 6, 9, 12, 15, 18 and 21

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, over 3-day intervals from GD 0 to 21.
- Compound intake was calculated as time-weighted averages from the consumption and body weight gain data: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #21 by CO2 asphyxiation
- Organs examined: gravid uterus, ovaries and other pelvic and abdominal visceral were inspected for signs of gross pathology

Oestrous cyclicity (parental animals):

not examined

Sperm parameters (parental animals):

not examined

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no, on GD 21.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
[number of corpora lutea, total implants per litter, % preimplantation loss, early and late resorptions, number and sex of pups, sex ratios, stillbirths and dead fetuses, live births, postnatal mortality at GD 21, presence of gross anomalies]

GROSS EXAMINATION OF DEAD PUPS:
[yes, for external and internal abnormalities]

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: no
- Maternal animals: All survival animals [sacrificed on GD21]

GROSS NECROPSY
- Gross necropsy consisted of [the gravid uterus, ovaries, and other pelvic and abdominal viscera. Ovarian corpora lutea were counted. Maternal and gravid uterine weights were measured. Uteri were dissected longitudinally, and live and dead fetuses and resorption sites counted.

HISTOPATHOLOGY / ORGAN WEIGHTS: yes

Postmortem examinations (offspring):

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical and abdominal viscera. One-half of each litter was examined for thoracoabdominal visceral abnormalities. These fetuses were decapitated and the heads fixed in Bouin's fluid for subsequent examination of craniofacial abnormalities using sectioning methods. The remaining fetuses in each litter were eviscerated, fixed in ethanol, processed for staining with alizarin red S, and examined for skeletal malformations and variations.]

Statistics:

The unit of comparison was the pregnant female or the litter. Quantitative continuous variables were intercompared using Levene's test for equal variances, ANOVA and t-tests with Bonferroni probablilities for pairwise comparisons. When Levene's test indicated heterogeneous variances, all groups were compared by an analysis of variance for unequal variances followed, if necessary, by the separate variance t-test.
Nonparametric data were analyzed statistically by the Kruskal-Wallis test followed by a Mann-Whitney U-test, if appropriate. Incidence data were compared using Fisher's exact test. For all statistical tests, a probability value of p < 0.05 (two-tailed) was used as the criterion for significance.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Decreased body weight gain, mild skin irritation and increased liver weights

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weights were decreased at the high dose

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Body weights were decreased at the high dose

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

No erythema or edema was seen at the dosing site. Exfoliation and crusting, possibly related to drying, were seen in a few animals of the mid and high dose groups.

One moribund female of the high dose group was sacrificed on GD11. Necropsy showed hydronephrosis and urinary bladder calculi and therefore death was considered not to be related to treatment. Corrected body weight change was slightly but not statistically significantly reduced at the high dose. Although not significant, maternal body weight gains were lower than for controls for the high dose group over the whole treatment period, particularly during the first 3 days of treatment. There were no significant or dose-related trends for changes in food consumption. There were no treatment-related differences from controls in terminal body weight or gravid uterine weights. Necropsies showed no treatment-related gross pathology in any animal.

There were statistically-significant increases in absolute liver weight at 4.0 ml/kg bw/d, and relative liver weight was increased at all dosages, with mean increases of 15.5% at the high dose, 7.8% at the middle dose, and 7.8% at the low dose.

Dose descriptor:

NOAEL

Effect level:

> 3 768 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Equivalent to 4.0 ml/kg bw/d

Clinical signs:

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Increased incidence of visceral malformations and variations

Histopathological findings:

no effects observed

Although statistically there was an increase in the incidence of total skeletal malformations on a "per litter" basis, this was considered not biologically significant because of an absence of a dose-response relationship.

There was no statistically significant increase in the incidence of total visceral malformations, but a statistically significant increase in the incidence of unilateral hydroureter, compared with the concurrent controls, was present at the high dose. There was no apparent predominance associated with the side affected. Three visceral variations were statistically significantly increased at high dose: fetal atelectasis or partial fetal atelectasis, bilateral dilated lateral cerebral ventricle, and bilateral dilated ureters. The incidences of dilated lateral ventricle and of bilateral dilated ureter were also significantly increased at the middle dose.

Thirteen skeletal variations indicating reduced ossification were statistically increased for several skeletal districts at the high dose. A reduced number of caudal segments was observed at both the high and low doses.

Reproductive effects observed:

not specified

There were no differences in the number of pregnancies resulting from mating as a result of treatment during gestation. There were no differences in reproductive factors or fetal body weights. This included the number of corpora lutea, % preimplantation loss, implantations, implantations per litter, viable implantations, resorptions, % live fetuses per litter, or sex ratio.

Conclusions:

EHD, when applied dermally to the skin of rats, for a duration of 6 h/day during gestation, resulted in minor maternal toxicity but no effects on female reproductive performance or fertility. The NOEL is > 4.0 ml/kg bw/day or 3768 mg/kg bw/day.

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 adverse effect observed

Dose descriptor:

NOAEL

3 768 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

inadequate for complete evaluation of fertility

Additional information

Short description of key information:
Limited information is available on the effects on fertility of this substance.

Justification for selection of Effect on fertility via dermal route:
provides some information but not typical of a reproductive toxicity guideline study.

Effects on developmental toxicity

Description of key information

Minor maternal toxicity and minor fetal teratogenicity were observed at dermal doses of 1884 mg/kg bw/d and higher in rats.  

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Reviewed in a peer-reviewed publication

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

no data

Frequency of treatment:

once daily on gestation days 6-15

Duration of test:

10 days

Remarks:

Doses / Concentrations:
500, 1000, 2000 and 4000 mg/kg bw/d
Basis:
nominal conc.

No. of animals per sex per dose:

8

Control animals:

yes, concurrent vehicle

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: lethality (7/8 at highest dose, 1/8 from high-mid dose group)

Details on maternal toxic effects:
Signs among the decedents were: weakness, respiratory difficulty, dehydration, sialorrhea, disturbance of gait, nasal discharge, diarrhea and decreased fecal volume. Animals from the high dose group also had hypothermia, partial blepharospasm and excessive lacrimation. Food consumption in all groups was reduced for the first 3 days of treatment. At pathology in the high dose group, there was necrosis of the gastric glandular mucosa, excess mucus in the cecum and thymic and adipose tissue atrophy.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: Resorptions and post-implantation losses were incrfeased and mean fetal body weights were decreased, for the mid-high dose group

Details on embryotoxic / teratogenic effects:
Resorptions and post-implantation losses were incrfeased and mean fetal body weights were decreased, for the mid-high dose group. Mortality prevented evaluation of high dose group effects. Malformations/variations in the mid-high group included: rudimentary tails, edematous and/or hemorrhagic tails, hindlimb curvature, arthrogryposis, shortened trunk, umbilical hernia and hematomas.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

Oral gavage dosing of EHD in pregnant rats during organogenesis resulted in maternal toxicity and lethality at doses higher than 2000 mg/kg bw/d. Teratogenic effects occurred at these maternally toxic doses but not at lower doses. The NOAEL is 1000 mg/kg bw/d.

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:

other: Published in a peer-reviewed journal

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc. Portage, MI, USA
- Age at study initiation:
- Weight at study initiation: 250-300 g (males) and 175-200 g (females)
- Housing: two per cage, in stainless steel wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad liitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-75 F.
- Humidity (%): 42-65
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: 1.5 x 1.5 inches
- % coverage:
- Type of wrap if used: occlusive, polyvinyl film over sterilized gauze square. A Lycra-Spandex jacket with Velcro closure covered the dosing site.
- Time intervals for shavings or clipplings: no data, but skin was clipped

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, warm water-dampened gauze
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):1.0-4.0 ml/day
- Concentration (if solution): 100%
- Constant volume or concentration used: no

USE OF RESTRAINERS FOR PREVENTING INGESTION: no; applied to dorsal trunk not accessible to mouth

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

No need to assay undiluted EHD

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Proof of mating: The presence of a dropped copulation plug was considered evidence of successful mating, and designated as gestation day (gd) 0

Duration of treatment / exposure:

10, days 6-15 inclusive

Frequency of treatment:

once daily, 6 h dermal exposure per day

Duration of test:

21 days after determination of successful mating

Remarks:

Doses / Concentrations:
4.0 ml/kg bw/d
Basis:
other: undiluted test article based on maternal body weight on GD 6. Equivalent to 3768 mg/kg bw/d.

Remarks:

Doses / Concentrations:
2.0 ml/kg bw/d
Basis:
other: undiluted test article based on maternal body weight on GD 6, equivalent to 1884 mg/kg bw/d.

Remarks:

Doses / Concentrations:
1.0 ml/kg bw/d
Basis:
other: undiluted test article based on maternal body weight on GD 6, equivalent to 942 mg/kg bw/d.

No. of animals per sex per dose:

25 successfully-mated females per dose group

Control animals:

yes, concurrent vehicle

Details on study design:

Controls were animals where 4.0 ml of water was applied under identical occlusive patches
- Dose selection rationale: Doses were those found to include the NOAEL for repeated dose exposure (see Section 7.5.2, Van Miller, 1994)
- Rationale for animal assignment (if not random): randomly assigned by computer-generated procedure.
- Other: Surviving females were sacrificed on GD21 by CO2 asphyxiation.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily, twice daily during the treatment period

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily, twice daily during the treatment period for clinical signs of toxicity or pharmacologic effects and local skin irritation

BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 6, 9, 12, 15, 18 and 21

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, over 3-day intervals from GD 0 to 21.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #21
- Organs examined: gravid uterus, ovaries and ohter pelvic and abdominal visceral were inspected for signs of gross pathology

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: 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: [half per litter]

Statistics:

The unit of comparison was the pregnant female or the litter. Quantitative continuous variables were intercompared using Levene's test for equal variances, ANOVA and t-tests with Bonferroni probablilities for pairwise comparisons. When Levene's test indicated heterogeneous variances, all groups were compared by an analysis of variance for unequal variances followed, if necessary, by the separate variance t-test.
Nonparametric data were analyzed statistically by the Kruskal-Wallis test followed by a Mann-Whitney U-test, if appropriate. Incidence data were compared using Fisher's exact test. For all statistical tests, a probability value of p < 0.05 (two-tailed) was used as the criterion for significance.

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
No erythema or edema was seen at the dosing site. Exfoliation and crusting, possibly related to drying, were seen in a few animals of the 2.0 and 4.0 ml/kg bw/d groups.

One moribund female of the 4.0 ml/kg bw/d group was sacrificed on GD11. Necropsy showed hydronephrosis and urinary bladder calculi and therefore death was considered not to be related to treatment. Corrected body weight change was slightly but not statistically significantly reduced at the high dose. Although not significant, maternal body weight gains were lower than for controls for the high-dose group over the whole treatment period, particularly during the first 3 days of treatment. There were no significant or dose-related trends for changes in food consumption. There were no treatment-related differences from controls in terminal body weight or gravid uterine weights. Necropsies showed no treatment-related gross pathology in any animal.

There were statistically-significant increases in absolute liver weight at 4.0 ml/kg bw/d, and relative liver weight was increased at all dosages, with mean increases of 15.5% at the high dose, 7.8% at the middle dose, and 7.8% at the low dose.

Dose descriptor:

NOEL

Effect level:

942 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: visceral malformations

Details on embryotoxic / teratogenic effects:
There were no treatment-related effects on the average number of corpora lutea or implantations (total, viable and nonviable), pre- and postimplantation losses. There were no significant differences in fetal body weights or the incidence of external malformations (or variations) or total visceral malformations.

A statistically significant increase in the incidence of unilateral hydroureter, compared with the concurrent controls, was present at the high dose, when analysed on a "per litter" basis. There was no statistically-significant effect when analysed on a "per fetus" basis. There was no apparent predominance associated with the side altered.

Independently, there was a statistically significant increase in the incidence of three variations at the high dose on a "per litter" basis: fetal atelectasis or partial fetal atelectasis, bilateral dilated lateral cerebral ventricle and bilateral dilated ureters. The incidences of dilated lateral ventricle and of bilateral dilated ureter were also significantly increased at the mid dose.

Although statistically there was an increase in the incidence of total skeletal malformations, this was considered not biologically significant because of an absence of a dose-response relationship. Thirteen skeletal variations indicating reduced ossification were statistically increased for several skeletal districts at the high dose. A reduced number of caudal segments was observed at both 4.0 and 2.0 ml/kg bw/d.

Abnormalities:

not specified

Developmental effects observed:

not specified

Compared with laboratory historical controls, the incidence of unilateral hydroureter at 4.0 ml/kg bw/d in this study was in excess of the upper limit in the historical values. For variants, while 11 of the current incidences fell within the range of the historical controls, six were in excess of the upper limit.

Conclusions:

EHD, when applied dermally to the skin of pregnant rats, for a duration of 6 h/day on gestational days 6-15, resulted in maternal body weight decreases and liver enlargement. A fetal visceral organ effect was also observed in the high-dose groups as unilateral hydroureter. Variations included dilated lateral cerebral ventricles, bilateral dilated ureter, and decreased ossification and caudal segments. The NOEL is 1.0 ml/kg bw/day or 942 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

adequate

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

942 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

adequate

Additional information

Experimental studies of EHD results in minor maternal toxicity and minor fetal teratogenicity. When applied to the skin of rats for 6 h per day under occlusive wrapping on gestation days 6 -15, EHD (at 3768 mg/kg bw/d) exerted minimal maternal toxicity (slight body weight decrease, minimal skin irritation, and liver enlargement). Hepatic enlargement was attributed to an adaptational effect of liver metabolism, documented in toxicokinetic studies, and was observed in repeated dose toxicity studies in adult rats. Weak developmental toxicity was observed in the teratology study at this high dose and marginally so at the mid dose (1884 mg/kg bw/d). This consisted of visceral malformations and variations, such as hydroureter, dilated cerebral ventricles and and fetal atelectasis. An applied dosage of 1.0 ml/kg bw/d (942 mg/kg bw/d) was a clear "no observed effect level" (NOEL) for dermal developmental toxicity in the rat. Oral gavage dosing of rats resulted in mild maternal and developmental toxicity (resorptions and fetal body weight decrements, and skeletal variants) at 2000 mg/kg bw/d. No hydroureter or dilated ventricles or atelectasis was observed by this route of administration. The NOAEL for oral dosing was 1000 mg/kg bw/d.

Consistency of reproductive effects between different routes was not demonstrated. There is no evidence of an intrinsic specific property producing an adverse effect on reproduction. The teratologic effects are not of major consequence or high incidence. Maternal toxicity effects likely associated with hepatic metabolism are demonstrated with both routes, with the fetal effects a possible result of the metabolic demand of the high dose. Effects are observed only after exaggerated exposures (occlusive 6 h repeated dermal doses or oral gavage).

EHD has been approved in several countries (US, Canada) as a consumer product (insect repellent) and cosmetic (US, Japan). The substance has a long history of safe use as a dermally-applied product, without reports of human developmental toxicity.

Out of an abundance of concern over the above-cited evidence of reproductive toxicity, EHD has been removed from the consumer market as an insect repellent (Canada, US).

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

Justification for selection of Effect on developmental toxicity: via dermal route:
experimental study

Justification for classification or non-classification

EHD has a long history of safe use as a dermally-applied insect repellent and cosmetic, without reports of human developmental toxicity. The conclusion from animal reproductive studies is that EHD is a weak developmental toxicant at high doses under exaggerated occlusive conditions. These studies show no evidence of an intrinsic specific adverse reproductive effect, nor effects in the absence of maternal toxicity. The substance does not meet the criteria of a reproductive toxicant under Regulation EC No. 1272/2008.