2-ethylhexane-1,3-diol

Endpoint summary

Description of key information

The LD50 values for oral and dermal exposures are both greater than 2000 mg/kg bw/d.  The LC50 value for inhalation was tested in a saturated atmosphere (up to 3.8 mg/L) with no findings of death or other significant toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Data are presented in two peer-reviewed publications.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Similar to standard acute method, wherein rats were administered oral doses and deaths were assessed for 14 days.

GLP compliance:

not specified

Remarks:

predates GLP

Test type:

other: no information

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200 and 300 g
- Fasting period before study: Overnight
- Housing: Animals were randomly assigned whose body weights were within the range of mean +/- 2 SD
- Acclimation period: At least 5 days prior to use

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68 to 80
- Humidity (%): 30- 60
- Photoperiod (hrs dark / hrs light): 12 hr light-dark cycle

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Remarks:

Undiluted

Details on oral exposure:

Intragastrically by means of a ball-ended stainless steel needle. Sample delivered by an attached syringe.

Doses:

4, 8 and 16 ml/kg for males and 2,4 and 8 ml/kg for females

No. of animals per sex per dose:

5 males and 5 females

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Twice daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: Clinical signs, body weight pre dosing and on 7 and 14 days post-dosing

Statistics:

LD values were calculated by the moving average method.

Sex:

male

Dose descriptor:

LD50

Effect level:

9 281 mg/kg bw

Based on:

test mat.

95% CL:

> 6 737 - < 12 814

Remarks on result:

other: reported as 9.85 ml/kg, x 0.9422 g/ml (relative density) =9.28 g/kg bw.

Sex:

female

Dose descriptor:

LD50

Effect level:

4 636 mg/kg bw

Based on:

test mat.

95% CL:

> 3 373 - < 6 387

Remarks on result:

other: reported as 4.92 ml/kg, x 0.9422 (relative density) = 4.64 mg/kg bw.

Mortality:

In males at 16 ml/kg, all 5 out of 5 rats died. At 8 ml/kg, 1 out of 5 rats died and all 5 rats survived at 4 ml/kg dose. In the female rats, 5/5 died at 8 ml/kg, at 4 ml/kg 1/5 died, and at 2 ml/kg, none of 5 died. Deaths occurred within 2 h to 2 days post-dosing, with the majority of mortalities occurring within 24 h.

Clinical signs:

other: Signs of toxicity in animals that died included sluggishness and unsteady gait appearing at 5–10 min and prostration at 15–50 min. Signs in survivors included sluggishness, unsteady gait, prostration and lacrimation; recovery occurred between 1 and 2 days

Gross pathology:

Necropsy of rats that died showed mottling of the lungs but otherwise no significant gross pathology. There was no gross pathology in survivors sacrificed at the end of a 14-day post-dosing observation period

Other findings:

- Other observations: At autopsy the victims had congestion of the lungs, and the abdominal viscera.

Interpretation of results:

not classified

Remarks:

Migrated information LD50 > 2000 mg/kg bw Criteria used for interpretation of results: EU

Conclusions:

2-Ethylhexane-1,3-diol was tested for acute oral toxicity and the LD50 in females was 4636 mg/kg bw and in males was 9281 mg/kg bw. The substance is not classified according to criteria of Regulation EC No. 1272/2008.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

4 636 mg/kg bw

Quality of whole database:

adequate

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data obtained from a peer-reviewed publication

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Sprague Dawley rats (200-300 g) were used for the aerosol inhalation studies.

Route of administration:

other: Static and dynamic vapor and 4 hr aerosol

Type of inhalation exposure:

whole body

Vehicle:

oxygen

Remarks:

20% Oxygen level was maintained

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Bubbler technique. For dynamically-generated vapour: 2.5 L/min of dry air passing through fritted glass disc immersed 1.5 " below the surface of EHD in a gas washing bottle.. For statically-generated vapour, EHD was introduced directly into exposure chambers and allowed to equilibrate for 18 h at a temperature of 25 degrees C. For EHD aerosol, an atomizer (Spraying Systems Co., Wheaton, IL, USA) attached to a compressed air source, and a piston pump (Fluid Metering Inc., Oyster Bay, NY, USA) was used.


TEST ATMOSPHERE for AEROSOL STUDY:
- Particle size distribution: particle size (MMAD): 2.0 µm; GSD (Geometric st. dev.): 4.3 µm.
- 4 hr exposure to EHD aerosol with mean ± SD concentration 3.8 ± 0.21 mg/L.


GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION Glass exposure chambers
- Exposure apparatus: Sealed glass Chamber
- Exposure chamber volume: For static saturated vapour exposure: 120 L. For dynamic saturated vapour exposure: 9 L
- Method of holding animals in test chamber: Animals were introduced into separate chambers through gasketed draws.
- Source and rate of air: compressed air tank
- Method of conditioning air: The EH Diol Vapor was allowed to equilibrate for 18 hrs at 25 degrees C.
- System of generating particulates/aerosols: The aerosol of EHD was generated using an atomizer (Spraying Systems Co., Wheaton, IL) attached to a compressed air source, and a piston pump (Fluid Metering Inc, Oyster Bay, NY) for the recirculation of EHD
- Temperature, pressure in air chamber: 23-25 deg C
- Duration: for static and dynamic saturated vapour exposure: 6 h. For aerosol, 4 h.

TEST ATMOSPHERE
- Brief description of analytical method used: The atmospheric concentration of EHD was determined by drawing chamber air samples through glass fiber filters, which were weighed before and after the sampling period. Particle size was measured by a cascade impactor (Sierra Instuments Inc., Carmel Valley, CA, USA).
- Samples taken from breathing zone: yes; The chamber was monitored continuously and oxygen added as required to maintain a concentration of 20% oxygen.

VEHICLE
- Composition of vehicle (if applicable): air

Analytical verification of test atmosphere concentrations:

yes

Remarks:

for aerosol only

Duration of exposure:

> 4 - < 6 h

Remarks on duration:

6 h for vapour exposures; 4 hr aerosol exposure

Concentrations:

Mean ± SD concentration 3.8 ± 0.21 mg/L and particle size 2.0 ± 4.3 µm)

No. of animals per sex per dose:

5 male and 5 female

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

No data

Sex:

male/female

Dose descriptor:

LC0

Effect level:

> 3.8 mg/L air (analytical)

Based on:

test mat.

Remarks on result:

other: As aerosol. Additionally, no deaths occurred at saturated vapour concentrations

Mortality:

No mortalities in 5 male and 5 female rats.

Clinical signs:

other: Within 30 mins of start of exposure, hypoactivity was observed which disappeared rapidly on removal of rats rom the exposure chamber.

Body weight:

With static, dynamic and aerosol methods, there was no effect on body weight.

Gross pathology:

No gross pathology was seen at necroscopy.

Other findings:

During exposure and for the first 24 h post exposure, there was perioral and perinasal wetness and some signs of irritation. Thereafter
there were no signs of irritation or toxicity

Inh., rat	M	LT50	6-h static killed 0/5	Ballantyne, et al., 2005
Inh., rat	F	LT50	6-h static killed 0/5	Ballantyne, et al., 2005
Inh., rat	M	LT50	6-h dynamic killed 0/5	Ballantyne, et al., 2005
Inh., rat	F	LT50	6-h dynamic killed 0/5	Ballantyne, et al., 2005
Inh., rat	M	LC50	4-h, 3.8 mg l^−1, 0/5	Ballantyne, et al., 2005
Inh., rat	F	LC50	4-h, 3.8 mg l^−1, 0/5	Ballantyne, et al., 2005

Saturated vapour exposure by static generation, dynamic generation or aerosol.

Interpretation of results:

not classified

Remarks:

Migrated information Data do not indicate toxicity at saturated vapour concentrations. Criteria used for interpretation of results: EU

Conclusions:

No toxicity or lethality was observed with 4 hours of aerosol exposure ( 3.8 mg/L) to 2-ethyl-1,3-hexanediol. Furthermore, rats exposed for 6 h to a statically and dynamically generated saturated vapor atmosphere did not show any signs of toxicity. Data are lacking for full classification according to the dosing criterion in Regulation EC No. 1272/2008. However, the data do not exist to support classification for acute inhalation toxicity, and thecurrent harmonized classification according to Table 3.1 in Annex VI of the Regulation does not include classification for acute toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

3 800 mg/m³ air

Quality of whole database:

inadequate for classification and labelling

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Weight: 2-3 kg.
Acclimatized for at least 5 days prior to use.
Randomly assigned to grouprs from pools whose body weights were within the mean +/- 2 SD.
Environmental temperature of 68-80 degrees F.
Relative humidity was 30-60%
Light/dark schedule: 12 h.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Undiluted EHD was applied to the clipped skin of the trunk, and covered using occlusive polyethylene sheeting, adhesive tape and plastic ties. Animals were immobilized for the contact period.

Duration of exposure:

24 h

Doses:

Males: 8.0, 11.3 and 16 ml/kg bw, equivalent to 7.5, 10.7 and 15.1 g/kg bw.
Females: 4.0, 8.0, and 16 ml/kg bw, equivalent to 3.8, 7.5, and 15.1 g/kg bw.

No. of animals per sex per dose:

5 per sex per dose

Control animals:

no

Details on study design:

On removal of the occlusive bandage, residual EHD was gently removed from the skin with moist tissue. Animals were examined twice daily for signs of local inflammation and systemic toxicity. Body weights were measured before dosing, and at 7 and at 14 days postdosing. Necropsies were performed on the animals that died, and on survivors sacrificed at the end of the 14-day observation period.

Statistics:

LD50 values were calculated by the moving average method.

Sex:

male

Dose descriptor:

LD50

Effect level:

10 251 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Reported as 10.88 ml/kg bw, equivalent to 10.25 g/kg bw.

Sex:

female

Dose descriptor:

LD50

Effect level:

8 960 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Reported as 9.51 ml/kg bw, equivalent to 8.96 g/kg bw.

Mortality:

Five of 5 treated males and 4 of 5 treated females in the high dose group succumbed. Three of 5 males and 2 of 5 females in the intermediate dose succumbed. Deaths occurred between 2 and 5 days

Clinical signs:

other: In animals which died, symptoms preceeding death included sluggishness, prostration and unsteady gait. Recovery occurred within 2 days.

Gross pathology:

Necropsies of animals which died revealed a few red mottled lungs, a few stomachs having black foci on their surface, and two instances of animals having brown colored liquid in the thoracic cavity. Survivors sacrificed at the end of the observation period did not show any gross pathologic features at necropsy.

Other findings:

Local signs of inflammation at the site of the contact with EHD with skin were eythema and edema on the first day, persisting to the time of death at the highest dose. Among the survivors, eythema and edema resolved within 7 days. Desquamation was apparent at 7 days until sacrifice.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Rabbits treated with 2-ethylhexane-1,3-diol under topical occlusive dressings for 24 h showed an LD50 of over 8000 mg/kg bw in males and females. The substance is not classified under Regulation EC No. 1272/2008.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

8 960 mg/kg bw

Quality of whole database:

adquate

Additional information

Justification for selection of acute toxicity – oral endpoint
experimental result

Justification for selection of acute toxicity – inhalation endpoint
experimental result

Justification for selection of acute toxicity – dermal endpoint
experimental result

Justification for classification or non-classification

The oral LD50 value for 2-ethyl-1,3-hexanediol in female rats is 4636 mg/kg bw, higher than the criterion for classification as an acute toxicant (2000 mg/kg bw) according to Regulation EC No. 1272/2008.

The dermal LD50 value in female rabbits is 8960 mg/kg bw, higher than the criterion for classification (2000 mg/kg bw).

The inhalation LC50 value in rats is greater than 3.8 mg/L or 3800 mg/m3, in an atmosphere saturated with vapour. No deaths or significant toxicity occurred at this concentration, suggesting that the lethal concentration is much higher. The harmonized classification according to Regulation EC No. 1272/2008 does not include acute toxicity.