2-ethylhexane-1,3-diol

Endpoint summary

Description of key information

No significant adverse effects were observed as a result of repeated dose exposure to EHD.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

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 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

dosed 5 days per week

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

no data avaialble

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days, 21 doses

Frequency of treatment:

once daily, 5 days per week

Remarks:

Doses / Concentrations:
1000 mg/kg bw/d
Basis:
no data

Remarks:

Doses / Concentrations:
300 mg/kg bw/d
Basis:
no data

Remarks:

Doses / Concentrations:
100 mg kg/bw/d
Basis:
no data

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

Administered intragastrically by gavage, 5 days per week for 21 treatments within 28 days.

Observations and examinations performed and frequency:

Clinical signs, body weights, food consumption, hematology, clinical chemistry and gross and microscopic pathology

Sacrifice and pathology:

Gross pathology and histopathology examinations performed

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight gains for males in the 300 and 1000 mg/kg bw/d groups were lower but not statistically significantly; this amounte to a 9 and 6% lower weight gain. Body weights of females were unaffected

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was slightly increased over the controls for the 100 and 1000 mg/kg bw/d groups.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Increased leukocyte counts in females at 300 and 1000 mg/kg bw/d. Differential leukocyte counts were unaffected. Platelet counts were significantly decreased in 1000 mg/kg bw/d females. No effects in males.

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Relative and absolute liver weights were increased for high dose females. Relative liver weights were increased for high dose males. Mean relative spleen weight was increased for high dose males.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Increased liver weights were not assoicated with any morphological or biochemical indications of organ damage.

Details on results:

There were no mortalities or signs of toxicity. Body weights of females were unaffected but mean body weights of the males of the 300 and 1000 mg/kg bw/d groups were lower, although not statistically significantly, than the controls on days 21 and 28. Body weight gains for these males were, respectively, 9% and 6% lower. Food consumption was slightly increased over the controls for the 100 and 1000 mg/kg bw/d groups. Leukocyte counts were higher in a dose-related manner for all female EHD groups, but with statistical significance only for the 300 and 1000 mg/kg bw/d groups; differential leukocyte counts were unaffected. Platelet counts were statistically significantly decreased for the 1000 mg/kg bw/d EHD females. Clinical chemistry was not affected compared with controls. Relative and absolute liver weights were increased for the 1000 mg/kg bw/d females and relative liver weights were increased for the 1000 mg/kg bw/d males. Mean relative spleen weight was increased, compared with the controls, for the 1000 mg/kg bw/d males. No dosage-related gross or microscopic pathology was seen. The increased liver weights were not associated with any morphological or biochemical indications of organ damage, and it is therefore most likely an adaptive response to the metabolism of EHD.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Increased leukocyte counts, dose-related, in mid- and high-dose females; decreased platelet counts in high dose females. Liver weight effects in high dose females and males.

Critical effects observed:

not specified

Conclusions:

The repeated dose toxicity of oral 2-ethylhexane-1,3-diol dosing (100, 300 and 1000 mg/kg bw/d) was studied in rats for 28 days. No deaths or signs of significant toxicity, including histopathologic findings, occurred. The oral NOAEL was 100 mg/kg bw/d, based on the observation of liver weight changes and minor hematologic findings at 1000 mg/kg bw/d, and hematologic effects in mid- and high-dose females.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

adequate

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

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 publication in a peer-reviewed journal

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

water

Details on exposure:

Dosages were 0.5, 2.0 and 4.0 ml/kg (equivalent to 471, 1884 and 3768 mg/kg) applied occlusively for 6 h per day. Controls received 2.0 ml/kg distilled water, also applied for 6 h/day. Applications of EHD and distilled water were made for five days/week for 13 weeks (65 applications to the skin over 91 days).

Duration of treatment / exposure:

13 weeks, 5 days per week

Frequency of treatment:

daily, 6 h per day under occlusive patch

Remarks:

Doses / Concentrations:
3768 mg/kg bw/d
Basis:

Remarks:

Doses / Concentrations:
1884 mg/kg bw/d
Basis:

Remarks:

Doses / Concentrations:
471 mg/kg bw/d
Basis:

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

An additional 5 animals per sex were added to the high dose EHD and water control groups and sacrificed 6 weeks after the final skin application (recovery group).

Observations and examinations performed and frequency:

Monitors for toxicity were clinical signs, body weights, food consumption, hematology (erythrocyte count, hemoglobin concentration, packed cell volume (PCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), platelet count, total and differential white cell count), clinical chemistry (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transferase (ɣ-GT), creatine phosphokinase (CPK), lactate and sorbitol dehydrogenases, glucose, total protein, albumin, globulin, bilirubin, creatine, urea nitrogen, phosphorus, Ca2+, Na+, K+ and Cl−), urinalysis (volume, specific gravity, pH, microscopy, blood, protein, ketones, glucose, bilirubin and urobilinogen), organ weights and gross and microscopic pathology.

Clinical signs:

no effects observed

Dermal irritation:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreased body weight gain in males at week 2 and in females during interim weeks and 1 week during recovery.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Decreased during interim weeks; no difference after a 6 week recovery.

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):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Increased liver weight in high-dose males

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

At the high dose there were interim body weight changes. Body weight gain was slightly but statistically significantly reduced the high-dose males at week 2, and with females for weeks 3–10 and 18 (9–18% reduction). At the end of the dosing period the difference in weight gain was 8%. At the end of the recovery period there were no differences in body weight gain between treatment and control groups. A statistically significant reduction in food consumption occurred for weeks 3, 4 and 6–12 with high-dose female rats, for weeks 3 and 7 for mid-dose females, and for weeks 3, 4, 6, 7 and 9 with low-dose females, but no differences were recorded during the recovery period with high-dose females. Relative liver weight was increased slightly (4%) in high-dose males (3.160 ± 0.147% versus 3.020 ±0.079%; P < 0.05) at the end of the dosing period; this resolved during the recovery period. The slight increases in relative liver weight were not accompanied by any biochemical or cytological evidence of liver injury.

Dose descriptor:

NOAEL

Effect level:

1 884 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Conclusions:

2-Ethylhexane-1,3-diol (EHD) at doses of 0.5, 2.0, and 4.0 ml/kg bw/d were applied daily under occlusive bandages to Fisher 344 rats for 13 weeks, with some rats continuing for 6 weeks in a recovery protocol. The rats were assessed for signs of toxicity and growth impairment. No deaths or signs of significant toxicity occurred. There was decreased body weight gains in high-dose females and increased relative liver weight without histopathology in high dose males. The NOAEL is the mid-dose of 2.0 ml/kg bw/d or 1884 mg/kg bw/d.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 884 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

adequate

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No significant adverse effects were observed as a result of repeated dose exposure to EHD. When EHD was given by the oral route,

there were transient mild decreases in food consumption and body weight gain. Females displayed minor hematologic effects which appeared to have no clinical significance. Relative liver weights were increased when EHD was given by the oral route, but no histopathology was present. This likely represents an adaptive response to enhanced metabolism of EHD. All parameters were normal in the study which included a recovery group assessed 6 weeks after cessation of dosing. The NOAEL is conservatively set at 100 mg/kg bw/d, but could be higher as no differences were observed at recovery.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
modern experimental result

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: dermal - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

There is no indication of specific target organ toxicity or other repeated dose effects. The substance is not classified for repeated dose toxicity effects in CLP000 of Regulation EC No. 1272/2008.