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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

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

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Repeated exposure toxicity of 2-ethyl-1,3-hexanediol by cutaneous applications to the rat for 9 and 90 days.
Author:
Van Miller JP, Losco PE, Neptun DA, Ballantyne B.
Year:
1995
Bibliographic source:
Vet Hum Toxicol. 37(1): 33-36
Reference Type:
publication
Title:
Toxicology Update 2-Ethyl-1,3-hexanediol
Author:
Ballantyne B
Year:
2005
Bibliographic source:
J. Appl. Toxicol 25: 248-259

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-ethylhexane-1,3-diol
EC Number:
202-377-9
EC Name:
2-ethylhexane-1,3-diol
Cas Number:
94-96-2
Molecular formula:
C8H18O2
IUPAC Name:
2-ethylhexane-1,3-diol
Test material form:
liquid: viscous
Details on test material:
98.9% purity.
Impurities were two isomers of monbutyrate ester of EHD.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

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
Doses / concentrationsopen allclose all
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).

Examinations

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.

Results and discussion

Results of examinations

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.

Effect levels

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'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

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.