Hexanedioic acid, mixed esters with decanoic acid, heptanoic acid, octanoic acid and pentaerythritol

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EU Method B.9 (Repeated Dose (28 Days) Toxicity (Dermal))

Deviations:

yes

Remarks:

except sites were not occluded and residual test material not wiped off

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Hexanedioic acid, mixed esters with decanoic acid, heptanoic acid, octanoic acid and pentaerythritol

EC Number:

268-597-2

EC Name:

Hexanedioic acid, mixed esters with decanoic acid, heptanoic acid, octanoic acid and pentaerythritol

Cas Number:

68130-55-2

Molecular formula:

C36H64O10

IUPAC Name:

6-[3-(decanoyloxy)-2-[(heptanoyloxy)methyl]-2-[(octanoyloxy)methyl]propoxy]-6-oxohexanoic acid

Test material form:

liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Details on exposure:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material not wiped off

Test article was applied to the clipped backs of four groups of Sprague-Dawley rats

Duration of treatment / exposure:

5-Days a week for 4-weeks

Frequency of treatment:

5-Days a week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

125 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

500 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

2 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Details on study design:

- Post-exposure recovery period in satellite groups: Only for control and high dose animals

Examinations

Statistics:

Analysis of variance (ANOVA), associated F-test, Dunnett's test or Tukey's multiple range test.

Results and discussion

Results of examinations

Description (incidence and severity):

Animals treated with test article exhibited no signs indicative of systemic toxicity. The test material was not visibly irritating to the skin at the exposure site.

Description (incidence and severity):

Animals exposed to test article at 2000 mg/kg/day gained slightly less weight than untreated controls, achieving statistical significance in the male regular group and in the female satellite group.

Description (incidence and severity):

Exposure to the test article had no effect on food consumption.

Description (incidence and severity):

Statistically significant (p<0.05) differences were observed between the data from the untreated control groups and the treated groups for 2 of the 13 hematology parameters evaluated at week 5.
Segmented neutrophils were statistically significantly increased in the female mid-dose group. A linear relationship was not found between dose and blood level for this parameter.
Lymphocytes were decreased in the male treated satellite group at both weeks 5 and 7. When the historical serum reference values were taken into consideration, the mean value for this parameter at weeks 5 and 7 fell within the normal range as defined by the 10th and 90th percentiles of the historical data. Statistically significant (p<0.05) differences were observed between the data from the untreated control groups and the groups treated with test article for 2 of the 19 serum chemistry parameters evaluated at week 5.
Aspartate aminotransferase was statistically significantly increased in the female low-dose group. A linear relationship was not found between dose and serum level for this parameter.
Alanine aminotransferase was increased in the male treated satellite group. When the historical serum reference values were taken into consideration, the mean value for this parameter fell slightly above the 90th percentile of the historical data. This finding was not considered to be biologically significant because the value was only slightly outside the normal range of the historical data and a similar effect was not observed in the other treated groups. One statistically significant difference (decreased albumin in males) was observed between the serum chemistry data from control and treated animals following the 2-week recovery period. This finding, while falling just outside the normal range (4.5-5.0 g/dL) of the historical data, was not considered to be biologically significant because of the small magnitude of the decrease (3%), and this parameter was not affected at week 5.

Description (incidence and severity):

No test material-related findings were observed at the time of necropsy.
No significant differences were seen between the absolute and relative organ weight data of the control and treated regular groups.
A significant increase was seen in the relative adrenal and brain weights of the females exposed to test material at 2000 mg/kg/day and sacrificed after a two-week recovery period when compared to those of the untreated controls. This difference is attributed to the statistically significant lower final body weights of the treated animals. Microscopically, the test material-related findings were only observed in the treated skin of the rats exposed to the test material at 500 mg/kg/day. Generally these findings were very minor and consisted of a dose-related increased incidence and severity of hyperplasia and hyperkeratosis of the epidermis and sebaceous gland hyperplasia. Microscopic evaluation of the satellite animals showed no differences between the control and treated animals, indicating complete reversibility after the 2-week recovery period.

Effect levels

Key result

Dose descriptor:

NOEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: hyperplasia and hyperkeratosis of the epidermis and sebaceous gland hyperplasia

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day (nominal)

System:

integumentary

Organ:

skin

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

In conclusion, a conservative NOEL was established to be 500 mg/kg/day for systemic toxicity.