Hexadecanedioic acid

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
Dicarboxylic acids are organic compounds that contain two carboxylic acid functional groups. They have the general type formula HOOC-(CH2)n-COOH. The present defined category comprises dicarboxylic acids with straight carbon chain having a “n” value from 6 to 16.
The physical and chemical properties as well as the toxicology and environmental fate and effects show that substances in this category have a similar order of toxicological and environmental fate properties, which supports the grouping of these substances as a category. (see attached justification)

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL)
There are number of unifying considerations justifying the similarity between these substances in some important aspects. These include:
(1) Similarity of Use: these dicarboxylic acids have several industrial uses in the production of adhesives, plasticizers, lubricants, copolymers (such as polyamides and polyesters), etc.
(2) Similarity of Functional groups: all these substances contain two common functional groups (2 carboxyl groups). The only difference between the substances of this group lies in the length of the carbon chain.
(3) Similarity of Physical / Chemical properties: the similarity of physical / chemical properties for these substances (see attached justification)
(4) Similarity of Metabolism: Dicarboxylic acids were shown to be rapidly absorbed from the gastrointestinal tract, introduced into the fatty acid catabolism and therefore extensively metabolized by the organism and excreted (Passi, S. et al, 1983).
(5) Similarity of Mammalian Toxicity: The constituents of this class have similar toxicological properties. They are not acutely toxic, irritating to skin or sensitizing. However, they all present, except for dodecanedioic acid, irritating effects on the eyes (from moderate to high effects). They do not produce systemic effects in repeated dose studies. They are neither mutagenic nor carcinogenic and do not produce developmental/reproductive toxicity. (see attached justification)
(6) Similarity of Environmental Toxicity and Fate Properties: The substances in this category have similar environmental effects properties. The environmental effects data are similar for most category members in that most members do not exhibit acute toxicity. (see attached justification)

Data source

Reference

Reference Type:

publication

Title:

Toxicity of disodium sebacate

Author:

Greco A.V., Mingrone G., Mastrimattei A. E., Finotti E., Castagneto M.

Year:

1990

Bibliographic source:

DRUGS EXPTL. CLIN . RES. XVI (10) 531 -536

Materials and methods

Principles of method if other than guideline:

The test animals were continuously fed a diet containing the test substance for 6 months. During the feeding period, animals were checked for signs of toxicity and substance-dependent mortality. Gross pathological findings of the animals too were also monitored and recorded before, during and at the end of the observation period. Body weights were taken every 15 days. All surviving animals were sacrificed on day 181, necropsied and histological examination of the different organs was performed.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Disodium sebacate (DSS)

IUPAC Name:

Disodium sebacate (DSS)

Constituent 2

Reference substance name:

Disodium sebacate

EC Number:

241-300-3

EC Name:

Disodium sebacate

Cas Number:

17265-14-4

IUPAC Name:

disodium sebacate

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Average weight at study initiation:
Male: 174.6 ± 6.3 g; 176.8 ± 13.2 g
Female: 142.2 ± 7.13 g; 141.7 ± 7.54 g
Two groups of twenty Wistar rats (ten males and ten females) were fed for 6 months a pellet diet containing IDSS at two different dosages : 500 mg/kg b.w. for the first group and 1000 mg/kg b.w. for the second group.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: pellet diet containing the test substance

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 months

Frequency of treatment:

continuously

Doses / concentrations

Remarks:

Doses / Concentrations:
500; 1000 mg/kg bw
Basis:
nominal in diet

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

The growth curve of rats was drawn based on the body weight at 15-day intervals.

Examinations

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: every 15 days

ORGAN: yes
- Time schedule for examination: at death or after sacrifice.
- Organs examined: no data

CLINICAL CHEMISTRY and HAEMATOLOGY: Yes
- Parameters checked: plasma, glucose, BUN, serum creatinin, SGOT, SGPT, Hb.

Sacrifice and pathology:

Surving animals were sacrificed 181 days after begin of feeding and macro- and microscopic examinations of the organ were performed.

Statistics:

The DSS concentration used and percentage of mortality were respectively plotted on abscissa and ordinate of a logarithmic paper according to Miller and Tainter The best fitting straight line of the plotted points allows calculation of the LD50 which is the dosage value at 50% of mortalit . The standard error (s.e.) was estimated by this formula : (doses 84% - 16%) x square root of 2N, where N is the number of animals contributing to the values plotted.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Details on results:

MORTALITY:
No death were observed during the chronic toxicity study.

CLINICAL SIGNS:
The general conditions of the animals determined by physical examination and general observation did not show qualitative toxic signs.

FOOD AND WATER CONSUMPTION:
Food and water consumption were normal, as confirmed by the analysis of body weight gains which were not different from those values obtained from the controls.

HISTOPATHOLOGY:
No histological alterations were observed in any of the tissues and organs examined

CLINICAL CHEMISTRY:
Biological parameters (plasma glucose, BUN, serum creatinine, SGOT, SGPT and Hb) were similar to those of the controls

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

clinical biochemistry

clinical signs

food consumption and compound intake

histopathology: non-neoplastic

mortality

water consumption and compound intake

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

After oral administration of disodium sebacate on rats for a 6 months period, no mortality and clinical signs were observed. Based on a read across (category approach), hexadecanedioic acid is not expected to show subchronic oral toxicity.