Hexadecanedioic acid

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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:

Following a 10 day mating period, each female animal (total of 20 animals) was placed in a single cage and fed a pellet diet containing the test substance or no test substance in the case of the controls for 25 days after which 10 animal were sacrificed. Treatment of the remaining 10 female animals was continued for another 3 months including the period of suckling. At the end, the animals were also sacrificed. Fetuses and reproduction organs of all animals (uterus, placenta, ovaries) were weighed post mortem and examined macroscopically as well as histologically.

GLP compliance:

not specified

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:

rabbit

Strain:

other: New Zealand

Administration / exposure

Route of administration:

oral: feed

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: pellet diet

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

The male and female animals were cohoused at a ratio of 1 male to 20 females for 10 days in a metabolic cage.

Duration of treatment / exposure:

Group 1: 10 animals: day 1 to 25 of pregnancy,
Group 2: 10 animals: day 1 to 25 of pregnancy plus 3 months

Frequency of treatment:

continuously

No. of animals per sex per dose:

10 females per group

Control animals:

yes

Examinations

Maternal examinations:

POST-MORTEM EXAMINATIONS: Yes
- Organs examined: Uterus, ovaries, placenta

Ovaries and uterine content:

The ovaries and uterine content was examined after termination

Fetal examinations:

External examinations: Yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Both macroscopic and microscopic features of the uterus, placenta and ovaries appeared normal.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No abortions or fetal malformations were observed in the animals sacrificed on day 25 of pregnancy. No still-born animals were found in the DSS groups and the newborns were free from malformations.

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Basis for effect level:

other: teratogenicity

2

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

No effect was found on the number of pregnancies, the macroscopic and microscopic features of uterus, placenta and ovaries. The number of live births and normal offsprings from the dosed groups was comparable to control, no teratogenic effect was observed.

Applicant's summary and conclusion

Conclusions:

No teratogenic effect was observed on animals after oral adminidtration of disodium sebacate. Based on a read across (category approach), hexadecanedioic acid is not expected as well to show teratogenic effects.