Hexadecyl hydrogen maleate

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

other: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: literature data

Justification for type of information:

Justification of Read Across is given in Section 13 of IUCLID

Data source

Reference

Reference Type:

publication

Title:

The Comparative Chronic Toxicities of Fumaric, Tartaric, Oxalic, and Maleic Acids

Author:

Fitzhugh G and Nelson A.A

Year:

1947

Bibliographic source:

Journal of the Americaln Pharmaceutical Association, 36, 217-219

Materials and methods

Principles of method if other than guideline:

The chronic toxicity of the substance is evaluated in a two-years feeding study

GLP compliance:

no

Remarks:

pre-GLP study

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Maleic acid

EC Number:

203-742-5

EC Name:

Maleic acid

Cas Number:

110-16-7

Molecular formula:

C4H4O4

IUPAC Name:

(2Z)-2-Butenedioic acid

Test animals

Species:

rat

Strain:

Osborne-Mendel

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: weanling rats (twenty-one days)
- All animals were kept in individual cages in a room with the temperature and humidity controlled for the duration of the experiment and were given free access to their respective diets and water

Administration / exposure

Route of administration:

oral: feed

Details on oral exposure:

Ground commercial rat biscuits with 1% added cod-liver oil served as the basic diet. The substance was mixed with the basic diet by means of a rotary batch mixer.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 years

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.5 other: %

Remarks:

% in diet

Doses / concentrations 2

Dose / conc.:

1 other: %

Remarks:

% in diet

Doses / concentrations 3

Dose / conc.:

1.5 other: %

Remarks:

% in diet

No. of animals per sex per dose:

12 male rats per dose

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

The weights of individual animals and their food consumption were determined at weekly intervals.

Sacrifice and pathology:

- Microscopic pathological examination was done to demonstrate the relatively minimal nature of the pathological changes produced by the substance
- Autopsy was done on nearly all the rats used in these experiments, a few being omitted because of advanced post-mortem autolysis. As the animals
were received in the pathology laboratory, alternate ones were taken for microscopic sectioning. Hematoxylin-eosin stained paraffin sections of the following structures were routinely made: lung, heart, liver, spleen, pancreas, stomach, small intestine, kidney, adrenal, and testis. The following additional structures were sectioned frequently enough to make it reasonably certain that no changes in them were being caused by the substance: colon, bone marrow, leg bones, leg muscles, lymph nodes, uterus, ovary, thyroid, and parathyroid

Results and discussion

Results of examinations

Description (incidence):

Statistical tests cannot be applied to the mean survival time since all surviving animals were sacrificed at the conclusion of two years on the experiment. Most of the deaths, except for a few animals distributed throughout all groups and killed because of middle ear disease, occurred during the second year of the experiment. The number of animals surviving at eighteen months and at two years, therefore, were selected as estimates of relative toxicity. At eighteen months the substance at concentrations of 1% and 1.5% in the diet increased the mortality rate; however, the difference between the mortality rate of either group of experimental animals and that of the controls was not significant. At two years the substance had increased the mortality rate significantly.
All of the 12 experimental animals on 1.5% and 10 on each of the other concentrations of the substance died whereas 6 of the controls survived to the end of the experiment.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

There was a significant difference between the mean gain in weight of the control animals and the mean gains in weight of the groups on 1% and 1.5% of the substance.
The substance at concentrations of 1 %, or more, retarded the growth rate of the rats.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

When the data for the weekly food consumption of each group during the first twenty-six weeks and during the second twenty-six weeks of the experiment were analyzed, the differences between the control and experimental animals were not statistically significant.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In all the foregoing structures, no difference could be seen between treated and control animals except the following. Enlarged and irregularly shaped epithelial cells in small to moderate numbers of renal tubules, generally the proximal convoluted, were seen in 4 rats on 1.5% and in 3 rats on 1.0% substance, and in no other rats in the entire series. Rats fed 1.5 % substance had distinctly more atrophy of the liver and less focal calcification in large arteries than did any of the other groups the gross and microscopic findings iri this series of rats showed no difference between control and treated animals.
Tumors and other more or less frequently occurring spontaneous diseases of older rats, such as periarteritis nodosa-like arterial lesions, bile duct proliferation in the liver, et cetera, showed no difference in incidence among the various animal groups.

Effect levels

Dose descriptor:

NOAEL

Remarks on result:

other: Toxic effects occurred in rats fed diets containing 0.5 % or more. NOAEL not specified

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Toxic effects occurred in rats fed diets containing 0.5 % or more

Executive summary:

The toxicity of the test material after a chronic exposure was evaluated in a 2 -year feeding study on rats. Twelve male rats per group were exposed to 0.5, 1.0 and 1.5 % of the substance in feed. The body weight, food consumption and mortality were monitored. Necropsy was performed in all surviving rats and microscopic pathological examination was performed.

Toxic effects occurred in rats fed diets containing 0.5 % or more of the substance. Detailed microscopic pathological examination showed no major visceral damage from the substance at any level, and only relatively minor differences between control and treated animals. Rats fed 1.5 % substance showed more atrophy of the liver and of the testis than did the control groups. Inanition seems at least partly responsible for these differences. The substance at a concentration of 1 % retarded the growth rate of rats. All concentrations of the substance increased the mortality rate.

The NOAEL was not identified but it can be extrapolated as to be 0.5 % of substance in feed.