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Toxicological information

Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
data not available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Complementary study well conducted on a sufficient number of embryos. No GLP.

Data source

Reference
Reference Type:
publication
Title:
Embryotoxic effects of salicylates: Role of biotransformation.
Author:
Greenaway J.C., Bark D.H., Juchau M.R.,
Year:
1984
Bibliographic source:
Toxicol. Appl. Pharmacol., 74, 141-149.

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
In vitro embryotoxicity test to compare effects of salicylate and its metabolites . Rat embryos were cultured with each substance during 5, 9 or 24-hr. Then, analyses of viability and malformations were performed. Crown-rump lenth, somite number and limb development were recorded.
GLP compliance:
not specified
Type of method:
in vitro

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance: sodium salicylate , purity > 99% for each.
No other data.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
not applicable (in vitro study)

Administration / exposure

Route of administration:
other: in vitro
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
5,9 or 24 hr
Frequency of treatment:
continuous
Duration of test:
24 hr
Doses / concentrations
Remarks:
Doses / Concentrations:
1.5 to 1.9 mM
Basis:
nominal conc.
No. of animals per sex per dose:
First experiment with an exposure of 24-hr:
34 embryos (sodium salicylate)
27 embryos (control)

Study of the kinetic aspects of salicylate teratogenicity:
12 embryos (5-hr and 9-hr exposure)
7 embryos (24-hr exposure)
16 embryos (control)
Control animals:
yes
Details on study design:
Duration of test: 24 hr
Statistics:
Student's t test was utilized for analyses of differences in crown-rump length, somite numbers, and protein concentration. For analyses of differences in viability and malformations the chi-square criterion was utilized with Yates' correction for continuity.

Results and discussion

Observed effects

At 1.9 mM, sodium salicylate produced embryolethality in 26 of 34 embryos and 38 % of the remaining viable embryos exhibited malformations. Abnormal closure of the neural tube and/or dilution or edema of the cephalic portion of the neural tube were the most frequent malformations observed in this study. For all embryotoxic effects examined (except malformations), the severity of the effect increased with the duration of exposure through the 24-hr culture period. The percentage of malformations observed after a 24-hr exposure period was no greater than that measured after only a 9-hr exposure. A 9-hr exposure period was sufficient to produce a significant increase in the number of malformed embryos compared with embryos not exposed to salicylate.

Any other information on results incl. tables

Results with metabolites:

The tested metabolites (salicyluric acid, gentisic acid and 2,3 -dihydroxybenzoate) at 1.9 mM caused no embryolethal effects or detectable malformations. However each of these metabolites produced significant reductions in crown-rump lengths and somite numbers.

Applicant's summary and conclusion

Conclusions:
Under the conditions of this test, sodium salicylate induced embryolethality and malformations in in vitro rat embryos, while its three major metabolites induced only a reduction in growth at the same concentration.
Executive summary:

In an in vitro embryotoxic study (Greenaway et al., 1984), rat embryos (day 10 of gestation) were cultured with sodium salicylate at 1.9 mM (concentration found in human maternal blood after singles doses of salicylates) during 5, 9 or 24 hr. Sodium salicylate produced embryolethality in 26 of 34 embryos and 38 % of the remaining viable embryos exhibited malformations, such as abnormal closure of the neural tube and/or dilation or edema of the cephalic portion of the neural tube. For all embryotoxic effects examined (except malformations), the severity of the effect increased with the duration of exposure through the 24 -hr culture period. Nevertheless, the percentage of malformations observed after a 24 -hr exposure period was no greater than that measured after only a 9 -hr exposure. In this study, embryotoxic effects of salicylate metabolites (salicyluric acid, gentisic acid and 2,3 -dihydroxybenzoate) were also examined. None of the three metabolites produced significant increases in the number of malformed embryos or in embryolethality. All the three agents reduced crown-rump lengths and somite numbers slightly but significantly (p <0.01). These results strongly suggest that the parent salicylate, rather the metabolites, was primarily or solely responsible for the malformations observed and that the duration of exposure of embryos to unmetabolised salicylate may be the critical factor for determining teratogenic outcome.