Methyl salicylate

Toxicity to reproduction: other studies

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:

supporting study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Embryonal disposition of salicylate: In vivo-in vitro comparisons

Author:

Daston GP, Francis WR, Baines D et al

Year:

1990

Bibliographic source:

Teratology, 42:225-232

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Comparison of salicylate concentration in foetal tissues in vitro and in vivo

GLP compliance:

not specified

Type of method:

other: in vitro and in vivo

Test material

Test material information

Constituent 1

Reference substance name:

Salicylic acid

EC Number:

200-712-3

EC Name:

Salicylic acid

Cas Number:

69-72-7

Molecular formula:

C7H6O3

IUPAC Name:

2-Hydroxybenzoic acid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Results and discussion

Observed effects

There was considerable binding of salicylate by maternal serum and culture medium proteins: less than 20% of the chemical was free at the 40 ug/ml concentration used in this experiment.

Any other information on results incl. tables

The distribution of salicylate to embryonal tissues was statistically comparable in vivo and in vitro, although the embryos in vitro accumulated slightly (but not significantly) less of the chemical. There was considerable binding of salicylate by maternal serum and culture medium proteins: less than 20% of the chemical was free at the 40 ug/ml concentration used in this experiment. Consequently, the salicylate concentration in embryonal compartments appeared to be quite low when compared to the surrounding serum/medium, but was actually equal to or greater than the concentration of unbound salicylate in serum or culture medium. The proportion of free salicylate in serum increased at concentrations higher than 40 ug/ml, resulting in somewhat higher concentrations of salicylate in in vitro embryos and extra-embryonic fluid (as compared to medium) when cultured in the presence of 200 or 400 ug/ml salicylate.

There was significantly more salicylate distributed to gestation day 20.5 fetal tissues than to gestation day 12.5 embryos. This appeared to result from a higher percentage of unbound salicylate in maternal serum in late gestation, but may also be due to other factors such as different placental characteristics or binding within embryo/fetal compartments. In summary, under the conditions of this study the disposition of salicylate to embryonal compartments was statistically comparable in vivo and in vitro. Disposition is influenced considerably by developmental stage and concentration of salicylate.

Applicant's summary and conclusion

Executive summary:

The distribution of salicylate to embryonal compartments for in situ and in vitro rat embryos under equivalent exposure conditions, and salicylate disposition in the in vivo mid-gestation embryo and late gestation fetus, were compared.

Pregnant Sprague-Dawley CD rats were exposed to steady-state blood levels of salicylate by infusing¹⁴C-salicylic acid iv for a 24 hour period from gestation day 11.5 to 12.5. Cultured Sprague-Dawley rat embryos (in medium consisting of 100% male rat serum) were exposed to the steady-state¹⁴C-salicylate concentration achieved in maternal serum in vivo for the same 24 hour developmental period. At the end of the exposure period radioactivity in visceral yolk sac, extra-embryonic fluid and embryos, and in maternal tissues, was measured.

The distribution of salicylate to embryonal tissues was statistically comparable in vivo and in vitro, although the embryos in vitro accumulated slightly (but not significantly) less of the chemical. There was considerable binding of salicylate by maternal serum and culture medium proteins: less than 20% of the chemical was free at the 40 ug/ml concentration used in this experiment. Consequently, the salicylate concentration in embryonal compartments appeared to be quite low when compared to the surrounding serum/medium, but was actually equal to or greater than the concentration of unbound salicylate in serum or culture medium. The proportion of free salicylate in serum increased at concentrations higher than 40 ug/ml, resulting in somewhat higher concentrations of salicylate in in vitro embryos and extra-embryonic fluid (as compared to medium) when cultured in the presence of 200 or 400 ug/ml salicylate.

Salicylate pharmacokinetics in the fetus were determined by infusing¹⁴C-salicylic acid iv into pregnant rats from gestation day 19.5 to 20.5 and concentrations in fetuses and dams on gestation day 20.5 were compared to those from gestation day 12.5 rats.

There was significantly more salicylate distributed to gestation day 20.5 fetal tissues than to gestation day 12.5 embryos. This appeared to result from a higher percentage of unbound salicylate in maternal serum in late gestation, but may also be due to other factors such as different placental characteristics or binding within embryo/fetal compartments. In summary, under the conditions of this study the disposition of salicylate to embryonal compartments was statistically comparable in vivo and in vitro. Disposition is influenced considerably by developmental stage and concentration of salicylate.