2-isopropoxyethanol

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

Study period:

1984

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented publication which meets basic scientific principles and provides strong evidence to support the mode of action for the hypothesis that developmental effects seen in developmental toxicity studies are secondary to maternal toxicity.

Data source

Reference

Reference Type:

publication

Title:

Diflunisal-induced maternal anemia as a cause of teratogenicity in rabbits

Author:

Clark, R.L., Robertson, R.T., Minsker, D.H., Cohen, S.M., Tocco, D.J., Allen, H.L., James, M.L., and Bokelman, D.L.

Year:

1984

Bibliographic source:

Teratology 30, 319-332.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study followed the basic principles of a developmental toxicity study but used a single dose on GD 5. This was designed to produce an anaemia that would be much more persistent than the drug itself, which is cleared quite rapidly from the animals' system. The study is therefore designed to see if hypoxia is the secondary cause of the developmental toxicity seen with the drug rather than it being a direct acting developmental toxicant.

GLP compliance:

not specified

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

Diflunisal

EC Number:

245-034-9

EC Name:

Diflunisal

Cas Number:

22494-42-4

Molecular formula:

C13H8F2O3

IUPAC Name:

2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid

Constituent 2

Reference substance name:

5-(2,4-difluorophenyl)-2-hydroxybenzoic acid

IUPAC Name:

5-(2,4-difluorophenyl)-2-hydroxybenzoic acid

Details on test material:

Source: Merck Sharp & Dohme Research Laboratories, West Point, PA

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, WIlmington MA

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Frequency of treatment:

Single dose on GD 5.

Duration of test:

to GD 20

Doses / concentrations

Remarks:

Doses / Concentrations:
100mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

4

Control animals:

yes

Results and discussion

Effect levels

Dose descriptor:

NOAEC

Effect level:

< 100 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: Qualitative nature of result and mode of action are more important than actual NOAEC.

Observed effects

Pregnant does given a single oral dose of diflunisal on gd 5 exhibited anemia that persisted through to gd 15, despite clearance of the drug from maternal blood by gd 9. Signs of anemia (present within 16 hours of dosing) in pregnant does included hemoglobinuria, and decreased erythrocyte counts (a 74 to 46 % decrease relative to controls on gd 9 to 15) and decreased hemoglobin concentrations (a 63 to 21 % decrease relative to controls on gd 9 to 15). Hematotoxicity was the most severe on gd 9, the first day of data collection, with some recovery by gd 15. These does showed an increase in preimplantation loss (10 of 25 inseminated does showed no evidence of implantations and there was an increase in preimplantation loss in other does), as well as an increase in totally resorbed litters (11 of 25 litters).

Any other information on results incl. tables

Effects were attributed to maternal anemia rather than a direct effect of diflunisal, because diflunisal is highly protein bound in maternal blood (greater than 98 %); thus, there are only low concentrations of diflunisal in rabbit embryos. Furthermore, rats, which are resistant to diflunisal-induced maternal anemia, do not demonstrate embryo/fetal effects, despite reaching approximately equivalent doses of diflunisal in rat embryos. Furthermore, there is little accumulation of diflunisal in embryos, which is likely a reflection of its low placental transfer. This study provides strong evidence that the embryo/fetal effects (similar to those seen with 2-butoxyethanol) were secondary to maternal anemia.

Applicant's summary and conclusion

Conclusions:

Anaemina causes embrotoxicity and fetal toxicity. The results provide strong support to the hypothesis that similar effects seen in studies with 2-butoxyethanol are secondary to anaemia

Executive summary:

In a developmental toxicity study designed to establish the mechanism of toxicity of the anti-inflammatory drug, diflunisal, pregnant rabbits were given a single 100mg/kg dose of the drug on GD5. The known metabolism of the drug meant that it would be cleared from the bloodstream by GD9, which is known to be the critical day for the induction of axial skeletal defects by hypoxia. Diflunisal also causes anaemia, which is persistent to GD15 and the study produced the same axial skeletal defects that were seen in a conventional developmental toxicity study. The results provided strong support for the hypothesis that, for this drug, the developmental toxicity was primarily caused by anaemia rather than directly by the drug itself.