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Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
other: Retrospective study in humans
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Reference
Reference Type:
publication
Title:
Reproductive toxicity study of the test chemical
Author:
Lewis RB and Schulman JD
Year:
1973
Bibliographic source:
Lancet

Materials and methods

Principles of method if other than guideline:
The effects of the test chemical in human gestation were investigated retrospectively.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material: Acetylsalicylic acid
- Molecular formula: C9H8O4
- Molecular weight: 180.16 g/mol
- Substance type: Organic
- Physical state: Solid
- Impurities (identity and concentrations): not specified

Test animals

Species:
other: humans
Sex:
female

Administration / exposure

Route of administration:
oral: capsule
Details on exposure:
The group of patients exposed to the test chemical had a therapeutic intake of the test chemical of greater than 3250 mg/day for at least the last 6 months of gestation.
Duration of treatment / exposure:
The group of patients exposed to the test chemical had a therapeutic intake of the test chemical of greater than 3250 mg/day for at least the last 6 months of gestation.
Frequency of treatment:
Daily
Duration of test:
Not specified.
Doses / concentrations
Remarks:
0 (Group 3), 0 (Group 2) and >3250 mg/day (Group 1)
No. of animals per sex per dose:
Group 1: 103 patients
Group 2: 52 patients
Group 3: 50 patients
Details on study design:
The study included three groups. Group 1 consisted of 103 patients, each with therapeutic intake of greater than 3250 mg/day of the test chemical, for at least the last 6 months of gestation. These patients had rheumatoid arthritis, non-specific collagen disease, or degenerative musculoskeletal disease. Group 2 included 52 patients with rheumatoid arthritis, non-specific collagen disease, or degenerative musculoskeletal disease during gestation who were no taking therapeutic doses of the test chemical. Group 3 consisted of 50 patients without known disease who were test chemical-free during gestation.
Statistics:
All data were obtained directly from patient records and were analysed statistically using the t or Chi-square tests. A P value of <0.05 was considered significant.

Results and discussion

Effect levels

Key result
Dose descriptor:
LOAEL
Effect level:
<= 3 250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Increased gestation lenght, increased frequency of postmaturity, increased labor duration, increased blood loss during delivery

Observed effects

The data revealed a significant increase in gestation length in Group 1 (mean, 286.1 days) as compared to Group 2 (mean 275.2 days) and Group 3 (mean, 278.6 days). Moreover, the authors noted a significant increase in the frequency of postmaturity (gestations over 42 weeks) in Group 1 compared to Group 3. Labor duration was also significantly increased in Group 1 (mean, 12.1 hours) compared to Group 2 (mean, 7.3 hours) and Group 3 (mean, 6.96 hours). Data from the study also revealed a significant increase in estimated blood loss during delivery in Group 1 compared to the other two groups. Treatment with the test chemical was found to have no significant effect on birth weight (mean, 3077 gram in Group 1 vs. mean, 2972 gram in Group 2). Mean birth weight in Group 3 was however significantly higher (mean, 3379 gram) compared to Group 1 and 2.

Applicant's summary and conclusion

Conclusions:
Exposure to the test chemical during human gestation was associated with increased gestation length, increased frequency of postmaturity, increased labor duration, and increased estimated blood loss during delivery. The findings need to be interpreted with caution as the effects were observed in seriously diseased patients with chronic intake of acetylsalicylic acid for therapeutic reasons.
Executive summary:

The effect of the test chemical on human gestation was investigated in this retrospective study. The study included three groups. Group 1 consisted of 103 patients, each with therapeutic intake of greater than 3250 mg/day of the test chemical, for at least the last 6 months of gestation. These patients had rheumatoid arthritis, non-specific collagen disease, or degenerative musculoskeletal disease. Group 2 included 52 patients with rheumatoid arthritis, non-specific collagen disease, or degenerative musculoskeletal disease during gestation who were no taking therapeutic doses of the test chemical. Group 3 consisted of 50 patients without known disease who were test chemical-free during gestation. The data revealed a significant increase in gestation length in Group 1 (mean, 286.1 days) as compared to Group 2 (mean 275.2 days) and Group 3 (mean, 278.6 days). Moreover, the authors noted a significant increase in the frequency of postmaturity (gestations over 42 weeks) in Group 1 compared to Group 3. Labor duration was also significantly increased in Group 1 (mean, 12.1 hours) compared to Group 2 (mean, 7.3 hours) and Group 3 (mean, 6.96 hours). The observed effects on gestation length and labor duration were attributed to the capacity of the test chemical to inhibit prostaglandin synthesis. Data from the study also revealed a significant increase in estimated blood loss during delivery in Group 1 compared to the other two groups. This outcome was attributed to the capacity of the test chemical to affect platelets and clotting activity. Treatment with the test chemical was found to have no significant effect on birth weight (mean, 3077 gram in Group 1 vs. mean, 2972 gram in Group 2). Mean birth weight in Group 3 was however significantly higher (mean, 3379 gram) compared to Group 1 and 2. This effect was attributed to the healthier state of the women in Group 3 who did not suffer from serious systemic diseases.