methyl 2-ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

toxicity to reproduction: other studies

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Justification for type of information:

The read-across of data from chemical source (candesartan) to chemical target (CAN5) is based on the following hypothesis:
- chemical source and chemical target have the same organic functional groups (according to the profile “Organic functional groups nested” of QSAR Toolbox)
- chemical source and chemical target have a very close structure similarity, as calculated by QSAR Toolbox
- chemical source and chemical target have the same general mechanistic profile, as calculated by QSAR Toolbox
- chemical source and chemical target have the same end point-specific mechanistic profile, as calculated by QSAR Toolbox
- chemical source and chemical target have similar partition coefficient n-octanol/water

Principles of method if other than guideline:

Read-across of data from chemical source (candesartan) to chemical target (CAN5)

GLP compliance:

not specified

Key result

Dose descriptor:

other:

Remarks:

no specified

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: - fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) - neonatal toxicity (renal failure, hypotension, hyperkalemia)

Administration of Candesartan in pregnant: case reports of oliguria, perinatal renal failure, neonatal kidney dysfunction, developmental delay, and death associated with use of candesartan during the 2nd and 3rd trimester.
A series of 20 pregnancies with oligohydramnios.

Conclusions:

No data are available for substance target (CAN 5). Read-across with Candesartan is performed for this hazard. The adverse fetal effects appear to reflect a pharmacologic response of the fetus to Candesartan during the second half of gestation rather than abnormal embryogenesis. There is a substantial risk of oligohydramnios and fetal distress or death in hypertensive women treated with Candesartan in the latter part of the pregnancy; therefore, the use of the drug during these trimesters is contraindicated.

Rats are not a good model for this human teratogen although fetal death and decreased weight occur after treatment on days 15-20.

Candesartan did not impair fertility in male or female rats. Overall, considering all these data, the substance should be classified for this hazard class into category 2.

Executive summary:

The substance should be classified as Repr 2; H361d.

Data source

Reference

Reference Type:

secondary source

Title:

Unnamed

Year:

2013

Report date:

2016

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Candesartan is an angiotensin-II receptor blocker used in the treatment of hypertension. Angiotensin converting enzyme (ACE) inhibitors have been associated with fetal abnormalities including oliguria, skull defects, and death after second or third trimester exposure, and the product labels for angiotensin-II receptor blockers carry a warning that assumes these agents are capable of the same effects. Case reports of oliguria, perinatal renal failure, neonatal kidney dysfunction, developmental delay, and death associated with use of candesartan during the 2nd and 3rd trimester support this assumption, as do case reports with other agents of this class (losartan, valsartan, or telmisartan). The U.S. Food and Drug Administration's Pregnancy Category is the Category D that states “There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylic acid

EC Number:

604-138-8

Cas Number:

139481-59-7

Molecular formula:

C24H20N6O3

IUPAC Name:

2-ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylic acid

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

No specified

Administration / exposure

Route of administration:

other: Oral administration

Details on exposure:

Candesartan exposure during the pregnancy.

Details on analytical verification of doses or concentrations:

No specified

Duration of treatment / exposure:

No specified

Frequency of treatment:

No specified

Duration of test:

No specified

Doses / concentrations

Remarks:

No specified

Results and discussion

Effect levels

Key result

Dose descriptor:

other:

Remarks:

No specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) - neonatal toxicity (renal failure, hypotension, hyperkalemia)

Remarks on result:

other:

Remarks:

Observation in Human

Observed effects

Case reports of oliguria, perinatal renal failure, neonatal kidney dysfunction, developmental delay, and death associated with use of candesartan during the 2nd and 3rd trimester.
A series of 20 pregnancies with oligohydramnios.

Applicant's summary and conclusion

Conclusions:

No data are available for the substance target (CAN 5). Read-across with Candesartan is performed for this hazard. The adverse fetal effects appear to reflect a pharmacologic response of the fetus to Candesartan during the second half of gestation rather than abnormal embryogenesis. There is a substantial risk of oligohydramnios and fetal distress or death in hypertensive women treated with Candesartan in the latter part of the pregnancy; therefore, the use of the drug during these trimesters is contraindicated.
Rats are not a good model for this human teratogen although fetal death and decreased weight occur after treatment on days 15-20. Candesartan did not impair fertility in male or female rats. Overall, considering all these data, CAN 5 should be classified for this hazard class into category 2.