1-Naphthaleneheptanoic acid, 8-(2,2-dimethyl-1-oxobutoxy)-1,2,6,7,8,8a-hexahydro-.beta.,.delta.-dihydroxy-2,6-dimethyl-, ammonium salt (1:1), (.beta.R,.delta.R,1S,2S,6R,8S,8aR)-

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Qualifier:

no guideline followed

Guideline:

other: no data

Principles of method if other than guideline:

no data

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Simvastatin

IUPAC Name:

Simvastatin

Test animals

Species:

rat

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Developmental and Reproductive Toxicity – Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk2.
Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation)2. No microscopic changes were observed in the testes of rats from either study2. At 180 mg/kg/day, seminiferous tubule degeneration was observed2. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day2.

Executive summary:

Developmental and Reproductive Toxicity – Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk2. Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation)2. No microscopic changes were observed in the testes of rats from either study2. At 180 mg/kg/day, seminiferous tubule degeneration was observed2. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day2.