Butanoic acid, 2-methyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester, (2S)-

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: no OECD test method used

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2005

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

2004

Materials and methods

Test guideline

Qualifier:

no guideline followed

Guideline:

other: not applicable

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate

EC Number:

616-212-7

Cas Number:

75330-75-5

Molecular formula:

C24-H36-O5

IUPAC Name:

(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate

Results and discussion

Results (fetuses)

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Developmental toxicity (birth defects) – Skeletal malformations were reported in

mice and rats orally administered 800 mg/kg/day (40 and 80 times the maximum

human dose, respectively, based on surface area) (PDR, 2005). No drug-induced

changes were seen in either species at multiples of 8 (rats) or 4 (mice) times the

human exposure based on surface area. In another study, an increased frequency

of abdominal wall defects and skeletal abnormalities was observed in the

offspring of rats treated with 60 mg/kg/day (TERIS, 2004; Reprotox, 2005). In an

additional rat study, skeletal defects and decreased fetal weight were observed in

offspring following gestational exposure to ≥100 mg/kg/day. No birth defects

were reported in rabbits given 15 mg/kg/day, the maximum tolerated dose (about

3 times the maximum human dose, based on surface area) (PDR, 2005).

Applicant's summary and conclusion

Conclusions:

Developmental toxicity (birth defects) – Skeletal malformations were reported in
mice and rats orally administered 800 mg/kg/day (40 and 80 times the maximum
human dose, respectively, based on surface area) (PDR, 2005). No drug-induced
changes were seen in either species at multiples of 8 (rats) or 4 (mice) times the
human exposure based on surface area. In another study, an increased frequency
of abdominal wall defects and skeletal abnormalities was observed in the
offspring of rats treated with 60 mg/kg/day (TERIS, 2004; Reprotox, 2005). In an
additional rat study, skeletal defects and decreased fetal weight were observed in
offspring following gestational exposure to ≥100 mg/kg/day. No birth defects
were reported in rabbits given 15 mg/kg/day, the maximum tolerated dose (about
3 times the maximum human dose, based on surface area) (PDR, 2005).

Executive summary:

Developmental toxicity (birth defects) – Skeletal malformations were reported in

mice and rats orally administered 800 mg/kg/day (40 and 80 times the maximum

human dose, respectively, based on surface area) (PDR, 2005). No drug-induced

changes were seen in either species at multiples of 8 (rats) or 4 (mice) times the

human exposure based on surface area. In another study, an increased frequency

of abdominal wall defects and skeletal abnormalities was observed in the

offspring of rats treated with 60 mg/kg/day (TERIS, 2004; Reprotox, 2005). In an

additional rat study, skeletal defects and decreased fetal weight were observed in

offspring following gestational exposure to ≥100 mg/kg/day. No birth defects

were reported in rabbits given 15 mg/kg/day, the maximum tolerated dose (about

3 times the maximum human dose, based on surface area) (PDR, 2005).