Developmental toxicity of butyl benzyl phthalate in the rat using a multiple dose study design.
The developmental toxicity of butyl benzyl phthalate (BBP) was investigated in the rat using ten dose groups between 270 and 2100 mg/kg/day. Exposure was by daily gavage from gestation day 5 through 16 or gestation day 5 through 20. Dose-response data were analyzed using the benchmark approach by fitting dose-response models to the various endpoints. BBP induced increased liver and kidney weights in dams, accompanied by liver enzyme increases in maternal serum. Extramedullary hematopoiesis, which was already substantial in control pregnant animals, was increased after BBP treatment. Fetotoxicity included increased resorptions, reduced fetal weights, increased incidence of skeletal anomalies, and reduced fetal testis weights in the presence of an increased incidence of retarded testicular descent. As embryotoxicity was found at lower dosages compared to observed maternal toxicity, BBP appeared to be a specifically embryotoxic compound. The extended exposure protocol (gestation day 5 through 20) appeared more sensitive for measuring fetotoxic effects. We recommend the use of more doses in toxicity tests, together with the benchmark approach as an appropriate and more accurate method for analyzing dose-response data compared to the NOAEL approach.
Piersma
A H
AH
Laboratory for Health Effects Research, National Institute for Public Health and the Environment, RIVM, P.O.Box 1, 3720 BA, Bilthoven, The Netherlands. ah.piersma@rivm.nl
Verhoef
A
A
te Biesebeek
J D
JD
Pieters
M N
MN
Slob
W
W
D000014:Abnormalities, Drug-Induced / Q000473:pathology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced / Q000473:pathology; D005333:Fetus / Q000187:drug effects; D008111:Liver Function Tests; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D012098:Reproduction / Q000187:drug effects; D016019:Survival Analysis
D010795:Phthalic Acids; C027561:butylbenzyl phthalate