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were no fetal abnormalities that could be related to maternaltreatment. The NOAELs for maternal and developmental toxicitywere 2 and 4 �g/kg/day, respectively.

doi:10.1016/j.toxlet.2010.03.650

Abstracts / Toxicology L

eveloping fetuses and breast-fed infants are the most highlyxposed population groups.

This study investigated the impacts of perinatal exposureo low doses of a chemical mixture (polychlorinated biphenyls,rganochlorine pesticides and methylmercury) present in thelood of the arctic Inuit population on the retinoid system and otherndpoints, including body and organ weights and enzyme induc-ion, in rat dams and their offspring. Pregnant Sprague–Dawleyats were given the reconstituted mixture (0, 0.05, 0.5 and 5 mg/kgw/day) from gestational day 1 through weaning. One male and oneemale offspring were sacrificed at postnatal days (PNDs) 35, 77 and50 and the dams at 7–10 days after weaning. Frozen samples of

iver and kidney were kept for subsequent analyses.Following high dose treatment; hepatic retinoids were

ecreased in both sexes of the offspring at PNDs 35, 77 and 350,s well as in the dams, while the renal retinoids were increased inoth sexes of the offspring but decreased in the dams. Also, body,

iver and kidney weights were decreased in the high-dose groupsf both sexes of offspring. The effects in the treated offspring wereess evident at PND350 than at PNDs 35 and 77, likely due to the dis-ontinued exposure after weaning. Critical effect doses (CEDs) forepatic retinyl palmitate modulation (5%) ranged between 0.41 and.09 mg/kg bw/day at PNDs 35 and 77 respectively; whereas CED forenal retinyl palmitate modulation (5%) at PND 77 was 0.36 mg/kgw/day. Maximum responses ranged from −21% to −75% for hep-tic retinoids. Renal retinyl palmitate showed a maximum responsef +97%. CEDs (100%) for hepatic and renal P450 enzyme induc-ion in the offspring at PND35 ranged between 0.42 and 2.87 mg/kgw/day respectively.

oi:10.1016/j.toxlet.2010.03.648

204-025elayed preputial separation in rats does not necessarily

ndicate antiandrogenicity—Evaluation of 2-generationoxicity studies of chemicals and agro-chemicals

. Melching-Kollmuss, K. Hempel, R. Buesen, I. Fegert, S.chneider, B. Van Ravenzwaay

BASF SE, Germany

ndocrine disrupters are under special focus of authorities. Whilearameters assessing potentially endocrine related effects are

nvestigated in both screening and regulatory toxicity studies ofhemicals and agro-chemicals, no clear guidance is given whichata provide definitive proof if a substance is an endocrine dis-uptor causing adverse effects. One of the parameters consideredo be able to detect antiandrogenicity in rats is the onset of maleuberty, determined by the age of animals at preputial separation.his parameter amongst others has therefore been included in theast into the regulatory guidelines for studies evaluating repro-uctive toxicity and offspring development (i.e. OPPTS 870.3800 a;ECD 416). Several factors have been discussed by different authors

o influence the onset of puberty: feed restriction, decreased mater-al/offspring body weight development, leptin levels, or intensiveandling.

Since the guidelines require setting the high dose at a levelhere significant signs of toxicity are seen, changes on food con-

umption or body weight development are commonly seen inegulatory toxicity studies. Thus, we have evaluated the poten-

ial relationship between the onsets of puberty in male animalsith parameters of maternal/offspring food consumption and bodyeight changes in several 2-generation toxicity studies in rats per-

ormed over the last 10 years in our laboratory with chemicals

196S (2010) S37–S351 S191

or agro-chemical. Onset of male puberty in control animals var-ied from day 40 to 47, with a median at day 42, the body weightsof our rat strain at day of preputial separation was in the rangeof 142–215 g (median value: 174 g). A comparison with the dosedgroups revealed that the age of animals at the onset of pubertyin male rats was correlated with maternal and/or offspring bodyweight development. In conclusion, the isolated finding of delayedpreputial separation is not sufficient to prove an antiandrogenicmode of action.

doi:10.1016/j.toxlet.2010.03.649

P204-026Maternal and developmental toxicity study of tetrodotoxin inrats

A. Guzmán 1, A. Ho 2, P. Ruth 3, A. Tortajada 1, A.R. Fernández DeHenestrosaa 1, P. Thirlwell 3, C. García 1, M.T. Ruiz 1, A.P. Marín 1

1 Esteve, United States, 2 WEX Pharmaceuticals Inc., United States,3 Huntingdon Life Sciences, United Kingdom

The naturally occurring neurotoxin tetrodotoxin (TTX;octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano-10aH-(1,3)dioxocino(6,5 d)pyrimidine-4,7,10,11,12-pentol) isamong the most deadly poisons known to man. TTX has sodiumchannel blocking activity and shows analgesic activity in animalpain models suggesting a possible use for TTX as an analgesic for thetreatment of human pain conditions. The maternal and develop-mental toxicity of TTX was assessed in pregnant Sprague–Dawleyrats (22 dams/group) following daily subcutaneous administrationof its injectable dose form (supplied by WEX Pharmaceuticals)during Days 6–17 of gestation at doses of 2, 4 or 8 �g/kg/day.Animals were killed on Day 20 of gestation and subjected to afull macroscopic examination. Uterine contents were examinedand the numbers of corpora lutea, implantation sites, early andlate resorptions, and live/dead fetuses recorded. Approximatelyhalf of each litter were eviscerated and processed for skeletalexamination, and the remaining fetuses were fixed in Bouin’s fluidfor internal examination by free-hand serial sectioning. Therewere no maternal deaths related to treatment with TTX. Signs ofunderactive behaviour and partially closed eyelids were observedat 4 and 8 �g/kg/day, with abnormal gait at 8 �g/kg/day. Duringtreatment bodyweight gain was low at all dose levels (although at2 �g/kg/day the effect was transient) and food consumption waslow at 4 and 8 �g/kg/day. Embryo-fetal survival was not affectedby treatment. Fetal weights were low at 4 and 8 �g/kg/day, andplacental weights were low at 8 �g/kg/day. A slightly high inci-dence of fetuses/litters with hepatic haemorrhages and incompleteossification/unossified sternebrae was observed at 8 �g/kg/day.These findings were considered to reflect a delay in fetal matu-ration consequent to maternal toxicity. At 2 or 4 �g/kg/day there