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Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

An understanding of the bioavailability of topically applied cosmetics ingredients is key to predicting their local skin and systemic toxicity and making a safety assessment. We investigated whether short-term incubations with S9 from the reconstructed epidermal skin model, EpiSkin™, would give an indication of the rate of chemical metabolism and produce similar metabolites to those formed in incubations with human skin explants. Both have advantages: EpiSkin™ S9 is a higher-throughput assay, while the human skin explant model represents a longer incubation duration (24 hours) model integrating cutaneous distribution with metabolite formation. Here, we compared the metabolism of 10 chemicals (caffeine, vanillin, cinnamyl alcohol, propylparaben, 4-amino-3-nitrophenol, resorcinol, 4-chloroaniline, 2-amino-3-methyl-3H-imidazo[4,5-F]quinoline and 2-acetyl aminofluorene) in both models. Both models were shown to have functional Phase 1 and 2 enzymes, including cytochrome P450 activities. There was a good concordance between the models with respect to the level of metabolism (stable vs. slowly vs. extensively metabolized chemicals) and major early metabolites produced for eight chemicals. Discordant results for two chemicals were attributed to a lack of the appropriate cofactor (NADP + ) in S9 incubations (cinnamyl alcohol) and protein binding influencing chemical uptake in skin explants (4-chloroaniline). These data support the use of EpiSkin™ S9 as a screening assay to provide an initial indication of the metabolic stability of a chemical applied topically. If required, chemicals that are not metabolized by EpiSkin™ S9 can be tested in longer-term incubations with in vitro human explant skin to determine whether it is slowly metabolized or not metabolized at all., (© 2019 John Wiley & Sons, Ltd.)

Perfluoroalkyl acids (PFAAs) have been found extensively in wildlife and human bodies by sources of drinking water and food. In this study, we investigated the effects of three PFAAs, perfluoropentanoic acid (PFPA), perfluorooctanoic acid (PFOA), and perfluorodecanoic acid (PFDA), on the antioxidative defense system and lipid peroxidation in erythrocytes separately. The results demonstrated that they could lead to significant decline trends in the glutathione (GSH) levels together with increases of malondialdehyde (MDA) content, suggesting that three PFAAs induced oxidative stress to erythrocytes. Also PFDA with a longer carbon chain length posed more of a threat than other two PFAAs. Furthermore, the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were also altered in the presence of PFAAs upon erythrocytes. The changes of oxidative stress markers and the concomitant alterations of antioxidant enzymes suggest the role of oxidative stress in PFAA-induced damage upon erythrocytes.

The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Reproductive toxicity was based on the Threshold of Toxicological Concern (TTC) of 0.03 mg/kg/day for a Cramer Class I material. The estimated systemic exposure is determined to be equal to this value while assuming 100% absorption from skin contact and inhalation. A systemic exposure at or below the TTC value is acceptable., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Emricasan, formerly IDN-6556, is a small molecule currently being evaluated in clinical trials to reduce hepatic injury and liver fibrosis. Since emricasan is an irreversible pan-caspase inhibitor that potently inhibits caspase-mediated apoptosis and inflammation, its carcinogenic potential was evaluated in a humanized mouse model. Tg.rasH2 mice received LabDiet formulated with 0, 10, 25, and 75mg/kg/day of emricasan, for 26weeks. At terminal sacrifice, blood was collected for clinical pathology analysis and tissues were collected, processed, and evaluated microscopically. There were no treatment related deaths or overt signs of toxicity for the duration of the study. There was no evidence of a carcinogenic effect in the peripheral blood leukocyte counts. Liver microgranulomas, which are background lesions, were slightly increased, especially in males. Increases in the incidence of the activated germinal centers were seen in the spleens and mesenteric lymph nodes of males and females, and in the mandibular lymph nodes of male mice. Atrophy of ovaries and testicular degeneration were also seen in emricasan treated animals. Although several non-neoplastic lesions were observed, there was no evidence of emricasan-related tumor formation in any tissue. In addition, the non-neoplastic lesions were not considered pre-neoplastic. Thus, emricasan is not considered carcinogenic., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate the stereoselective anticonvulsant activity, neurotoxicity, pharmacokinetics, and teratogenic potential of two stereoisomers of valnoctylurea (VCU), a central nervous system (CNS)-active urea derivative of valnoctic acid, which is a constitutional isomer of valproic acid (VPA)., Methods: VCU stereoisomers (2S,3S)-VCU and (2R,3S)-VCU were synthesized. Their anticonvulsant activity was determined and compared to VPA and racemic-VCU in rats utilizing the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scMet) tests. Neurotoxicity was determined in rats using the positional sense test, muscle tone test, and gait and stance test. The induction of neural tube defects (NTDs) by VCU stereoisomers was evaluated in a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of VCU was studied in a stereoselective manner following intraperitoneal (i.p.) administration to rats., Results: (2S,3S)-VCU and (2R,3S)-VCU median effective dose ED(50) values were 29 mg/kg [95% confidence interval (CI) = 8-60 mg/kg] and 42 mg/kg (95% CI = 36-51 mg/kg) (MES) and 22 mg/kg (95% CI = 13-51 mg/kg) and 12 mg/kg (95%CI = 7-21 mg/kg) (scMet), respectively. (2S,3S)-VCU was more potent and had a wider safety margin (p < 0.05), defined as the protective index (PI = TD(50)/ED(50)), at both the MES (PI > 17) and scMet (PI > 23) tests than racemic-VCU or (R,S)-VCU (PI = 2.8 and 9.9, respectively). VCU stereoisomers caused NTDs at doses >4 times that of their anticonvulsant ED(50) values. At a dose of 112 mg/kg, (2R,3S)-VCU was nonteratogenic and less embryotoxic than its stereoisomer (2S,3S)-VCU. No stereoselective pharmacokinetics was observed following intraperitoneal dosing of racemic-VCU to rats. VCU was mainly eliminated by metabolism with a half-life of 2 h., Conclusions: VCU anticonvulsant activity and wide PI values make it a potential candidate for development as a new, potent antiepileptic drug (AED).

The present study investigated whether treatment of female rats with pivalate affects their reproductive function. Therefore, two experiments with female rats were performed. The first experiment included two groups of rats which received drinking water without (control) or with 20 mmol pivalate/L. The second experiment included a control group (which received drinking water without pivalate and a diet without added carnitine) and four groups which received drinking water with 20 mmol/L pivalate and diets without or with 1, 3 or 5 g added carnitine/kg, respectively. In both experiments, rats treated with pivalate had a lower number of pups born alive and, as a consequence of this, lower litter weights than control rats (p<0.05); pup weights were not altered by pivalate treatment. Supplementation of dietary carnitine in Experiment 2 increased plasma and tissue carnitine concentration even in excess of those in control rats but did not restore normal litter sizes. This study shows for the first time that pivalate affects the reproductive function in female rats independent of its effect on the carnitine status.

1. Patients affected by isovaleric acidemia (IVAcidemia) suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. The objective of the present study was to investigate the in vitro effects of the metabolites that predominantly accumulate in IVAcidemia, namely isovaleric acid (IVA), 3-hydroxyisovaleric acid (3-OHIVA) and isovalerylglycine (IVG), on important parameters of energy metabolism, such as (14)CO(2) production from acetate and the activities of the respiratory chain complexes I-IV, creatine kinase and Na(+), K(+)-ATPase in synaptic plasma membranes from cerebral cortex homogenates of 30-day-old rats. 2. We observed that 3-OHIVA acid and IVG did not affect all the parameters analyzed. Similarly, (14)CO(2) production from acetate (Krebs cycle activity), the activities of creatine kinase, and of the respiratory chain complexes was not modified by IVA. In contrast, IVA exposition to cortical homogenates provoked a marked inhibition of Na(+), K(+)-ATPase activity. However, this activity was not changed when IVA was directly exposed to purified synaptic plasma membranes, suggesting an indirect effect of this organic acid on the enzyme. Furthermore, pretreatment of cortical homogenates with alpha-tocopherol and creatine totally prevented IVA-induced inhibition on Na(+), K(+)-ATPase activity from synaptic plasma membranes, whereas glutathione (GSH) and the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) did not alter this inhibition. 3. These data indicate that peroxide radicals were probably involved in this inhibitory effect. Since Na(+), K(+)-ATPase is a critical enzyme for normal brain development and functioning and necessary to maintain neuronal excitability, it is presumed that the inhibitory effect of IVA on this activity may be involved in the pathophysiology of the neurological dysfunction of isovaleric acidemic patients.

Using neat vapors of selected homologous aldehydes (decanal, undecanal, dodecanal) and carboxylic acids (pentanoic, hexanoic, heptanoic, octanoic, nonanoic), we explored the point where a certain homolog (and all larger ones) becomes undetectable by eye irritation (i.e. by ocular chemesthesis). This phenomenon has been observed in other homologous series that also reach a break-point, or cutoff, in chemesthetic detection. Participants (11

Objective: To compare the effects of hydrochloric acid (HCl) and various concentrations of volatile fatty acids (VFAs) on tissue bioelectric properties of equine stomach nonglandular (NG) mucosa., Sample Population: Gastric tissues obtained from 48 adult horses., Procedures: NG gastric mucosa was studied by use of Ussing chambers. Short-circuit current (Isc) and potential difference (PD) were measured and electrical resistance (R) and conductance calculated for tissues after addition of HCl and VFAs (5, 10, 20, and 40 mM) in normal Ringer's solution (NRS)., Results: Mucosa exposed to HCl in NRS (pH of 1.5 and, to a lesser extent, 4.0) had a significant decrease in Isc, PD, and R, whereas tissues exposed to acetic acid at a pH of < 4.0, propionic and butyric acids at a pH of

In a high dose toxicity study of pivalic acid (PA), PA caused skeletal muscle disorder in dog, and a significant increase of pivaloyl carnitine (PC) was observed in canine muscle, but not in rat muscle. In order to understand species difference of the toxicity of PA, we compared the in vitro metabolism of PA among dog, rat and rabbit, especially focussing on the carnitine conjugate. Canine muscle showed low, but significant carnitine conjugating activity, while that of rat was negligible. Canine kidney mitochondria had significant activity in the pivaloyl CoA synthesis (7 nmol/mg protein/h), but muscle mitochondria showed only trace activity. Both kidney and muscle mitochondria displayed similar carnitine acyltransferase activity (2-3 nmol/mg protein/h) towards pivaloyl CoA. On the other hand, with respect to the activity of carnitine acyltransferase in the reverse direction using PC as substrate, canine muscle mitochondria showed higher activity than that of kidney mitochondria. This means that PC is not the final stable metabolite, but is converted easily to pivaloyl CoA in canine muscle. These results suggest one of the possible mechanisms for canine selective muscle disorder to be as follows. Only canine muscle can metabolize PA to its carnitine conjugate slowly, but significantly. In canine muscle, PC is not the final stable metabolite; it is easily converted to pivaloyl CoA. As carnitine conjugation is thought to be the only detoxification metabolic route in canine muscle, under certain circumstances such as carnitine deficiency, the risk of exposure with toxic pivaloyl CoA might increase and the CoASH pool in canine muscle might be exhausted, resulting in toxicity in canine muscle.

A toxicologic and dermatologic review of linalyl isovalerate when used as a fragrance ingredient is presented.

The nonprotein amino acids 2-amino-3-cyclopropylbutanoic acid and 2-amino-5-chloro-4-pentenoic acid were isolated from the mushroom Amanita cokeri. The cyclopropyl amino acid is toxic to the fungus Cercospora kikuchii, the arthropod Oncopeltus fasciatus (milk weed bug), and the bacteria Agrobacterium tumefaciens, Erwinia amylovora, and Xanthomonas campestris. Toxicity to bacteria was reversible by addition of isoleucine to the medium. No toxicity was observed for 2-amino-5-chloro-4-pentenoic acid.

The teratogenic properties of valproic acid (VPA) and its analogues depend to a great extent on their chemical structure. We investigated the structure-teratogenicity relationships of VPA, its structural isomer, valnoctic acid (VCA), and their two amide analogues, valpromide (VPD) and valnoctamide (VCD), respectively. Each substance was injected (3 mmol/kg) in NMRI-mice on the morning of day 8 of gestation. Embryolethality, fetal weight and exencephaly rates were recorded on day 18 of gestation. VPA caused 53% exencephaly, VPD induced 6%, VCA and VCD produced only 1% exencephaly (control values between 0 and 1%). VPA-treated mice also had increased embryolethality rates (52%). There was no significant change of embryolethality in the other treatment groups. Pharmacokinetic studies showed that VCD was eliminated from plasma at a slower rate than VPA. Also, the residual teratogenic activity of VPD was not accounted for by the relatively small amounts of its hydrolysis product VPA. This study indicates that VPD, VCA and VCD were distinctly less teratogenic than VPA. Apparently the amidation of the free carboxylic group and/or methyl-substitution at the beta-position of the carbon chain greatly decreased the teratogenic activity of VPA.

It is postulated that the hepatotoxicity of valproic acid (VPA) results from the mitochondrial beta-oxidation of its cytochrome P450 metabolite, 2-propyl-4-pentenoic acid (4-ene VPA), to 2-propyl-(E)-2,4-pentadienoic acid ((E)-2,4-diene VPA) which, in the CoA thioester form, either depletes GSH or produces a putative inhibitor of beta-oxidation enzymes. In order to test this hypothesis, 2-fluoro-2-propyl-4-pentenoic acid (alpha-fluoro-4-ene VPA) which was expected to be inert to beta-oxidative metabolism was synthesized and its effect on rat liver studied in comparison with that of 4-ene VPA. Similarly, the known hepatotoxicant 4-pentenoic acid (4-PA) and 2,2-difluoro-4-pentenoic acid (F2-4-PA) were compared. Male Sprague-Dawley rats (150-180 g, 4 rats per group) were dosed ip with 4-ene VPA (0.7 mmol/kg per day), 4-PA (1.0 mmol/kg per day), or equivalent amounts of their alpha-fluorinated analogues for 5 days. Both 4-ene VPA and 4-PA induced severe hepatic microvesicular steatosis ( > 85% affected hepatocytes), and 4-ene VPA produced mitochondrial alterations. By contrast, alpha-fluoro-4-ene VPA and F2-4-PA were not observed to cause morphological changes in the liver. The major metabolite of 4-ene VPA in the rat urine and serum was the beta-oxidation product (E)-2,4-diene VPA. The N-acetylcysteine (NAC) conjugate of (E)-2,4-diene VPA was also found in the urine. Neither (E)-2,4-diene VPA nor the NAC conjugate could be detected in the rats administered alpha-fluoro-4-ene VPA. In a second set of rats (3 rats per group), total liver GSH levels were determined to be depleted to 56% and 72% of control following doses of 4-ene VPA (1.4 mmol/kg) and equivalent alpha-fluoro-4-ene VPA, respectively. Mitochondrial GSH remained unchanged in the alpha-fluoro-4-ene VPA treated group but was reduced to 68% of control in the rats administered 4-ene VPA. These results strongly support the theory that hepatotoxicity of 4-ene VPA, and possibly VPA itself, is mediated largely through beta-oxidation of 4-ene VPA to reactive intermediates that are capable of depleting mitochondrial GSH.

The hepatocellular glutathione content is partitioned into a cytosolic pool, which accounts for about 85% of the cellular glutathione content, and a mitochondrial pool, which accounts for about 15% of the cellular glutathione content. Previous studies indicated that the mitochondrial glutathione pool may play a critical role in cytoprotection against xenobiotic-induced cell damage. Tests of the role of mitochondrial glutathione in cytoprotection have been hampered by the lack of agents that selectively deplete the mitochondrial glutathione pool. To test the hypothesis that mitochondrial glutathione plays a critical role in protecting against cytotoxic agents, we developed a method to deplete selectively mitochondrial glutathione concentrations. (R,S)-3-Hydroxy-4-pentenoate, an analog of (R)-3-hydroxybutanoate, caused a rapid and selective depletion of mitochondrial glutathione concentrations. Incubation of (R,S)-3-hydroxy-4-pentenoate with rat liver mitochondria or with 3-hydroxybutyrate dehydrogenase in the presence of glutathione afforded a glutathione conjugate whose chromatographic properties were identical with synthetic S-(3-oxo-4-carboxybutyl)glutathione, indicating that (R,S)-3-hydroxy-4-pentenoate was oxidized to the Michael acceptor 3-oxo-4-pentenoate, which reacts with glutathione. Exposure of rat hepatocytes to (R,S)-3-hydroxy-4-pentenoate, which was not cytotoxic and did not induce mitochondrial dysfunction, potentiated the cytotoxicity of tert-butyl hydroperoxide. These results establish the critical role of mitochondrial glutathione in cytoprotection and demonstrate and (R,S)-3-hydroxy-4-pentenoate may find utility in exploring mitochondrial glutathione homeostasis.

A modified FETAX (Frog Embryo Teratogenesis Assay: Xenopus) protocol was used to assess the joint action of ten aliphatic carboxylic acids on Xenopus embryo development. Stock solutions of each acid alone, made up at twice the EC50 of the individual acids, were prepared for testing alone and in a mixture with an equal volume of each acid stock solution. For each treatment, five concentrations and a control dish, each with 25 embryos, were tested for 96 h, with solution renewal every 24 h. The embryos were then fixed and evaluated for gross malformations. For each dish, the number and types of malformations were recorded. An EC50 was calculated for each acid alone and this value was defined as 1.0 toxic unit (TU) for malformation induced by the acid. An EC50 was also calculated for the mixture. The concentration of each acid at the mixture EC50 and the TU values corresponding to these concentrations were then determined. A TU value of 0.990 (0.923-1.060) was obtained for the mixture by adding the TU values for each acid in the mixture. This represents a concentration additive rate of malformation. Microcephaly, TU = 1.09 (1.01-1.18), was the primary malformation, but did not completely account for the response. The concentration additive rate of malformation indicates that all ten acids are likely to induce malformation in Xenopus embryos in a similar manner. Quantitative structure-activity relationship (QSAR) analysis revealed developmental malformation induced by the acids was highly correlated (r2 = 0.979) with hydrophobicity and molar refractivity (r2 = 0.949). The approach has potential application in determining compounds that induce developmental malformations in a similar manner, when metabolism and pharmacokinetic factors are considered.

Using a whole-embryo culture system valproic acid (VPA) and some of its metabolites (2-en-VPA, 4-en-VPA, 4,4'-dien-VPA) and analogues (ethyl-propyl-acetic acid, propyl-butyl-acetic acid, di-butyl-acetic acid, 2-methyl-2-ethyl-hexanoic acid, 1-methyl-1-cyclohexanoic acid) were tested for their potential to induce abnormal development. With regard to embryonic growth, development and abnormality rate, the tested compounds showed a wide range of "teratogenic potency" in vitro. In order to verify some of the in vitro results, in vivo experiments were performed. Pregnant rats were treated subcutaneously on day 10 of gestation with 2 x 330 mg VPA/kg, or 2 x 400 mg 2-en-VPA/kg, respectively. Evaluation of the embryos was performed on day 11.5 of gestation, corresponding to the in vitro experiments. VPA showed a high potential to induce abnormal development in vivo as well as in vitro, whereas 2-en-VPA was inactive under our experimental conditions. Problems connected with the evaluation of the predictive value of an in vitro test system for the detection of embryotoxic effects, such as "validation" and significance of pharmacokinetic data, are discussed.

We examined the effects of topically applied pivalylphenylephrine (PPE) and pivalic acid (PA) on the corneal endothelium of rabbits and the direct effects of PPE and PA on monolayer cultures of bovine corneal endothelium. The PPE-treated corneas without epithelium significantly increased in thickness, whereas no change in thickness was observed in corneas with epithelium intact. The PA did not alter the thickness of corneas with or without epithelium. Although 0.001% PE had no noticeable effect in two hours, 0.01% PPE caused breakdown of intercellular junctions in cultured cells in five minutes. Higher concentrations of PPE caused the cells to detach from the culture dishes within 30 minutes of treatment. Only 1% PA caused cell elongation and loss of intercellular contact after 60 to 90 minutes of exposure; lower concentrations did not effect cultured cells.

Gemfibrozil, a novel hypolipidemic agent identified chemically as 2,2-dimethyl-5-(2,5-xylyoxy) valeric acid, was evaluated for mutagenic potential in in vitro assays with Salmonella typhimurium. For evaluation of tumorigenic potential, gemfibrozil was administered in the diet (0.30, and 300 mg gemfibrozil/kg) to groups of noninbred CD-1 mice (72/sex) and noninbred CD rats (50/sex) for 78 and 104 weeks, respectively. In the bacterial mutagenesis assays, between 100 and 2,500 microgram gemfibrozil/plate failed to induce a significant increase in revertant bacterial colonies. Neither was a mutagenic response in bacterial assays induced at concentrations up to 300 microgram of five in vivo metabolites of gemifibrozil isolated from rat urine/plate. In mice, gemfibrozil did not significantly increase the frequency or the mean latency period of tumors. In rats, the statistically significant increases in hepatocellular tumors and interstitial cell tumors of the testes were dose related. Adrenal medullary and pancreatic acinar tumors were increased in male rats but were inversely dose related. Under the conditions of this assay, gemfibrozil did not elicit a tumorigenic potential in mice and female rats. In male rats and related to the hepatocellular tumor response, the peroxisome proliferation seen did not occur in humans chronically administered hypolipidemics.

4-Pentenoic acid, an analog of hypoglycin which is believed to cause Jamaican vomiting sickness, was administered intraperitoneally to rats in an attempt to produce the features of Reye's syndrome in rats. Mean ammonia levels in plasma were found to be elevated approximately four-fold after injection of 200 mg/kg pentenoic acid in fed rats. Pentenoic acid caused hypoglycemia in fasted rats and hyperglycemia in fed rats. In chronic experiments rats were injected intraperitoneally every 4 hr with 50 mg/kg body weight of pentenoic acid for 10 doses, followed by a single dose of 200 mg/kg. The livers of the treated group were enlarged and yellow and showed extensive fatty degeneration. The blood-urea-nitrogen (BUN) was significantly higher and the free fatty acids (FFA's) significantly lower in these rats. This study shows that pentenoic acid administered to rats produces findings similar to those of Reye's syndrome and Jamaican vomiting sickness.

Gemfibrozil, a new lipid-regulating agent, was evaluated in rats and rabbits for effects on various phases of the reproduction process. In teratology studies groups of pregnant rats and rabbits received gemfibrozil at doses up to 200 mg/kg during organogenesis (rat, Days 6-15; rabbit, days 6-18). For peri- and postnatal studies, groups of pregnant rats were given 92 or 331 mg/kg from Day 15 of gestation through weaning. In fertility studies groups of sexually mature male rats were given 93 or 326 mg/kg of gemfibrozil for 61 days and females were given 94 or 318 mg/kg for 15 days prior to mating within treatment groups. Drug administration continued in females through gestation and weaning of the F1 offspring. In subsequent fertility experiments, treated male rats were mated with untreated females and treated females were cohabitated with untreated males. Gemfibrozil did not elicit a teratogenic response in either rats or rabbits up to doses that resulted in maternal toxicity. Reduced pup weights during the neonatal and weaning periods in the female fertility study as well as in the perinatal-postnatal study were the only apparent drug effect. Treatment of female rats prior to mating had no significant effects on general reproductive parameters. Male rats given doses of about 300 mg/kg/day showed inconsistent and equivocal lower rates of fertility relative to the concurrent controls. No adverse effects were seen in the reproductive performance of offspring of gemfibrozil-treated male rats.