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The effects of hydroquinone (HQ) on reproductive performance and fertility were assessed in a two-generation study with CD Sprague-Dawley rats (one litter per generation). HQ was administered in an aqueous solution by gavage at doses of 0, 15, 50, and 150 mg/kg/day. F0 and F1 parental animals were dosed daily for at least 10 weeks prior to cohabitation, during cohabitation, and until scheduled termination. At all dose levels tested, no adverse effects were observed on feed consumption, survival, or reproductive parameters for the F0 or F1 parental animals. Mild, transient tremors were observed shortly after dosing at 150 mg/kg/day in several F0 and F1 parental animals and in a single F0 male at 50 mg/kg/day. These tremors occurred infrequently and were considered to be due to an acute stimulatory effect of HQ on the nervous system. Body weights for F0 and F1 parental females were similar between all dose groups throughout the study. Body weights for F0 parental males were also comparable to those of control throughout the study. Statistically significant differences in body weights were noted for the F1 parental males in the 50 and 150 mg/kg/day dose groups at several intervals during the premating, mating, and postmating periods. No treatment-related effects on pup weight, sex distribution, or survival were noted for pups of either generation. Upon postmortem examination, no treatment-related gross lesions were observed in either the F0 or F1 parental animals or their weanlings. Histopathologic examination of reproductive tissues and pituitary glands from high-dose F0 and F1 parental animals did not reveal any changes related to treatment with HQ.(ABSTRACT TRUNCATED AT 250 WORDS)

To obtain information on potential developmental toxicity, hydroquinone (HQ) was administered to pregnant New Zealand White rabbits (18 mated per dose group) in aqueous solution (0, 25, 75, or 150 mg HQ/kg/day) by gavage on Gestation Days (GD) 6 to 18. Caesarean sections were performed on GD 30. Doses of 75 and 150 mg/kg/day adversely affected feed consumption and/or body weights of dams during the treatment period. At these doses, however, treatment-related effects were not evident from physical observations, liver and kidney weights, premature delivery incidence, and caesarean sectioning data. The NOEL for maternal toxicity was 25 mg/kg/day. In the 150 mg/kg/day dose group, total incidences of external, visceral, and skeletal findings for fetuses did not differ statistically from controls. Slight, statistically insignificant, increases were found, however, in the incidences of ocular and minor skeletal malformations (micro-ophthalmia, vertebral/rib defects, angulated hyoid arch) on both a per fetus and a per litter basis. Under the conditions of this study, HQ at 150 mg/kg/day produced minimal developmental alterations in the presence of maternal toxicity. The NOEL for developmental toxicity was 75 mg/kg/day.

To determine the potential developmental toxicity of hydroquinone (HQ), pregnant rats (COBS-CD-BR) were given 0, 30, 100, or 300 mg/kg HQ by gavage on the 6th through the 15th days of gestation. Maternal effects included a slight, but significant (p less than or equal to 0.05), reduction in body weight gain and feed consumption for the 300 mg/kg HQ dams. Reproductive indices, i.e., pregnancy rate, numbers of corpora lutea, implantation sites, viable fetuses, and early and late resorptions, fetal sex ratio, pre- and postimplantation losses, and gravid uterine weights, were not affected by treatment with HQ. A slightly reduced (p less than or equal to 0.05) mean fetal body weight seen at the 300 mg/kg dose level was associated with the slightly reduced body weight gain seen for the dams at this dose level. Gross external, internal soft tissue, and skeletal examinations of the fetuses revealed no HQ-related malformations. The incidences of gross external variations (small hematomas) and internal soft tissue variations (dilated renal pelvis, hydronephrosis, and hydroureter) in the HQ-treated litters were not statistically different from the control incidences. Skeletal variations (delayed ossification of membranous skull bones, hyoid bone, thoracic centra 1-3, sacral arches 3 and 4, and bilobed thoracic centra 9-13) were seen with similar frequency in the control and HQ-treated groups. A statistically significant increase in the incidence of total common vertebral variations seen at the 300 mg/kg HQ dose level was not considered toxicologically significant. The incidences of total skeletal variations were not statistically different between the control and the HQ-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the potential developmental toxicity of ethylene glycol monopropyl ether (EGPE), groups of pregnant New Zealand white rabbits were exposed to target concentrations of 0, 125, 250, or 500 ppm EGPE vapors for 6 hr a day on Days 6-18 of gestation. Maternal effects included a slight reduction in feed consumption during the first week of treatment at the 250- and 500-ppm exposure levels and slightly reduced body weight gain at the 500-ppm level compared to those of the controls, but the differences were not statistically significant. One doe exposed to 500 ppm had red-colored urine during the 24-hr period following the second exposure. Hematologic determinations, absolute and relative organ weights, and observations at necropsy revealed no treatment-related maternal effects. Reproductive indices, i.e., pregnancy rate, number of corpora lutea, implantation sites, viable fetuses, early and late resorptions, fetal body weights, fetal sex ratio, and the gravid uterine and corrected body weights, were not affected by exposures to EGPE. The occurrences of external and internal soft tissue malformations and variations and the incidences of skeletal malformations in the EGPE-exposed groups were not significantly different from those in the control group. Common skeletal variations, in many instances, were seen less frequently in EGPE-exposed fetuses than in control fetuses. In those cases where the incidence of fetuses with a skeletal variation was greater for EGPE-exposed fetuses than that for control fetuses, the number of litters involved was not significantly different from that of the control group. Thus, EGPE vapor concentrations as high as 500 ppm did not produce teratogenicity or other developmental toxicity in the rabbit conceptus.

There is currently no well-accepted standard method for evaluation of developmental toxicity data. This paper presents one approach to the evaluation of developmental toxicity data. We initially identify some pertinent factors that influence the interpretation of animal data and summarize the literature pertaining to these factors. Such factors include the quality and quantity of data and the relationship between maternal and developmental toxicity. We proceed with a discussion of quantitative assessment of data and propose schemes for qualitative and quantitative developmental hazard assessments.

In order to determine the potential developmental toxicity of ethylene glycol monopropyl ether (EGPE), pregnant rats were exposed to vapor concentrations of 100, 200, 300, or 400 ppm of the compound for 6 hours per day on days 6-15 of gestation. Maternal effects included a slight reduction in red blood cell count and increased mean corpuscular volume and mean corpuscular hemoglobin at the 200-, 300-, and 400-ppm concentrations. Reticulocyte counts and polychromasia of the red blood cells were increased at all exposure levels, while anisocytosis was increased at 300 and 400 ppm and macrocytosis was increased at 200, 300, and 400 ppm. Hematocrit, hemoglobin concentration, platelet, and total and differential white blood cell counts were comparable to those of the controls. Red urine was seen in the females after the first and second exposures to 200, 300, and 400 ppm of EGPE, but not after subsequent exposures. Absolute and relative spleen weights were increased by 200, 300, and 400 ppm EGPE. Histologic changes were seen in the maternal spleen, liver, and thymus, particularly after exposure to 300 and 400 ppm. Kidneys, bone marrow, and mesenteric lymph nodes were normal. Pregnancy rate, number of corpora lutea, implantation sites and viable fetuses per dam, the incidence of resorptions per litter, and the mean fetal body weights were comparable to those of the controls. Gross external, internal soft tissue, and skeletal examinations of the fetuses revealed that EGPE did not produce teratogenicity or significant embryo/fetotoxicity in the rat at vapor concentrations as high as 400 ppm. Variations in the ossification of certain skeletal elements and the incidence of 14th thoracolumbar rudimentary ribs were increased by exposure to 200, 300, and 400 ppm EGPE.

Pregnant rats were exposed by inhalation to vapor concentrations of 100, 200, 400 or 800 ppm of ethylene glycol monopropyl ether acetate on days 6 through 15 of gestation. Concentrations of 400 and 800 ppm reduced the feed intake, mean body weight and red blood cell counts. Mean corpuscular volume and mean corpuscular hemoglobin were increased. Clinical signs of toxicity included lethargy and red discolored urine in the dams exposed to 400 or 800 ppm. The incidence of resorptions was significantly increased and the mean fetal body weight was reduced in litters of dams exposed to 800 ppm. Reproductive indices were not affected. Examinations at cesarean section revealed no major external malformations. Internal soft tissue examinations revealed three fetuses with a cardiovascular defect consisting of a right-sided aortic arch. Two of these fetuses were from dams exposed to 800 ppm, while the third was from a control litter. Skeletal examinations revealed no major skeletal malformations, while minor rib anomalies were slightly increased in litters from dams exposed to 400 or 800 ppm of ethylene glycol monopropyl ether acetate. The incidence of common skeletal variants was slightly increased at 200 ppm.

The acute toxicity of ethylene glycol monopropyl ether (EGPE) and ethylene glycol monopropyl ether acetate (EGPEA) was determined in a series of standardized tests. The oral LD50 in rats was 3089 and 9456 mg/kg EGPE and EGPEA, respectively. Skin irritation was slight following an occluded single dose application of either compound to the guinea pig abdomen. The dermal LD50 for guinea pigs was 1 to 5 mL/kg and greater than 20 mL/kg EGPE and EGPEA, respectively. EGPE produced a very weak positive sensitization response in one of five guinea pigs. No positive response was elicited when 10 guinea pigs were similarly challenged with EGPEA. EGPE produced transient moderate to severe eye irritation in rabbits while EGPEA produced slight eye irritation. Subchronic toxicity was determined in a series of oral and inhalation studies. Groups of 10 male rats were dosed with 15, 7.5, 3.75 or 1.88 mmole/kg EGPE and 30, 15 or 7.5 mmole/kg EGPEA by gavage 5 days/week for 6 weeks. Hemoglobinuria was seen at least once at all dose levels of both compounds. EGPE had little effect on feed consumption or body weight gain, while body weight gain was reduced in the two high dose groups exposed to EGPEA and feed consumption was reduced at all dose levels. Hematologic changes were seen at all dose levels of both compounds. Absolute and/or relative spleen weights were increased at all but the lowest EGPE dose level and at all EGPEA dose levels. Gross and histopathologic examinations revealed significant effects on the spleen of animals exposed to EGPE and on the spleen, liver, kidney and testes of animals exposed to EGPEA. The no-observed effect level (NOEL) for splenic changes was 1.88 mmole/kg EGPE. A NOEL for hematology was not established. The NOEL for liver and testicular changes were 15 and 7.5 mmole/kg EGPEA, respectively while a NOEL for hematologic, splenic and renal changes was not established. Groups of 10 rats (5M, 5F) were exposed to 800, 400, 200 or 100 ppm EGPE or EGPEA 6 hr/day, 5 days/week for a total of 11 exposures. Body weight gains in all exposure groups were comparable to controls. Hemoglobinuria was seen only after the first or second exposure in males and females exposed to 800 ppm EGPE and in males exposed to 400 ppm EGPE. Males and females exposed to 800 ppm EGPEA and females exposed to 400 and 200 ppm EGPEA also exhibited hemoglobinuria.(ABSTRACT TRUNCATED AT 400 WORDS)

The potential for tertiary butylhydroquinone (TBHQ) to produce hemorrhagic death similar to that seen after butylated hydroxytoluene (BHT) treatment was tested in male rats. Groups of male rats were given three consecutive daily doses of 380, 760 or 1520 mg/kg/day BHT or 50, 100 or 150 mg/kg TBHQ. Twenty-four hours following the last dose, the rats were killed, blood was taken for prothrombin determinations and gross autopsies were performed. No evidence of hemorrhage was found in any of the animals. BHT caused a significant dose-dependent increase in prothrombin times, while the prothrombin times of the TBHQ rats were comparable to the controls. Since hypoprothrombinemia plays a major role in producing hemorrhagic death, these data indicate that the potential for THBQ to have such an effect is low.

Ethyl n-butyl ketone (EBK, 3-heptanone) has not been reported to produce neurotoxicity in previous studies when it was given by oral or inhalation routes. In the present study, EBK given by gavage at 2 g/kg/day, 5 days/week for 14 weeks produced a typical central-peripheral distal axonopathy characterized by "giant" axonal swelling and neurofilamentous hyperplasia. This dose approximates the single dose LD50 (2.76 g/kg) of EBK determined by Smyth et al., (J. Ind. Hyg. Toxicol. 31, 60-62, 1949). Large multiple doses (1.5 g/kg/day, 5 days/week, 14 weeks) of methyl ethyl ketone (MEK) given by gavage potentiated EBK neurotoxicity but 5-methyl-2-octanone did not. MEK modestly increased the urinary excretion of two neurotoxic gamma-diketones, 2,5-heptanedione, and 2,5-hexanedione, when MEK was given by gavage with EBK. When rats were exposed to EBK (700 ppm) and MEK (700 or 1400 ppm) in combination by inhalation exposure, serum 2,5-heptanedione levels were increased approximately 2.5 times. This effect was absent at MEK levels of 70 ppm. The serum from rats exposed to EBK or EBK/MEK combinations did not contain 2,5-hexanedione. The toxicity of EBK appears to involve the metabolism of EBK to two neurotoxic gamma-diketones, 2,5-heptanedione and 2,5-hexanedione. Combined EBK/MEK exposure modestly increased gamma-diketone levels in the serum and urine suggesting that MEK potentiates EBK neurotoxicity by stimulating the metabolism of EBK to neurotoxic metabolites. The magnitude of the doses used in the present study to produce neurotoxicity and the absence of neurotoxicity in previous subchronic studies suggest that the neurotoxic hazard of EBK is low.

Tertiary butylhydroquinone (TBHQ), a phenolic antioxidant used in foods, was tested for its potential to produce lung damage in mice similar to that seen following administration of butylated hydroxytoluene (BHT). Male mice (CRL:CD-1) were given single intraperitoneal injections of 62.5, 125, 250 or 500 mg/kg TBHQ or 300, 625 or 1230 mg/kg BHT in corn oil. Survivors were killed five days after treatment and the lungs were removed, weighed, and processed for histologic examination. Lung weights of the TBHQ treated animals were comparable to the controls, while BHT produced a statistically significant increase in lung weight. Histologically, BHT produced hyperplasia of pulmonary pneumocytes as previously reported. No treatment-related lung lesions were seen in the TBHQ mice. The results of this study indicate that TBHQ does not produce pulmonary lesions in mice.

Tertiary butylhydroquinone (TBHQ), and approved antioxidant used alone or in combination with other antioxidants produced no teralogenic effects after administration via the diet to pregnant rats at concentration of 0.125, 0.25 and 0.50% during the sensitive period of gestation. The mean body weight and feed consumption of the dams were unaffected. The average number of corpora lutea, implantation sites, viable fetuses, resorptions and fetal body weights and mortality did not differ between the control and treated groups. A significant number of rudimentary ribs were seen in all groups. However, the incidence of this variation was two times greater in the control group than in any treatment group. It is concluded that TBHQ is not teratogenic in rats at 62.5, 125 and 250 times the approved use level for humans.

Adult male rats (Crl:COBS CD (SD)BR) were given undiluted ethylene glycol monobutyl ether (EGBE) by gavage in doses of 222, 443, or 885 mg/kg/day, 5 days/week over a 6-week period. A dose-dependent decrease, which was statistically significant at the high dose, was seen in body weight gain. Feed consumption was also significantly reduced at the 885-mg/kg dose. The most significant toxic effects produced by EGBE were on the red blood cells including a significant dose-dependent decrease in hemoglobin concentration, red blood cell counts, and mean corpuscular hemoglobin concentration. Mean corpuscular hemoglobin and mean corpuscular volume were increased at all dose levels. Effects secondary to the red cell effects included increased spleen weights, splenic congestion, and hemosiderin accumulation in the liver and kidneys. Relative liver weights and serum alkaline phosphatase (443- and 885-mg/kg doses) and serum alanine aminotransferase (885-mg/kg dose) levels were increased. Glucose was significantly reduced in the animals given 885 mg/kg/day. EGBE had no adverse effects on the testes, bone marrow, thymus, or white blood cells.