ABSTRACT
Highly refined mineral hydrocarbons (MHCs) such as low melting point paraffin wax (LMPW) and low viscosity white oils can cause inflammatory changes in the liver and mesenteric lymph nodes (MLNs) of the Fischer-344 (F-344) rat. In contrast, only minimal MLN changes are seen in the Sprague-Dawley (S-D) rat with no changes in the liver. In this study, the response of female F-344 and S-D rats was compared after 90days dietary treatment with 0%, 0.2% or 2% LMPW. Effects in the F-344 rats were significantly greater than in the S-D rats: increased liver and splenic weights and inflammatory changes (hepatic microgranulomas) in these tissues were observed only in the F-344 rats. Microgranulomas in the MLNs were observed in both strains but the effects were substantially greater in the F-344 rats. Cellular markers of inflammation were examined in a subset of rats from each group using immunohistochemical staining. An increase in staining for CD3 (T-cells), CD8a (suppresser/cytotoxic T-cells) and CD4 (helper T-cells) correlated with an increase in lymphoid cells in the livers of treated F-344 rats. The majority of macrophages in the hepatic microgranulomas of treated F-344 rats were negative for the ED2 marker, indicating a likely origin from non-resident macrophages. Electron microscopy showed Kupffer cell hypertrophy and hyperplasia in treated F-344 rats. However, lysozyme staining (indicating activation of epithelioid macrophages) decreased with increasing granuloma size. Non-ED2 expressing cells may have been recruited but not sufficiently activated to be lysozyme positive. Inflammatory changes in the cardiac mitral valve noted in previous studies of LMPW were also seen in the F-344 rats in this study but not in the S-D rats. Chemical analysis showed that MHC accumulated in livers from treated F-344 but not S-D rats and the concentration was more than 2-fold greater in MLNs from the F-344 than from the S-D rats. The F-344 appears to be more immunologically sensitive to a number of agents than other rat strains and the results of this study suggest that this may contribute, along with pharmacokinetic differences, to the inflammatory response of F-344 rats to dietary MHCs.
Subject(s)
Paraffin/toxicity , Animals , Blood Cell Count , Blood Chemical Analysis , CD3 Complex/analysis , CD4-CD8 Ratio , Chemical and Drug Induced Liver Injury/pathology , Diet , Female , Hemoglobins/metabolism , Immunohistochemistry , Liver/pathology , Lymph Nodes/pathology , Microscopy, Electron , Muramidase/metabolism , Organ Size/drug effects , Paraffin/chemistry , Paraffin/pharmacokinetics , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Species Specificity , Tissue Distribution , ViscosityABSTRACT
Food-use applications of mineral hydrocarbons (MHC) derived from petroleum sources result in dietary exposure to these compounds by consumers. Food applications of MHC, including white mineral oils, paraffin waxes, microcrystalline waxes and petrolatum, include both direct-additive uses in which the MHC is intentionally applied to the food and indirect-additive uses in which the MHC become components of the food due to migration from food-contact surfaces. A key consideration in evaluating the safety of these uses of MHC is the level of exposure that results. We estimated exposures to MHC in the US from food applications based primarily on a food-consumption approach, in which MHC concentrations in foods were multiplied by the amount of these foods consumed. This was a conservative estimate, because it assumes that all foods that might contain MHC in fact do so at maximum possible concentrations. A "poundage approach", in which the amount of MHC used in food applications was divided by the US population to determine maximum potential per capita exposures, was used to validate the consumption-based estimates. Exposures to MHC from food-packaging applications were estimated using the FDA's food-factor approach, which takes into account the volume and kinds of food packaged with specific types of materials. A conservative estimate of mean exposure to all MHC types combined is 0.875 mg/kg BW/day. Half of this, 0.427 mg/kg BW/day, is white mineral oils used as pan-release lubricants in baking, for de-dusting of stored grain, in confectioneries, and in coatings for fruits and vegetables. Nearly all of the remainder, 0.404 mg/kg BW/day, is petrolatum, primarily from its use as trough grease in bakery applications. Exposure to paraffin and microcrystalline waxes combined is only 0.044 mg/kg BW/day.
Subject(s)
Diet , Food Additives/analysis , Hydrocarbons/analysis , Data Collection , Food Analysis , Food Handling , Food Industry , Humans , Mineral Oil/analysis , United States , United States Food and Drug AdministrationABSTRACT
Tridecyl acetate was administered to male and female Sprague-Dawley rats by oral gavage, 5 days per week for 13 weeks (90 days). Treated rats received daily doses of 0.1, 0.5, or 1.0 g/kg/day and control rats received distilled water at a dose of 1.0 g/kg/day. After 45 days an interim termination was made to evaluate potential hematologic or hepatic effects of tridecyl acetate. Blood samples were collected for routine hematology and serum chemistry determinations and liver tissue was obtained for histological examination. After 90 days all animals were necropsied. Blood samples were obtained and selected organs were weighed and prepared for histological examination. Treatment-related effects observed in the mid and high dose groups consisted of (1) increased liver weights and/or liver/body weight ratios in both sexes at the interim and 13 week termination, (2) increased kidney weights and/or kidney/body weight ratios in both sexes at the terminal necropsy, (3) histopathologic evidence of hydrocarbon nephropathy in males, and (4) a slight decrease in serum glucose levels in male rats at both the interim and terminal necropsies. The increases in liver weight are believed to be a normal physiological response to a chemical challenge. The nephropathy produced by tridecyl acetate is characteristic of that produced by a diverse group of hydrocarbons and, to date, appears to be limited to male rats. The low dose in this study was a no observed effect level. These results are indicative of an overall low degree of systemic toxicity following subchronic oral administration of tridecyl acetate at doses up to 1 g/kg body weight.
Subject(s)
Acetates/toxicity , Animals , Blood Glucose/analysis , Body Weight/drug effects , Eating/drug effects , Female , Hemoglobins/analysis , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Male , Organ Size/drug effects , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
Octyl acetate (CAS RN 108419-32-5) was administered via oral gavage to pregnant Sprague-Dawley rats on Gestation Days 6 through 15 at dose levels of 0, 0.1, 0.5, and 1.0 g/kg. The dams were weighed and observed for clinical signs of toxicity during pregnancy, and food consumption was measured. On Gestation Day 20 the dams were sacrificed and the fetuses were examined for external, visceral, and skeletal malformations and variations. The mid- and high-dose levels resulted in maternal toxicity as evidenced by reductions in body weight gain and food consumption. There were no statistically significant effects on embryo-fetal lethality or fetal growth for any treatment group. The number of litters with at least one malformed fetus and the mean percentage of the litter malformed were significantly (p less than 0.05) elevated in the high-dose group only. The results of the present study demonstrate that octyl acetate produced some evidence of developmental toxicity at a dose (1.0 g/kg) that was maternally toxic. Developmental toxicity was not observed at the maternally toxic 0.5 g/kg dose level or the maternally nontoxic dose level (0.1 g/kg). Therefore, these data indicate that octyl acetate is not a selective developmental toxicant in the rat.
Subject(s)
Acetates/toxicity , Teratogens , Animals , Body Weight/drug effects , Eating/drug effects , Embryo Implantation/drug effects , Female , Fetus/drug effects , Growth/drug effects , Male , Pregnancy , Rats , Rats, Inbred StrainsABSTRACT
The subchronic toxicity of octyl acetate was assessed following its administration to rats via oral gavage, 5 days per week for 13 weeks. Treated rats received undiluted octyl acetate at doses of 0.1, 0.5, or 1.0 g/kg. Control rats received distilled water at a dose of 1.0 g/kg. An interim termination was made after 45 days of dosing at which time five animals per sex per group were terminated and necropsied. Blood samples were collected and liver tissues were prepared for histological examination. After 13 weeks of dosing all animals were terminated and necropsied. Blood samples were obtained and selected organs were weighed and prepared for subsequent histological examination. Several treatment-related effects were observed in the high-dose group (1.0 g/kg) animals. These effects included slight reductions in body weight and food consumption, increased liver and kidney weights, and evidence of hydrocarbon nephropathy in high-dose males only. The significance of these observations is discussed in the report. With the exception of increased liver weights in the mid-dose group, no other significant treatment-related effects were observed in the mid- or low-dose groups of animals. It is believed that the increases in liver weight which were observed are a compensatory response to an increased metabolic load, and not a reflection of true hepatotoxicity. The results of this study indicated that octyl acetate possessed an overall low degree of systemic toxicity when administered orally to rats for 13 weeks.
Subject(s)
Acetates/toxicity , Solvents/toxicity , Animals , Blood Chemical Analysis , Body Weight/drug effects , Eating/drug effects , Enzymes/blood , Female , Liver/drug effects , Male , Organ Size/drug effects , Rats , Rats, Inbred Strains , Time FactorsABSTRACT
In general, the carcinogenic potential of petroleum-derived materials is related to the polycyclic aromatic hydrocarbon (PAH) content. Thus it has been assumed that liquids which boil below the PAH distillation range (i.e., below approx. 370 degrees C (700 degrees F) would not be carcinogenic. Several early studies supported this conclusion but were of relatively short duration. Several recent and more rigorous studies have shown that repeated application of certain petroleum-derived materials boiling between approximately 177-370 degrees C (350-700 degrees F) (i.e., middle distillate fuels) can produce tumors in mouse skin. The current studies assessed the tumorigenic potential of a series of middle distillates which varied with respect to boiling range, composition, and source of blending stocks. All of the samples produced evidence of weak tumorigenic activity which was characterized by low tumor yields and long median latencies. However, the majority of the tumor yields were significantly different from the control. There were no apparent differences in response among the samples. Thus the various parameters examined did not substantially influence tumor outcome. In particular, there was no association of tumorigenic activity with aromatic carbon content; this finding, coupled with evidence that PAH levels were low, suggested that the tumorigenic responses were not PAH-dependent. In addition to the tumors, there was evidence of non-neoplastic dermal changes including hyperplasia. These may have contributed to the tumorigenic responses; however, the actual mechanism of tumor induction is unknown.
Subject(s)
Fuel Oils/toxicity , Petroleum/toxicity , Skin Neoplasms/chemically induced , Administration, Cutaneous , Animals , Chemical Phenomena , Chemistry, Physical , Fuel Oils/analysis , Male , Mice , Mice, Inbred C3H , Neoplasms, Experimental/chemically inducedABSTRACT
Male rats exposed to target concentrations of methyl tertiary butyl ether (MtBE) at 300, 1300 and 3400 ppm for 6 hours/day, 5 days/week for 12 weeks were mated to female rats exposed to the same concentrations for a 3-week period. Exposures continued through the mating period and the females continued exposures during gestation and from days 5-21 lactation of the litters (F1a) (no exposures days 0-4 lactation). A second litter (F1b) was produced under the same mating and post mating exposure regimen. No adverse effect of treatment was observed with the adult animals (Fo) throughout the in-life portion of the study. The only remarkable finding was an increased incidence of dilated renal pelves in the low- and high-dose females (Fo). All gonad weights, male accessory reproductive organ weights, organ-to-body weight ratios and reproductive organ histopathology were unremarkable upon comparison of treated animals with air sham controls. The mating indices and fertility indices in exposed animals for both mating intervals (F1a and F1b) were not significantly different from controls. Pregnancy rates were comparable between treated and control females for the first litter interval (F1a) but were slightly lower (not statistically significant) than control on the second litter interval (F1b). Treated animal mean gestation length and the mean number of pups at birth were not statistically different from controls. The pup viability indices at birth were comparable for control and treated groups for the F1a generation, but the mid- and high-dose groups displayed a slight statistically significant decrease in the F1b generation; the decrease was not considered to be biologically significant and perhaps not treatment-related. Litter survival indices were comparable between control and treated groups for both litter intervals. Pups of mid- and high-dose females had slightly lower (not statistically significant) mean weights at days 14 and 21 of lactation but this was not considered treatment-related. The most frequent post-mortem observation for pups sacrificed at day 21 of lactation was dilated renal pelves. This did not appear to be related to treatment. It is concluded that MtBE inhalation in rats results in little adverse reproductive toxicity as shown in a two litter, one generation reproduction assay in rats.
Subject(s)
Ethers/toxicity , Methyl Ethers , Reproduction/drug effects , Administration, Inhalation , Animals , Animals, Newborn , Ethers/administration & dosage , Ethers/analysis , Female , Fertility/drug effects , Lactation/drug effects , Male , Organ Size/drug effects , Pregnancy , Rats , Rats, Inbred Strains , Sexual Behavior, Animal/drug effectsABSTRACT
The acute toxicity of a series of potential streams from the EDS coal liquefaction process have been assessed in animal bioassays. In general, the materials present minimal acute toxic hazards. However, there was some evidence of ocular and dermal irritation. These results indicate that eye and dermal contact should be minimized, particularly when the process streams contain high concentrations of phenolic materials.
Subject(s)
Coal/toxicity , Alkanes/toxicity , Animals , Chemical Phenomena , Chemistry , Eye Diseases/chemically induced , Female , Irritants , Lethal Dose 50 , Male , Mice , Rabbits , Respiratory Tract Diseases/chemically induced , Skin Diseases/chemically induced , Time FactorsSubject(s)
Fuel Oils/toxicity , Hydrocarbons/toxicity , Petroleum/toxicity , Alkanes/toxicity , Animals , Coal/adverse effects , Eye/drug effects , Female , Irritants/toxicity , Kidney/drug effects , Male , Rabbits , Rats , Skin/drug effectsABSTRACT
A 72:25 mixture of 1-chloro-2-propanol and 2-chloro-1-propanol was tested for genetic activity in a battery of short term tests. Chloropropanol was tested over a dose range of 527-167,250 micrograms/plate in the Salmonella/mammalian microsome mutagenicity assay. A dose dependent mutagenic response was observed in strains TA 1535 and TA 100. Metabolic activation enhanced mutagenicity in both strains. Although chloropropanol was mutagenic in the TK+/-mouse lymphoma assay with and without metabolic activation, a smooth linear dose response relationship was not observed. Non-toxic mutagenic doses ranged from 5,000 to 10,000 micrograms/mL without activation. Chloropropanol was also mutagenic in the rat bone marrow cytogenetic assay. Rats dosed orally with 10, 31 and 100 mg/kg/day for 5 days displayed no significant difference in mean body weight gain or mean mitotic index when compared to controls, however, a dose-response increase (significant) in the number of aberrations, mostly chromatid breaks, was observed in each case.
Subject(s)
Chlorohydrins/toxicity , Mutagens , Animals , Biotransformation , Bone Marrow/ultrastructure , Chlorohydrins/metabolism , Dose-Response Relationship, Drug , Female , Lymphoma/genetics , Male , Mice , Mutagenicity Tests , Rats , Salmonella/drug effectsABSTRACT
A community study of the incidence of clinically diagnosed otitis media and middle ear effusions was undertaken in the City of Galveston, Texas, based on a random sample of records of patients aged 0-8 years receiving medical care from four major sources during 1975. No overall sex or ethnic differences were observed in association with otitis media. Thirty-five per cent of the sample had at least one episode of otitis media during 1975 and, of these, one-third had two or more episodes, yielding a conservative annual incidence rate of 55.1 per cent for this age group. The overall age-specific incidence pattern indicated the highest rates for the 0-2 year age group (71 to 114 episodes per 100 children) with a steady decline in risk with increasing age. Infants who received an initial diagnosis within the first 12 months of life experienced significantly more episodes of otitis during a two-year period than did children who received an initial diagnosis after one year of age. Seasonal patterns of otitis media were comparable with those reported in other studies. Analysis by birth month of children who experienced repeated episodes of otitis indicated an increased number of children born in the late summer and fall.
Subject(s)
Epidemiologic Methods , Otitis Media/epidemiology , Age Factors , Child , Child, Preschool , Ethnicity , Female , Humans , Infant , Infant, Newborn , Male , Recurrence , Seasons , TexasABSTRACT
This study investigates the possible role of impurities in dibromochloropropane in inducing mutations, and discusses the importance of contaminants in mutagenicity and carcinogenicity testing. A technical grade sample and a pure sample of DBCP (no epichlorohydrin added) were assayed in Salmonella typhimurium TA1535, with and without S-9 activation, using agar overlay procedures and dessicator procedures. Assays performed with both technical and pure DBCP without metabolic activation resulted respectively in an increase in revertants with increasing dose (0-1600 microgram/plate) when the technical grade was tested, and no substantial increase in revertants over the same dose range when the pure DBCP was tested. Distillation of technical grade DBCP yielded an initial fraction containing high amounts of epichlorohydrin (verified by GC-MS) which was highly mutagenic. The amount of epichlorohydrin in the technical DBCP sample was calculated for each dose level tested, and the number of revertants obtained in tests of the technical DBCP sample could be attributed solely to the calculated amount of epichlorohydrin in each test dose. Tests of pure and technical DBCP using a dessicator technique produced a similar differential between the technical and pure compounds in mutagenicity. Activation of both technical and pure DBCP with S-9 from Aroclor pre-treated rats resulted in high mutagenic responses, of equal magnitude, from both preparations.