Methyl isobutyl carbinol (MIBC) is an oxygenated solvent that is metabolized to methylisobutyl ketone (MIBK) and then to 4-hydroxymethyl-4-methyl-2-pentanone (HMP). Plasma levels of MIBC, MIBK and HMP were determined up to 12 h after a single oral 5 mmol/kg dose of MIBC or MIBK to male rats. The major material in the plasma in both cases was HMP, with similar areas-under-the-curve (AUC) and Cmax at 9 h after dosing. MIBK plasma levels and AUC were also comparable after MIBK or MIBC administration. MIBC AUC was only about 6% of the total material in the blood after MIBC, and insignificant after MIBK administration. No other metabolites were detected in the plasma under the analytical conditions used. The extent of metabolism of MIBC to MIBK, by comparing combined AUCs for MIBK and HMP, was at least 73%. The limited systemic toxicity data for MIBC are consistent with those for MIBK, which has been well studied. The metabolic equivalency of MIBC with MIBK indicates that MIBC will have a low potential for toxicity similar to that of MIBK, and reduces the need for additional animal studies.

The toxicity of phenol vapor was evaluated in male and female Fischer 344 rats (20/sex/group) via flow-past nose-only inhalation exposure. The test animals were exposed to target concentrations of 0 (air control), 0.5, 5.0, or 25 parts per million (ppm) of phenol in air for 6 hours/day, 5 days/week, for 2 weeks. High pressure liquid chromatography (HPLC) measurement of phenol test atmospheres determined mean (+/- standard deviation) analytical concentrations of 0.0 +/- 0.0, 0.52 +/- 0.078, 4.9 +/- 0.57, and 25 +/- 2.2 ppm, respectively. After 2 weeks of exposure, 10 test animals/sex/group were sampled for clinical chemistry and hematology parameters, and then sacrificed. Histopathological examination included the nasopharyngeal tissues, larynx, trachea, Lungs with mainstem bronchi, kidney, liver, and spleen. The remaining 10 animals/sex/group were retained for a 2-week recovery period, Recovery groups of animals were evaluated as described previously and then sacrificed, No signs of toxicity in clinical observations (including overt neurological signs), body weights, food consumption, clinical pathology, organ weights, macroscopic pathology or microscopic pathology were seen during the exposures or at either sacrifice interval, In conclusion, 2-week inhalation exposures to phenol vapor at concentrations up to and including 25 ppm did not produce any adverse effects.

Abstract Phenol was originally isolated from coal‐tar streams, but now it is almost exclusively produced by the oxidation of cumene and subsequent cleavage of the cumene hydroperoxide to form phenol and acetone. The U.S. production of phenol for 1995 was 4.16 billion lb (3). Phenol is used in the petroleum industry to extract lube (lubricating) oil from residual oil. It is reacted with aldehydes such as formaldehyde to form “phenolic resins,” which are widely used as adhesives, structural products, and electrical laminates. Other uses include the manufacture of caprolactam (an intermediate in the manufacture of nylon), bisphenol A (an intermediate in the manufacture of epoxy resins and polycarbonates), herbicides, wood preservatives, hydraulic fluids, heavy‐duty surfactants, lube‐oil additives, tank linings and coatings, and intermediates for plasticizers and other specialty chemicals. Phenol is used medically in throat lozenges, disinfectants, and ointments; for facial skin peels; and to cause nerve block. With rare exceptions, human exposure in industry has been limited to accidental contact of phenol with the skin or to inhalation of phenol vapors. Other major sources of inhalation exposure include residential burning and automobile exhaust. Similar details are given for phenolics, including chloro and bromo compounds.

This study evaluated the potential reproductive toxicity of phenol in a rat two-generation reproduction study, which included additional study endpoints, such as sperm count and motility, developmental landmarks, histological evaluation of suspect target organs (liver, kidneys, spleen, and thymus), weanling reproductive organ weights, and an immunotoxicity screening plaque assay. Phenol was administered to 30 Sprague-Dawley rats/sex/group in the drinking water at concentrations of 0, 200, 1000, or 5000 ppm. Parental (P1) animals were treated for 10 weeks prior to mating, during mating, gestation, lactation, and until sacrifice. The F1 generation (P1 offspring) was treated using a similar regimen, while the F2 generation was not treated. After mating, 10 P1 males/group were evaluated using standard clinical pathology parameters and an immunotoxicity screening plaque assay. Significant reductions in water and food consumption were observed in the 5000-ppm group in both generations; corollary reductions in body weight/body weight gain were also observed. Mating performance and fertility in both generations were similar to controls, and no adverse effects on vaginal cytology or male reproductive function were observed. Vaginal opening and preputial separation were delayed in the 5000-ppm group, and were considered to be secondary to the reduction in F1 body weight. Litter survival of both generations was reduced in the 5000-ppm group. Absolute uterus and prostate weights were decreased in the F1 generation at all dose levels; however, no underlying pathology was observed and there was no functional deficit in reproductive performance. Therefore, these findings were not considered to be adverse. No evidence of immunotoxicity was noted in the 5000-ppm group. The effects noted at the high concentration were presumed to be associated with flavor aversion to phenol in the drinking water. Based on a comprehensive examination of all parameters, the no-observable-adverse-effect level (NOAEL) for reproductive toxicity of phenol administered in drinking water to rats is 1000 ppm. The corresponding daily intake of phenol for an adult rat at the NOAEL of 1000 ppm is equivalent to about 70 mg/kg/day for males and 93 mg/kg/day for females.

This study was conducted to provide screening information concerning the potential systemic, reproductive and developmental toxicity of 1-hexene when administered orally, by gavage, to male and female rats using a modified OECD 421 protocol. 1-Hexene was administered at doses of 100, 500, and 1000 mg/kg/day in corn oil; the control group received the vehicle at an equivalent volume. The males were treated for 28 days prior to mating and until euthanasia (44 days of dosing). The females were treated for 14 days prior to mating and during mating, gestation, and lactation until euthanasia (41–55 total days of dosing). Females were allowed to deliver and rear their offspring until lactation day 4. The parental rats were subject to a gross and microscopic examination. Viability and development of the pups were followed through lactation day 4. There was no mortality, and there were no clinical signs of toxicity or differences in body weights, weight gain, feed consumption or organ weights. Copulation and fertility indices, precoital intervals, gestation lengths and pregnancy rates were comparable among the groups, and no signs of prolonged delivery or unusual nesting behaviors were noted. Pup viability, body weights, external observations and necropsy data were comparable among the groups. Pitted kidneys were observed at necropsy for two parental males in the 500 mg/kg/day group and three males in the 1000 mg/kg/day group. Microscopic changes in the kidneys of some male rats from the 100, 500, and 1000 mg/kg/day groups consisted of dose-related accumulations of hyaline droplets in the epithelial cells of the proximal convoluted tubules of the kidneys. In summary, the only treatment-related effect noted in this study was hydrocarbon nephropathy in male rats, which is not considered relevant for human health. The NOAEL for systemic and reproductive toxicity was 1000 mg/kg/day, excluding the finding of male rat hydrocarbon nephropathy.

1,3-Propanediol was a specialty chemical that, due to a novel manufacturing process, is now commercially available in large quantities. Its subchronic toxicity has been evaluated in rats, with special emphasis on potential male reproductive effects. 1,3-Propanediol in deionized water was administered orally by gavage to three groups of 10 male and 10 female Crl:CD(SD)BR rats for a period of 90 consecutive days. Dosage levels were 100, 300, and 1000 mg/kg/day, and a control group received water at a constant volume of 10 ml/kg/day. All animals survived to the scheduled necropsy, and there were no effects on the clinical condition of the animals, body weights, body weight gains, food consumption or organ weights. There were no effects on hematology or serum chemistry parameters. Spermatogenic endpoints were unaffected in all treated males. No treatment-related changes were observed on macroscopic or microscopic examinations of selected organs. Under the conditions of the study, the no-observed-effect level (NOEL) for systemic toxicity of 1,3-propanediol administered orally via gavage to male and female rats for 90 consecutive days was 1000 mg/kg/day, the highest dose tested.

The objective of this study was to evaluate the toxicity of 1-hexene following repeated inhalation exposures in male and female Fischer 344 rats. Groups of 40 male and 40 female rats were exposed for 6 hours per day, 5 days per week, over a 13-week period. Treatment groups consisted of air-exposed control (0 ppm) and three test groups of 300, 1000, and 3000 ppm 1-hexene. During the treatment period, the rats were observed daily for clinical signs of toxicity; body weights and neuromuscular coordination [females only] were measured at 7-day intervals. After 7 weeks of exposure and at the end of the treatment period, the rats were subject to macroscopic and microscopic pathology, clinical chemistry, hematology, urinalysis, and sperm counts. No mortalities were observed during the course of the study. No clinical signs of toxicity attributable to 1-hexene exposure were observed. Female rats exposed to 3000 ppm had significantly lower body weights compared to control rats from exposure day 5 persisting throughout the treatment period. Male rats exposed to 3000 ppm had slightly but not statistically significant lower body weights in comparison to controls. Male rats exhibited slightly increased absolute and relative testicular weights, and female rats had slightly decreased absolute [but not relative] liver and kidney weights, at 3000 ppm. There were no gross or microscopic morphological findings attributed to treatment. Exposure to 1-hexene did not affect neuromuscular coordination in females as determined using the Rotarod, nor sperm counts in male rats. Several statistically significant effects in hematology, clinical chemistry, and urinalysis evaluations were observed, but were either of small magnitude or did not correlate with histopathological findings, and thus did not appear to be of biological significance. In summary, the no-adverse-effect-level for this study was determined to be 1000 ppm, based on decreased weight gain in female rats, and on slight organ weight changes in both sexes at 3000 ppm.

The mammalian toxicity of a C9–11 linear primary alcohol 6-mole ethoxylate, used in aqueous cleaning formulations, has been evaluated. The rat acute oral LD50 was 1.4 g/kg, and the rabbit acute dermal LD50 was greater than 2 g/kg. Undiluted material was severely irritating to the skin, but a 1% w/v aqueous dilution was not a skin sensitizer. There was no evidence of mutagenicity in the Ames assay. In a rat dermal subchronic study, there were no treatment-related effects at 1% and 10% aqueous concentrations, but at 25%, there was flaking of the skin and microscopic evidence of hyperkeratosis at the treatment site as the only compound-related effect. Potential reproductive toxicity was evaluated in a two-generation study in Fischer rats exposed similarly to the subchronic study. No compound-related effects on the reproductive performance or on the growth and development of the offspring were detected. It is concluded that this ethoxylate is typical of the more widely used alcohol ethoxylates with alkyl chains in the C12–18 range, being moderately acutely toxic by the oral route. By the dermal route—the relevant route of human exposure—it is not expected to produce skin irritation or systemic or reproductive toxicity at concentrations used in formulated cleaning products.

Selected hydrazines and related compounds were examined for their mutagenic activity in S. typhimurium strains TA1535 and TA1537. These in vitro assays were conducted with and without metabolic activation by Aroclor-induced rat-liver enzymes. Relatively high levels of mutagenicity were observed with phenylhydrazine · HCl, methylhydrazine, N′-acetyl-4-(hydroxymethyl)phenylhydrazine, and 4-(hydroxymethyl)benzenediazonium tetrafluoroborate, the stabilized salt of a carcinogenic metabolite of agaritine; only low levels of mutagenicity were observed with other compounds, although most are strong carcinogens. Several of the compounds were highly toxic to the bacteria, and detection of mutagenicity was enhanced by calculating the increase in mutagenic activity on the basis of the surviving fractions of bacteria.

Rat and hamster mammary gland, in comparison with the liver, were examined for their in vitro ability to metabolize polycyclic aromatic hydrocarbons, and for the effects of pretreatment with various mixed function oxidase inducers on this metabolism. Hamster mammary microsomal benzo(a)pyrene (BP) hydroxylase activity was 4-fold greater than that in the rat, and this activity was induced 3- to 5-fold in the hamster, and 7- to 13-fold in the rat, by pretreatment with 7,12-dimethylbenz(a)anthracene, beta-naphthoflavone, Aroclor 1254 or 3-methylcholanthrene. Hamster hepatic microsomal BP-hydroxylase activity was 80-fold greater than in the rat. Whereas pretreatment with these enzyme inducers enhanced rat hepatic activity by 20- to 30-fold, little effect of "inducers" was observed on the hamster hepatic enzyme, even when the formation of the various BP metabolites was determined by high pressure liquid chromatography.

The covalent binding of 7,12-[3H]dimethylbenz[a]anthracene ([3H]DMBA) to mammary gland macromolecules was studied in hamsters fed a contraceptive mixture, Enovid, those exposed transplacentally to diethylstilboestrol (DES), and controls. Compared with rats, hamsters are relatively resistant to DMBA mammary carcinogenesis, but susceptibility is increased by either of the above treatments with Enovid or DES. The amount of DMBA bound to DNA and protein was 4–5 times greater than to RNA, but only DNA binding was persistent. Fifty-three percent of the DNA-bound DMBA was still present after 8 days. The amount of DMBA bound to hamster mammary DNA and its persistence was similar to that found in rats. Neither Enovid nor DES treatment altered the levels of binding to mammary macromolecules, nor their persistence. These results indicate that the species differences in the susceptibility to DMBA-induced mammary carcinogenesis in hamsters and rats, and modification of the former by hormones, is not due to differences in the activation of carcinogens. The role of hormones such as prolactin in the promotion phase of mammary gland carcinogenesis may explain these differences.

The alkylation of hamster liver, lung and pancreas DNA by [1-14C]- and [2,3-14C]N-nitrosobis (2-oxopropyl) amine (BOP) has been examined. The specific activity of pancreas DNA after [2,3-14C]BOP administration was only 2% of that when [1-14C]BOP was given. 7-Methylguanine, but not O-6-methylguanine, was found in hydrolysates of liver and pancreas DNA. Nearly equal amounts of alkylation were produced in the liver when [1-14C]- and [2,3-14C]BOP were given. At least one-half of the radioactivity in the liver was associated with N-alkylated purines, whereas only 20% was in this form in the pancreas.

The 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) metabolic intermediate 1-chloro-2,2-bis(p-chlorophenyl)ethene (DDMU) is partially metabolized in vivo by mice to 2-hydroxy-2,2-bis(p-chlorophenyl)acetic acid (αOH-DDA) and other metabolites which are excreted in urine. The subsequent DDT metabolic intermediates 1-chloro-2,2-bis(p-chlorophenyl)ethane (DDMS) and 1,1-bis(p-chlorophenyl)ethene (DDNU) are metabolized to αOH-DDA to a much lesser extent. These results imply that DDMU may be metabolized via an α-chloroepoxide. The authentic DDMU-epoxide, which after oral administration is excreted as αOH-DDA, is mutagenic in the Ames assay, and thermally rearranges rapidly to the corresponding α-chloroaldehyde, 2,2-bis(p-chlorophenyl)-2-chloroacetaldehyde (αCl-DDCHO). As expected αCl-DDCHO yielded the same urinary metabolites as DDMU-epoxide. This suggested metabolic pathway for DDMU via a chloroepoxide intermediate may account for the tumorigenicity of DDT in mice.

A liver and lung cell-mediated-V79 cell mutagenesis system using intact cells as metabolic activation systems was employed to study the relative ability of cells from these organs to activate chemical carcinogens. Primary cultures of liver and lung cells from male Sprague Dawley rats were used to metabolically activate the chemicals and the mutation of Chinese hamster V79 cells to ouabain resistance used to detect mutagenic intermediates. 7,12-Dimethylbenz[a]anthracene and 3-methylcholanthrene, were more active in the lung system than in the liver cell system. Benzo[a]pyrene (B[a]P) was inactive in the liver cell-mediated system but mutagenic to V79 cells in the lung cell-mediated system. Dimethylnitrosamine (DMN) was inactive in the presence of liver cells. Aflatoxin B1 was mutagenic in the liver cell-mediated system, but only weakly mutagenic in the lung cell-mediated system. Because the mutagenicities of DMN and B[a]P were organ-specific, the metabolism of these carcinogens in the two primary cell systems was investigated. DMN was metabolized by liver but not by lung cells, possibly accounting for its lack of mutagenicity in the lung cell system. B[a]P was extensively metabolized by both cell types, but quantitative differences were observed when the metabolic products were analyzed by high pressure liquid chromatography. Comparing total organic and water soluble metabolites, lung cells produced similar amounts of 7,8- and 9,10-diols but little 4,5-diol, while liver cells produced equivalent total amounts of the three diols. Lung cells produced twice the amount of B[a]P glucuronide conjugates as liver cells, while liver cells produced twice the amount of B[a]P sulfate conjugates as lung. The data suggest that intact cells from various organs can be used as metabolic activating systems in vitro assays and that studies into organ specificity can be investigated by this approach.

Syrian hamsters present a unique species for induction of pancreatic tumors that in many aspects resemble human pancreatic cancer. The specific response of Syrian hamsters, in contrast to may other rodents, for development of pancreatic ductal (ductular) tumors is not yet known. All pancreatic carcinogens thus far tested show certain common features. They are all nitrosamines that possess or can be metabolized to compounds with 2-oxopropyl- or 2-hydroxypropyl substituents. All but one, N-nitroso-methyl(2-oxopropyl)amine, occur or metabolize to nitrosamines with the ability to cyclize and form structures resembling glucose. Hence it is suggested that this cyclic structure may be responsible for the pancreatic carcinogenicity of these nitrosamines, as has been proposed for the pancreatotropic effect of streptozotocin. It is also of further interest that one pancreatic ductal (ductular) carcinogen, N-nitroso-2-methoxy-2,6-dimethylmorpholine, which possesses a totally cyclic structure, acts, like streptozotocin, as beta-cell cytotoxic and diabetogenic when given in a high single dose. Modification of pancreatic tumor induction has been demonstrated by specific procedures. A high fat diet significantly increases both the incidence and number of induced cancers. Methods for early diagnosis and therapy are being developed and their significance and applicabilities for clinical use will be of major importance. Compared with the other most common types of human cancer, pancreatic cancer has extraordinary characteristics, which make the disease one of the most mysterious of maladies. Consequently, pancreatic cancer represents a serious international problem and requires urgent resolution, especially with regard to its etiology, early diagnosis, prevention, and therapy.

The mutagenic activity of N-nitrosobis(2-oxopropyl)amine (BOP), N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP), N-nitrosobis(2-hydroxypropyl)amine (BHP), N-nitrosomethyl-2-oxopropylamine (MOP), and N-nitrosomethyl-2-hydroxypropylamine (MHP) was examined in the Ames liquid incubation assay, using hamster liver homogenate for metabolic activation, and in the hamster liver cell-mediated V79 cell assay. At similar concentrations, the cell-mediated assay showed a greater mutagenic response over background to these nitrosamines than did the bacterial assay. Also, the relative mutagenic potency in the cell-mediated assay (MOP > MHP > BOP > HPOP > BHP) correlated better than that in the Ames assay (HPOP > MHP greater than or equal to BOP = BHP = MOP) with overall carcinogenic potency in the hamster (MOP > BOP > HPOP > BHP). The liver cell-mediated assay may be an important adjunct to the battery of short-term tests for carcinogenicity prescreening.

The effect of norethynodrelmestranol (“Enovid”) pretreatment on the metabolism of 7,12-dimethylbenz(a)anthracene (DMBA) was examined in vivo in rats and hamsters, and in vitro in hamsters. “Enovid” pretreatment caused a decrease in bile flow, and increased by 44% the amount of DMBA metabolites excreted in the bile of rats; however, such effects were not found in hamsters. In vitro metabolism of DMBA by hamster liver 10,000g homogenates was also not modified by “Enovid” pretreatment. Aroclor and 3-methylcholanthrene pretreatments were used as positive controls for induction. Aroclor induced in vitro DMBA metabolism in hamster liver homogenates, whereas 3-methylcholanthrene unexpectedly had no effect. Results for in vitro benzo(a)pyrene metabolism were similar to those for DMBA. These studies suggest that the reported enhancement by Enovid E pretreatment of DMBA mammary carcinogenesis in the hamster is not mediated by an effect on overall hepatic metabolic activation of DMBA.