Abstract  Acetylene, C2H2, is a highly reactive, commercially important hydrocarbon. Its reactivity is related to its triple bond between carbon atoms and, as a consequence, its high positive free energy of formation. Because of its explosive nature, long distance shipping or pressurized storage is not recommended. Thus acetylene is generally used as it is produced without shipping or storage. Commercially, acetylene is used primarily as a raw material for the synthesis of a variety of organic chemicals. In the United States, this accounts for ∼90% of acetylene usage, with the balance being used for metal welding and cutting. Worldwide acetylene production peaked in the mid-1960s, after which it declined dramatically as processes were developed to substitute lower cost olefins and paraffins for the acetylene feedstock. 1,4-Butanediol production accounts for 90% of the demand for acetylene for chemical production. Although acetylene production in Japan, China, and Eastern Europe is still based on the calcium carbide process, the large producers in the United States, Western Europe, and Russia now rely principally on the partial oxidation of natural gas. However, much of the incremental growth in production is based on producing acetylene as a coproduct of ethylene in the steam cracking process. As a coproduct, acetylene is much less costly than as produced from partial oxidation or calcium carbide.

Abstract  Alcohols are widely used as industrial solvents. In spite of the fact that ethanol is a human teratogen, there has not been systematic investigation of the potential teratogenic effects of other alcohols, particularly using the inhalation route of exposure, as would be appropriate in assessing occupational and environmental types of experience. As part of a large teratological examination of industrial alcohols, methanol and ethanol were administered by inhalation to groups of approximately 15 pregnant Sprague-Dawley rats. Methanol was administered at 20,000 ppm (20ME), 10,000 ppm (10ME), 5000 ppm (5ME), and 0 ppm (MECO) for 7 hr/day on Days 1-19 of gestation (Days 7-15 for 20ME). Ethanol was administered at 20,000 ppm (20ET), 16,000 ppm (16ET), 10,000 ppm (10ET), and 0 ppm (ETCO) for 7 hr/day on Days 1-19 of gestation. Dams were sacrificed on Day 20 (sperm = Day 0). One-half of the fetuses were examined using the Wilson technique for visceral defects, and the other half were examined for skeletal defects. The highest concentration of methanol (20ME) produced slight maternal toxicity and a high incidence of congenital malformations (p less than 0.001), predominantly extra or rudimentary cervical ribs and urinary or cardiovascular defects. Similar malformations were seen in the 10ME group, but the incidence was not significantly different from controls. No adverse effects were noted in the 5ME group. Dams in the 20ET group were narcotized by the end of exposure, and maternal weight gain and feed intake were decreased during the first week of exposure. The 16ET dams had slightly depressed weight gain (p less than 0.01) during the first week of exposure, but there were no significant effects on feed consumption. There was no definite increase in malformations at any level of ethanol, although the incidence in the 20ET group was of borderline significance.

Abstract  In experiments with the atomization of n-butyl acetate in chambers with rats, the LC50 was as low as 156 ppm.(4) However, workplace exposures occur almost universally to n-butyl acetate vapor, and direct exposure to atomized n-butyl acetate exposure did not occur in occupational situations.^ Accordingly, the marked toxicity of the atomized n-butyl acetate observed in animal bioassays is not of practical concern in the workplace. A TLV-TWA of 150 ppm is recommended for n-butyl acetate to minimize the potential risk of eye and mucous membrane irritation reported in volunteers exposed at 200 to 300 ppm of n-butyl acetate for 3 to 20 minutes.(35,37) A TLV-STEL of 200 ppm is recommended to control the excursions that produced mucous membrane irritation in the volunteers at exposures of 200 to 300 ppm for 3 to 20 minutes.(35,37) Given the high vapor pressure of this compound and the fact that topical application of n-butyl acetate in rabbits(27) and guinea pigs(20) failed to elicit systemic toxicity, the skin notation is not warranted Sufficient data were not available to recommend SEN or carcinogenicity notations. The reader is expected to be familiar with the section on Excursion Limits in the "Introduction to the Chemical Substance TLVs" of the current edition of the Documentation of the TLVs and BEIs for the guidance and control of excursions above the TLV-TWA, even when the 8-hour TWA is within the recommended limit.

Abstract  1. Human alcohol dehydrogenase (ADH) has been investigated by spectrophotometry assay and by starch-gel electrophoresis. 2. Assays were carried out at pH 8-8 and pH 11-0 on liver samples obtained post mortem from 129 adults over the age of 20, 37 premature infants and infants less than one year old and 56 foetuses. Sixteen cases of the previously described atypical pH ratio phenotype were identified among the 166 adults and infants tested. No examples of the atypical pH ratio phenotype were encountered among the foetuses. On average the foetal liver ADH activity was less than in adults and it appeared to increase with increasing gestational age. 3. Electrophoretic analyses of ADH in liver samples obtained from 117 foetuses of various gestational ages, 62 premature infants and infants less than a year old and a group of more than 200 adults over the age of 20, indicate that developmental changes occur during intrauterine life. 4. The atypical pH ratio phenotype liver ADH isozyme pattern was found to be electro-phoretically different from that of the usual pH ratio phenotype. 5. The ADH isozyme pattern in lung tissue was the same in adults, infants and foetuses. The overall activity was low and mainly concentrated in a single isozyme which was electrophoretic-ally indistinguishable from the main ADH isozyme of adult liver. Usual and atypical pH ratio phenotypes were identified, both by assay and by starch-gel electrophoresis, in foetal, infant and adult lung specimens. 6. The ADH activity of kidney and intestine was too weak for assay with ethanol as substrate. In adults the isozyme patterns in kidney were similar to those found in adult liver. In foetal intestine and kidney, however, the ADH isozymes were quite different from those of adult liver and also foetal liver. Three distinct phenotypes, designated ADH3 1, ADH3 2-1 and ADH3 2, were recognized in foetal kidney and intestine, occurring with frequencies of 0–42, 0–42, and 0–16 respectively in a survey of 117 specimens. 7. The appearance of the ADH isozyme patterns in liver and in foetal kidney and intestine is consistent with the hypothesis that ADH has a dimeric sub unit structure. 8. The findings suggest that at least three autosomal gene loci may be concerned in determining the structure of alcohol dehydrogenase in man. (a) Locus ADH1primarily active in the liver in early foetal life, becoming less active during gestation and only weakly active during adult life. (b) Locus ADH2 (i) expressed in lung in early foetal life and remaining active in this tissue throughout life, (ii) active in liver after about the first trimester and gradually becoming more active so that in adults this locus is responsible for most of the liver ADH activity, (iii) also active in adult kidney, (iv) the atypical pH ratio phenotype is probably determined by a variant allele at the ADH2 locus. (c) Locus ADH3- active during foetal and early post-natal life in intestine and kidney. The variant phenotypes ADH3 1, ADH3 2-1 and ADH3 2 are thought to represent the genotypes ADH13ADH31,ADH32ADH32 and ADE31ADH32 respectively, where ADH31 and ADH32 are alleles at the ADH3 locus. The gene-frequency estimate of ADH31 is 0.63 and of ADH32 is 0.37.

Abstract  For four decades, the Draize test has remained the accepted method for evaluating eye irritation. Criticisms center around the inhumane treatment of animals and the irreproducibility of the subjective scoring procedure. The objective of this study was to determine if changes in corneal thickness obtained using a slit-lamp pachometer could be used to replace the Draize scoring procedure and provide a method for quantifying ocular irritation. Twenty-four chemicals (six surfactants, seven alcohols, four ketones, four acetates, and three aromatics) were instilled in the conjunctival sacs of rabbits and irritation monitored by Draize scoring and changes in corneal thickness. The Draize procedure was more adept at detecting minor conjunctival damage, but corneal thickness exhibited less variation and increased sensitivity for detection of healing reactions. A significant linear correlation (y = l.736x + 92.883) was established between Draize score and corneal thickness changes with a correlation coefficient (r) of 0.86 and an F-value for regression of 261.3. Using these findings, an ocular irritation ranking system is proposed based upon the percentage of corneal swelling. Ocular irritation potential was ranked for the chemical groups tested (surfactants> alcohols> ketones or acetates> aromatics). Quantitation of ocular irritation from changes in corneal thickness provides objective, numerical data applicable to standard parametric statistical procedures. This should eliminate the subjective bias inherent to Draize scoring and decrease intra- and interlaboratory variability. ® 1989 Society orToxicology.

Abstract  The purpose of this study was to assess the utility of the thermoregulatory system as an end point in predicting the toxicity of various short-chain alcohols. Male Fischer rats developed significant hypothermia following acute administration (ip) of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, or 2-butanol. The hypothermic responses to the six alcohols all showed similar segmented responses characterized by a threshold dose below which no change in body temperature occurred, and a suprathreshold regression with increasing dose causing greater hypothermia. Relative potency of the alcohols was assessed using both the threshold dose to cause hypothermia and the dose that would cause body temperature to decrease by 1 degree C. Both measures gave the progression of toxicity from least to most potent of methanol less than ethanol less than 2-propanol less than 1-propanol less than 2-butanol less than 1-butanol. The effective dose of each alcohol was compared to its membrane/buffer partition coefficient (Pm/b), and there was a high inverse correlation between the hypothermic dose of an alcohol and its lipid solubility. That the potency of an alcohol was strongly correlated with its Pm/b suggests that the membrane disordering theory of narcosis may also be used to explain the hypothermic action of alcohols.

Abstract  Ethanol inhibits astroglial cell proliferation, an effect that may contribute to the development of alcoholic embryopathy in humans. In the present study, we investigated inhibitory effects of ethanol and butanol isomers (1-, 2- and t-butanol) on astroglial cell proliferation induced by the strongly mitogenic phorbol ester, 4beta-phorbol-12alpha,13beta-dibutyrate (PDB). 4beta-Phorbol-12alpha,13beta-dibutyrate (PDB) induced a 10-fold increase of [3H] thymidine incorporation in cortical astrocytes prepared from newborn rats (EC50: 70 nM) which was blocked by Ro 31-8220, a cell-permeable protein kinase C (PKC) inhibitor. Ethanol blocked PDB-induced astroglial proliferation in a concentration-dependent manner; significant effects were already seen at 0.1% (v/v). Concomitantly, ethanol caused the formation of phosphatidylethanol (PEth) by phospholipase D (PLD) and reduced PLD-mediated formation of phosphatidic acid (PA). The butanols also inhibited the mitogenic action of phorbol ester; the inhibitory potency of the butanols was 1-butanol > 2-butanol > t-butanol. The same range of potencies was observed for the inhibitory activity of the butanols towards protein kinase C activity measured in vitro. At 0.3% concentration, 1-butanol potently suppressed the PDB-induced formation of phosphatidic acid while 2- and t-butanol were less active. Taken together, our results suggest that ethanol and 1-butanol exert a specific inhibitory effect on PKC-dependent astroglial cell proliferation by synergistically inhibiting PKC activity and the PLD signaling pathway.

Abstract  The family approach for related compounds can be used to evaluate hazard and estimate reference concentrations/doses using internal dose metrics for a group (family) of metabolically related compounds. This approach is based upon a simple four-step framework for organizing and evaluating toxicity data: 1) exposure, 2) tissue dosimetry, 3) mode of action, and 4) response. Expansion of the traditional exposure-response analysis has been increasingly incorporated into regulatory guidance for chemical risk assessment. The family approach represents an advancement in the planning and use of toxicity testing that is intended to facilitate the maximal use of toxicity data. The result is a methodology that makes toxicity testing and the development of acceptable exposure limits as efficient and effective as possible. An example is provided using butyl acetate and its metabolites (butanol, butyraldehyde, and butyrate), widely used chemicals produced synthetically by the industrial oxo process. A template pharmacokinetic model has been developed that comprises submodels for each compound linked in series. This preliminary model is being used to coordinately plan toxicity studies, pharmacokinetic studies, and analyses to obtain reference concentrations/doses. Implementation of the family approach using pharmacokinetic modeling to obtain tissue dose metrics is described and its applications are evaluated.

Abstract  1. 5-HT3 receptor-mediated ion current was recorded from NCB-20 neuroblastoma cells using the whole-cell patch-clamp technique. Rapid drug superfusion was used to study the mechanism of alcohol potentiation of 5-HT3 receptor function and to analyse effects of alcohols on receptor-channel kinetics in detail. 2. Trichloroethanol (TCEt) increased in a dose-dependent way the initial slope, 20-80% rise time and measured desensitization rate of the current induced by low concentrations (1-2 microM) of 5-HT. Ethanol (EtOH) and butanol (ButOH) had similar effects on the 5-HT3 receptor-induced current. 3. TCEt and ButOH decreased the measured desensitization rate of current induced by 10 microM 5-HT, a maximally effective concentration of agonist. These alcohols also increased the relative amplitude of steady state to peak current induced by 2 or 10 microM 5-HT, indicating a possible decrease in the intrinsic rate of desensitization. 4. TCEt also decreased the deactivation rate of the current activated by 2 microM 5-HT after a short pulse of agonist application. 5. Current sweeps generated by 1 microM 5-HT in the presence or absence of 10 mM TCEt or 100 mM EtOH were well fitted using a modified standard kinetic model derived from the nicotinic acetylcholine receptor. This analysis indicated that potentiation by alcohols could be accounted for by increases in the association rate constant coupled with decreases in the dissociation and desensitization rate constants. 6. This study suggests that alcohols potentiate 5-HT3 receptor-mediated current by both increasing the rate of channel activation and stabilizing the open state by decreasing the rates of channel deactivation and desensitization.

Abstract  During in vitro culture of murine preimplantation embryos, we have observed that exposure to 0.1% ethanol induces an immediate increase in intracellular calcium levels and subsequently accelerates embryogenesis. If the observed effects of ethanol on developing embryos is mediated by its membrane disordering potency, we hypothesized that the relative membrane disordering potencies of related alcohols would correspondingly effect embryonic intracellular calcium levels and developmental rates. Two-cell embryos were exposed to 0.1% ethanol or 0.05 to 1.0% (w/v) n-butanol, n-propanol, isopropanol, 1,2-propanediol, glycerol, or methanol for 24 hr at 37 degrees C, and development to the blastocyst stage was monitored after 5 days. n-Butanol, n-propanol, isopropanol, and methanol treatment caused a dose-dependent inhibition (p < 0.01) of development to the blastocyst stage, whereas 1,2-propanediol or glycerol neither accelerated nor inhibited development. In a second experiment, 8-cell morulae were treated with 1,2-propanediol or glycerol, and cavitation rates were examined. There was no significant difference from control embryos in the onset of cavitation or the blastocoel expansion rate of 1,2-propanediol- or glycerol-exposed embryos, whereas exposure to 0.1% ethanol accelerate cavitation (p > 0.05). In a third experiment, morulae were exposed to 0.1% or 1.0% of each alcohol and were monitored for changes in intracellular calcium levels using the fluorescent indicator, fluo-3-acetoxymethyl ester. There was an immediate increase in intracellular calcium levels when morulae were treated with 1.0% ethanol or n-butanol, but only ethanol induced an increase (p < 0.05) in the level of intracellular calcium at 0.1%. These data suggest that ethanol is unique in its ability to accelerate embryogenesis and that the membrane disordering potency of ethanol does not directly underlie its effects on intracellular calcium release and the acceleration of preimplantation development.

Abstract  Female rats were given aqueous solutions of n-butanol containing 0.24, 0.8 and 4% n-butanol (0.3; 1.0 and 5.0 g/kg/day) for 8 weeks before and during gestation. The control animals received tap water. The experiment was performed in two stages. The first comprised of the assessment of the oestrous cycle before exposure and then during 4-5 and 7-8 weeks of exposure, and the second stage of the fertility of female rats and their foetal development. The duration of the cycle and its individual stages in the control and the exposed females were similar. It was found that n-butanol alcohol is a foetotoxic agent and produces developmental anomalies in a foetus's skeleton and central nervous system.

Abstract  We recently reported that ethanol and other aliphatic alcohols exert a selective inhibition on the binding of enkephalins to delta opioid binding sites. We report here a more detailed investigation of the characteristics of this inhibition. Opioid binding sites of the kappa subtype are similar to mu opioid binding sites in their relative insensitivity to inhibition by aliphatic alcohols. Scatchard analysis of saturation data of enkephalin binding showed that inhibition is the result of a decrease in affinity. Results of kinetic experiments demonstrated that the inhibition can be entirely accounted for by an increase in the dissociation rate of the ligand-receptor complex. The presence of sodium ions in the incubation medium and raising the temperature of incubation exacerbate the inhibitory effectiveness of alcohols. The order of potency among structural isomers of alcohols for inhibition of delta receptor binding is as follows: straight-chain primary greater than isoprimary greater than secondary greater than tertiary. The order of inhibitory potency of the aliphatic alcohols tested correlates well with their ability to disorder the cell membrane lipid bilayer. It is suggested that this is a probable mechanism by which alcohols inhibit binding to delta opioid binding sites.

Abstract  Administration of single doses of ethanol, 1-propanol, 1-butanol or 1-pentanol to mice caused hypothermia and impairment of rotarod performance. Repetitive doses, at 24-72 hr intervals led to development of tolerance to the hypothermic effects of ethanol but not of the other alcohols. No tolerance was seen in the impairment of rotarod performance with repeated doses of any of the alcohols. Ethanol did show an intersession tolerance on rotarod performance; at 20 and 80 min after injection, blood levels were similar, while performance was impaired at 20 but not at 80 min.

Abstract  Exposure to n-butanol vapour gave rise to a sensory irritation response which was measured by the reflexively induced decrease in respiratory rate in mice according to the American standard method (E981-84). The response reached maximum within the 1st min of exposure. In this period the expected threshold response (RD-0) and the concentration expected to depress the respiratory rate by 50% (RD-50) were extrapolated to be 233 ppm and 11,696 ppm, respectively. The response followed the dynamics of a bimolecular reaction between butanol and the sensory irritant receptor. For concentrations below 3000 ppm, the response faded due to desensitization. However, concentrations above 3000 ppm gave rise to a new decrease in respiratory rate due to activation of lung receptors. Two types of lung receptors, probably J-receptors and stretch receptors, were involved. The sensory irritation response measured by the standard method gave a threshold response which was comparable to that found by electrophysiological experiments in rats. The irritation response in man as well as the maximum allowable concentration in the working environment were adequately predicted from the sensory irritation response in mice.

Abstract  Two concentrations of 1-butanol (3000 and 6000 ppm) were administered by inhalation to separate groups of 15 pregnant Sprague-Dawley rats for 7 hr per day throughout gestation; 18 male rats were similarly exposed for 7 hr per day for 6 weeks, and mated to unexposed females. Litters were culled to 4 female and 4 male pups and fostered to untreated controls. From days 10-90, offspring were tested as follows: a) ascent on a wire mesh screen, b) rotorod, c) open field and photoelectrically-monitored activity, d) running wheel, e) avoidance conditioning, and f) operant conditioning. Additionally, brains from 10 offspring at 21 days of age were dissected into cerebrum, cerebellum, brainstem, and midbrain. Each sample was assayed for protein and the neurotransmitters acetylcholine, dopamine, norepinephrine, serotonin, met-enkephalin, beta-endorphin, and substance P. Overall, there were few behavioral or neurochemical alterations detected in the offspring following maternal or paternal exposure to either 3000 or 6000 ppm 1-butanol. This scarcity of effects is important to risk assessment extrapolations drawn from ethanol. Based on the structural similarity of 1-butanol to ethanol and long-standing observations that toxicity to adult animals generally increases with chain length among the alcohols, significant behavioral and neurochemical deviations were predicted. The scarcity of effects from butanol needs to be accounted for in hypotheses relating toxicity to alcohol chain length and in risk assessment extrapolations from findings with ethanol.

Abstract  Long-term treatment of rats with n-butanol leads to a change in in vitro brain protein synthesis which increases the resistance of this process to either ethanol or isopropanol. The change seems to be related to ribosomal events since the synthesis of aminoacyl-tRNA was not affected in the same conditions.

Abstract  We have assessed the morphometric parameters of rat small intestinal microvillous vesicles, prepared by a Ca(2+)-precipitation method, from normal, long term ethanol-treated and pair-fed saccharose -treated control rats. The vesicles from normal rats were also directly exposed to ethyl, butyl and benzyl alcohols, respectively. Computerized morphometric analysis was carried out on electron micrographs of microvillous vesicles. The size of vesicles from ethanol-treated rats, as well as control rats, was significantly reduced as compared to normals. Direct exposure of vesicles to alcohols significantly increased vesicle dimensions, with a potency order reflecting the liposolubility of alcohols. These data support the hypothesis that variations in vesicle diameter may be ascribed at least in part to the fluidizing effect of alcohols. Thiamin transport by the vesicles has been measured in the presence of ethanol. The time course of thiamin uptake was not affected by ethanol.