Issues in assessing the health risks of n-butanol.

A literature review and health effects evaluation were conducted for n-butanol, a chemical that occurs naturally in some foods, which is an intermediate in the production of butyl esters and can be used as a gasoline additive or blend. Studies evaluating n-butyl acetate were included in the review as n-butyl acetate is rapidly converted to n-butanol following multiple routes of exposure. The primary n-butanol health effects identified were developmental and nervous system endpoints. In conducting the literature review and evaluating study findings, the following observations were made: (1) developmental findings were consistently identified; (2) neurodevelopmental findings were inconsistent; (3) evidence for nervous system effects was weak; (4) comparing internal doses from oral and inhalation exposures using physiologically based pharmacokinetic models introduces uncertainties; and (5) a lack of mechanistic information for n-butanol resulted in the reliance on mechanistic data for ethanol, which may or may not be applicable to n-butanol. This paper presents findings from a literature review on the health effects of n-butanol and proposes research to help reduce uncertainty that exists due to database limitations.

Simultaneous multiagent hyperpolarized (13)C perfusion imaging.

PURPOSE: To demonstrate simultaneous hyperpolarization and imaging of three (13)C-labeled perfusion MRI contrast agents with dissimilar molecular structures ([(13)C]urea, [(13)C]hydroxymethyl cyclopropane, and [(13)C]t-butanol) and correspondingly variable chemical shifts and physiological characteristics, and to exploit their varying diffusibility for simultaneous measurement of vascular permeability and perfusion in initial preclinical studies. METHODS: Rapid and efficient dynamic multislice imaging was enabled by a novel pulse sequence incorporating balanced steady state free precession excitation and spectral-spatial readout by multiband frequency encoding, designed for the wide, regular spectral separation of these compounds. We exploited the varying bilayer permeability of these tracers to quantify vascular permeability and perfusion parameters simultaneously, using perfusion modeling methods that were investigated in simulations. "Tripolarized" perfusion MRI methods were applied to initial preclinical studies with differential conditions of vascular permeability, in normal mouse tissues and advanced transgenic mouse prostate tumors. RESULTS: Dynamic imaging revealed clear differences among the individual tracer distributions. Computed permeability maps demonstrated differential permeability of brain tissue among the tracers, and tumor perfusion and permeability were both elevated over values expected for normal tissues. CONCLUSION: Tripolarized perfusion MRI provides new molecular imaging measures for specifically monitoring permeability, perfusion, and transport simultaneously in vivo.

Final report of the addendum to the safety assessment of n-butyl alcohol as used in cosmetics.

n-Butyl Alcohol is a primary aliphatic alcohol historically used as a solvent in nail care cosmetic products, but new concentration of use data indicate that it also is being used at low concentrations in eye makeup, personal hygiene, and shaving cosmetic products. n-Butyl Alcohol has been generally recognized as safe for use as a flavoring substance in food and appears on the 1982 Food and Drug Administration (FDA) list of inactive ingredients for approved prescription drug products. n-Butyl Alcohol can be absorbed through the skin, lungs, and gastrointestinal tract. n-Butyl Alcohol may be formed by hydrolysis of butyl acetate in the blood, but is rapidly oxidized. The single oral dose LD(50) of n-Butyl Alcohol for rats was 0.79 to 4.36 g/kg. The dermal LD(50) for rabbits was 4.2 g/kg. Inhalation toxicity studies in humans demonstrate sensory irritation of the upper respiratory tract, but only at levels above 3000 mg/m(3). Animal studies demonstrate intoxication, restlessness, ataxia, prostration, and narcosis. Exposures of rats to levels up to 4000 ppm failed to produce hearing defects. High concentrations of n-Butyl Alcohol vapors can be fatal. Ocular irritation was observed for n-Butyl alcohol at 0.005 ml of a 40% solution. The behavioral no-effect dose for n-Butyl Alcohol injected subcutaneously (s.c.) was 120 mg/kg. Fetotoxicity has been demonstrated, but only at maternally toxic levels (1000 mg/kg). No significant behavioral or neurochemical effects were seen in offspring following either maternal or paternal exposure to 3000 or 6000 ppm. n-Butyl Alcohol was not mutagenic in Ames tests, did not induce sister-chromatid exchange or chromosome breakage in chick embryos or Chinese hamster ovary cells, did not induce micronuclei formation in V79 Chinese hamster cells, did not have any chromosome-damaging effects in a mouse micronucleus test, and did not impair chromosome distribution in the course of mitosis. Clinical testing of n-Butyl Alcohol for nonimmunological contact urticaria was negative in 105 subjects. Repeat-insult patch test (RIPT) studies of nail colors and enamels containing 3% n-Butyl Alcohol in one study produced reactions on challenge, but further study linked significant positive reactions to another solvent. In other RIPT studies, only minimal reactions were reported. A photopatch test demonstrated that a nail enamel containing 3% n-Butyl Alcohol resulted in no reactions. Workers complained of ocular irritation, disagreeable odor, slight headache and vertigo, slight irritation of nose and throat, and dermatitis of the fingers and hands when the air concentration of n-Butyl Alcohol was greater than 50 ppm, as compared to an odor threshold in air of 0.83 ppm. The available safety test data were considered adequate to support the safety of n-Butyl Alcohol in all cosmetic product categories in which it is currently used.

Derivation of a human equivalent concentration for n-butanol using a physiologically based pharmacokinetic model for n-butyl acetate and metabolites n-butanol and n-butyric acid.

The metabolic series approach for risk assessment uses a dosimetry-based analysis to develop toxicity information for a group of metabolically linked compounds using pharmacokinetic (PK) data for each compound and toxicity data for the parent compound. The metabolic series approach for n-butyl acetate and its subsequent metabolites, n-butanol and n-butyric acid (the butyl series), was first demonstrated using a provisional physiologically based pharmacokinetic (PBPK) model for the butyl series. The objective of this work was to complete development of the PBPK model for the butyl series. Rats were administered test compounds by iv bolus dose, iv infusion, or by inhalation in a recirculating closed chamber. Hepatic, vascular, and extravascular metabolic constants for metabolism were estimated by fitting the model to the blood time course data from these experiments. The respiratory bioavailability of n-butyl acetate (100% of alveolar ventilation) and n-butanol (50% of alveolar ventilation) was estimated from closed chamber inhalation studies and measured ventilation rates. The resulting butyl series PBPK model successfully reproduces the blood time course of these compounds following iv administration and inhalation exposure to n-butyl acetate and n-butanol in rats and arterial blood n-butanol kinetics following inhalation exposure to n-butanol in humans. These validated inhalation route models can be used to support species and dose-route extrapolations required for risk assessment of butyl series family of compounds. Human equivalent concentrations of 169 ppm and 1066 ppm n-butanol corresponding to the rat n-butyl acetate NOAELs of 500 and 3000 ppm were derived using the models.

Condensation of supersaturated n-butanol vapor on charged/neutral nanoparticles of D-mannose and L-rhamnose.

The effects of size, charge, and solubility on the condensation of supersaturated n-butanol vapor on monodisperse nanoparticles of D-mannose and L-rhamnose are investigated in a flow cloud chamber. The dependence of the critical supersaturation S(cr) on particle size in the range from 30 to 90 nm is determined experimentally. The results show that the experimental S(cr) decreases with increasing particle size and solubility, qualitatively in agreement with the prediction by the Volmer theory of nucleation on soluble particles and by the Kohler theory, but quantitatively smaller than both theoretical predictions. The condensation of supersaturated vapor on singly positive/negative charged particles with diameters of 30, 60, and 90 nm is examined, and no obvious charge effect and sign preference are observed.

Influence of evaporation and solvent mixtures on the absorption of toluene and n-butanol in human skin in vitro.

The influence of forced ventilation on the percutaneous absorption of butanol and toluene was studied in vitro. Human skin was exposed to the neat solvents and the solvents in binary mixtures with each other and in ternary mixtures with chloroform:methanol. The exposure was either unventilated or ventilated with various flow rates. At the ventilated exposure the skin absorption of all solvents and solvent mixtures was markedly reduced compared to unventilated exposure. Exposure with solvent mixtures increased the amounts of solvent absorbed as well as absorption rates. The absorption of the butanol component was most influenced. Increase in absorption was 11 to 9 times depending on whether toluene or chloroform/methanol was cosolvent. There was also an interindividual variation of absorption rate, varying with a factor of 3.5 for toluene and 4.3 for n-butanol within the 3 skin donors used. Skin absorption of volatile organic solvents at continuous ventilated conditions is related to their volatility and to the ventilation rate.A sufficient workplace ventilation is an important occupational hygienic measure not only to reduce exposure via respiration but to reduce absorption via the skin of volatile compounds as well.

Water transport in neonatal and adult rabbit proximal tubules.

We have recently demonstrated that although the osmotic water permeability (P(f)) of neonatal proximal tubules is higher than that of adult tubules, the P(f) of brush-border and basolateral membrane vesicles from neonatal rabbits is lower than that of adults. The present study examined developmental changes in the water transport characteristics of proximal convoluted tubules (PCTs) in neonatal (9-16 days old) and adult rabbits to determine whether the intracellular compartment or paracellular pathway is responsible for the maturational difference in transepithelial water transport. The permeability of n-butanol was higher in the neonatal PCT than the adult PCT at all temperatures examined, whereas the diffusional water permeability was identical. Increasing the osmotic gradient increased volume absorption in both the neonatal and the adult PCT to the same degree. The P(f) was not different between the neonatal and the adult PCT at any osmotic gradient studied. To assess solvent drag as a measure of the paracellular transport of water, the effect of the osmotic gradient on mannitol and chloride transport were measured. There was no change in chloride or mannitol transport with the increased osmotic gradient in either group, indicating that there was no detectable paracellular water movement. In addition, the mannitol permeability of the neonatal PCT was found to be lower than that of the adult PCT with the isotonic bath (8.97 +/- 4.01 vs. 40.49 +/- 13.89 microm/s, P < 0.05). Thus the intracellular compartment of the neonatal PCT has a lower resistance for water transport than the adult PCT and is responsible for the higher than expected P(f) in the neonatal PCT.

Morphologic basis for a pore-pathway in mammalian stratum corneum.

Although prior morphologic studies have shown that both polar and nonpolar materials permeate across the stratum corneum (SC) via a paracellular route, the actual pathway through these heterogeneous domains is unknown. We applied hydrophilic and hydrophobic tracers in vivo to murine skin under basal conditions and/or after permeation enhancement with occlusion, vehicle enhancers, a lipid synthesis inhibitor, sonophoresis, and iontophoresis. Ruthenium tetroxide, ruthenium red plus osmium tetroxide, in situ precipitation with osmium vapor, and microwave postfixation methods were used to visualize penetration pathways. Tracers invariably localized to discrete lacunar domains embedded within the extracellular lamellar membrane system, regardless of their polarity or the enhancement method. Moreover, while the lacunar domains remained discontinuous under basal conditions, they appeared to gain structural continuity with permeation enhancement. These results indicate that extracellular lacunar domains comprise a pore pathway for penetration of polar and nonpolar molecules across the SC.