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    BUTANE-1,3-DIOL

    Explanation

         This compound has been evaluated for acceptable daily intake by
    the Joint FAO/WHO Expert Committee on Food Additives

         Based on research conducted in Germany in early 1950s, several
    investigators have conducted extensive experiments to develop new
    synthetic source(s) of dietary calories for animals and man.
    1,3-butanediol (BD) was selected as the most promising "high-energy
    metabolite" and subjected to intensive study. Some of the relevant
    studies with BD are discussed in the following monograph.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Rat. Rosmos et al. (1974) examined the effects of
    1,3-butanediol (BD) on hepatic fatty acid synthesis and metabolite
    levels in the rat. Several groups of male Sprague-Dawley rats, 10
    each, weighing about 200 g were fed for 23 days, a basal diet
    containing 66.1% glucose, sucrose or the isocaloric equivalent of BD
    at 18% or 36% of the carbohydrate energy (the energy value of BD is
    6.5 kcal/g). A separate group of rats were injected i.p. with 800 mg
    of BD in 2 ml of water. In vitro studies with rat liver slices were
    also performed with 10 mm BD as the substrate.

         The biochemical analyses showed that the plasma levels of glucose
    and triglycerides were significantly (p <0.05) decreased in rats fed
    BD. The acute administration of BD, however, increased the plasma
    levels of glucose in the rat. The levels of free fatty acids in the
    plasma were not affected by acute administration of BD, although the
    hepatic free fatty acid synthesis was significantly (P <0.05)
    decreased. Chronic administration of BD also increased the levels of
    -hydroxybutyrate and acetoacetate in the rat liver. The in vitro
    studies showed that 10 mm of BD decreased the conversion of glucose to
    free fatty acids in the liver without affecting the acetate conversion
    to free fatty acids, suggesting that BD might have inhibited the
    conversion of glucose to acetoyl CoA. Furthermore, the release of
    pyruvate from the liver slices was decreased, while the lactate
    release was not. The synthesis of free fatty acids in the adipose
    tissue was not affected by BD. The data further showed that BD was
    metabolized to -hydroxybutyrate and acetoacetate by the rat liver.
    The ratio of lactate/pyruvate was significantly (p <0.05) increased,
    indicating that there was a shift in the cytoplasmic redox state
    towards a more reduced state.

         To determine if depression of central nervous system from chronic
    ingestion of an alcohol was related to changes in metabolite content
    in the brain, Veech et al. (1974) fed three groups, 10 each, of male
    albino rats of CFN Wistar strain, a standard rat diet for two weeks

    until they weighed 270 g. They were fasted for five days, and
    thereafter, were fed commercial liquid diet in which 47% of the total
    calories were substituted with appropriate amounts of either glucose,
    ethanol, or BD for 62 days. The diet supplied 6.3% protein, 1.2% fat,
    13% carbohydrate minerals and vitamins. The caloric values of glucose,
    ethanol, and BD were 3.68, 6.93 and 6.0 kcal/g, respectively. Twenty-
    four hours after the last day of the treatment, brains and blood were
    analysed for metabolites. The concentration of lactate in the brain
    was significantly (p <0.005) decreased in BD-fed rats but not in
    ethanol-fed rats, as compared to glucose-fed rats. The concentration
    of malate, aspartate, dihydroxyacetone phosphate, glucose-6-phosphate,
    NH4 or creatinine phosphate were not affected by either treatment.
    Brain glucose was decreased approximately 8-fold in rats fed BD and
    3.5-fold in rats fed ethanol, as compared to control rats fed glucose.
    The brain citrate levels were higher in both BD- and ethanol-fed rats,
    while the glutamate levels were elevated only in BD-fed rats. The
    concentration of BD in the BD-fed rats was 23.4  mol/g. Feeding of BD
    decreased blood glucose from 4.95 to 2.91 -mol/ml, while increasing
    the ketone bodies in the blood. Further, the cytoplasmic NADP/NADPH
    ratio was increased both in ethanol- and BD-fed rat brains suggesting
    that the CNS depression following chronic ingestion of alcohol may not
    be associated with these changes in the rat brain.

         Mehlman et al. (1975) also reported that 1,3-butanediol breaks
    down to -hydroxybutyrate and acetoacetate in rats. The feeding of
    butanediol at 30% of the fat in the diet caused a significant
    (p <0.001) elevation in the blood levels of ketone bodies. Acute oral
    administration of butanediol at 50% in solution in water to overnight
    fasted rats or administration at 20% in solution, for 14 days also
    resulted in a significant elevation (p <0.001) of blood levels of
    ketone bodies. The in vitro studies using liver slices from rats fed
    butanediol at 30% of fat in the diet also indicated that butanediol is
    metabolized to ketone bodies in the rat. Furthermore, addition of
    butanediol to rat liver perfusate greatly elevated tissue
    lactate/pyruvate ratio when lactate was used as the substrate. The
    cytosol ratio of NADH/NAD was also elevated suggesting that oxidation
    of butanediol in rats occurs via alcohol dehydrogenase.

         Rosmos et al. (1975) fed several groups of rats, pigs, and chicks
    high fat basal diet containing butanediol at 0 or 17-19% of the
    dietary carbohydrate energy. They found that feeding of butanediol
    significantly decreased (p <0.05) the synthesis of free fatty acids
    in the rat liver, but not in pigs or chicks. The synthesis of free
    fatty acids in the adipose tissue was unchanged in all the animal
    species tested. The blood level of -hydroxybutyrate, acetoacetate,
    plasma levels of glucose, and triglycerides were increased by 48%,
    24%, 89%, and 65%, respectively in the rats fed butanediol, as
    compared to the controls. The blood levels of -hydroxybutyrate and
    acetoacetate in pigs and chicks were elevated, while the plasma
    glucose levels remained unchanged. The fact that the weight gain in
    rats, pigs, and chicks was not affected by butanediol up to 20% of
    their dietary carbohydrate energy, although there was a dose-dependent

    decrease in body weights if butanediol in the diet exceeded 20%, the
    authors suggested that rats, pigs, and chicks were able to utilize
    butanediol without loss of body weight. Their data further confirmed
    that butanediol is metabolized to hydroxybutyrate and acetoacetate,
    and that it decreases the hepatic fatty acid synthesis in the rat.

    TOXICOLOGICAL STUDIES

    Special studies

         Mackerer et al. (1975) tested 1,3-butanediol (BD) for its
    antidiabetic effects in rats that were made diabetic with
    streptozotocin. The Charles River (CR-CD strain) rats were pair-fed a
    high-fat diet containing BD at dose levels of 13.5 or 27% of the diet
    calories. An equal number of rats were fed Purina Rat Chow as the
    control diet. At the end of 30-31 days, blood from each rat was
    analysed for glucose and fatty acids; the livers were analysed for
    protein, cholesterol, fatty acids, triglycerides, phospholipids and
    glycogen; and the pancreata were analysed for insulin. The diet
    containing 27% BD increased the -hydroxybutyrate, acetoacetate,
    increased the pancreatic insulin, and decreased the blood glucose. The
    lower dose of BD only increased the cholesterol concentrations in the
    liver without affecting any other biochemical parameters (Mackerer et
    al. 1975). The data further showed that BD was readily utilized by the
    diabetic rat as a source of dietary energy. The rate of food
    consumption by rats fed 27% BD was significantly reduced as compared
    to the controls. These effects lasted for the entire period of the
    study without affecting the food efficiency since the caloric value of
    BD remained at 5.9 cal/g at both dose levels.

    Short-term studies

         Dog. In a subchronic study, Reuzel et al. (1978) administered
    1,3-butanediol (BD) in diet to groups of four male and four female
    beagle dogs, seven to eight weeks of age, at doses of 3, 6, 9, or
    12 g/kg of body weight, daily for 13 weeks. A separate group of four
    male and four female dogs were fed basal diet as control. Periodic
    observations of behaviour, general health and food consumption were
    made. In addition, haematologic investigations at weeks 2, 6, and 12,
    clinical chemistry tests at weeks 6 and 12, urinalysis at the
    beginning and at weeks 6 and 12, the liver and kidney function tests
    at week 13, and a complete autopsy of all the surviving dogs at the
    termination of the study were performed. There was a significant
    decrease in the body weights of dogs that were fed 9 and 12 g/kg of
    BD. These two doses also produced frequently epilepsy-like seizures in
    dogs of both sexes. The highest dose, 12 g/kg produced slight
    ketonuria in dogs at week 12. Although the relative weights of liver
    and kidneys were increased both by 9 and 12 g/kg doses, the liver and
    kidney function tests were normal. There were nonsignificant dose-
    related increases in blood free fatty acid levels, -hydroxybutyric
    acid, and lactic acid levels, but significantly (p <0.001) at the
    12 g/kg dose. Small quantities of BD were found in faeces of dogs that

    were fed 9 or 12 g/kg of BD. At autopsy, none of the test animals
    showed any significant gross or histopathological changes in any of
    the organs examined. The lower doses did not produce any toxic effects
    in any of the dogs, except 6 g/kg, which increased thrombocytes in
    blood of some animals. Reuzel et al. (1978) concluded that 6 g/kg was
    the "no toxic-effect" dose level of 1,3-butanediol in the present
    study.

         Cattle. Young in 1975 reported that when a group of seven
    lactating Holstein cows were fed 1,3-butanediol (BD) at 4% of their
    total diet, there were no abnormal physiological effects in these cows
    as compared to those fed high-fat diet. The percentage of fat in milk
    and total production of fat were higher in BD-fed cows than in
    controls. The concentrations of glucose in blood were normal in cows
    fed BD. However, when the concentration of BD in their diet was
    increased to 5%, there was significant elevation of ketones in blood.

         In growing cattle, the feeding of BD at 4% increased the ratio of
    rate of gain and feed efficiency in cattle fed BD as compared to those
    cattle fed diets which did not contain BD. When a group of 12 growing
    cattle were fed 5%, 10%, 15% or 20% BD for a week, the heifers (>10%)
    became hyperactive, nervous, began to urinate profusely, and exhibited
    muscular tremors. One of the 12 heifers went into tetany when a loud
    noise occurred nearby. No such toxic effects were observed in calves
    fed 10% BD in grain for five days, although the concentrations of
    ketone bodies in blood and urine were elevated. Fat-depressed cows fed
    BD usually had greater milk fat than cows not fed BD. BD did not alter
    rumen fatty acid ratios, rumen pH, nor blood glucose levels. Blood
    ketones were sometimes elevated in cows fed BD.

         Young (1975) suggested that the toxic effects in growing cattle
    fed high amounts of BD may be associated with the build-up of blood
    ketones. However, BD can be fed to both lactating and growing cows,
    that it can be utilized effectively as an energy source, and that with
    up to 4% in diets for growing cattle and up to 6% in diets for
    lactating cows fed high-drain diets, there are not indications of any
    problems with feeding BD.

    Long-term studies

         Rat. To determine the oral toxicity of 1,3-butanediol in rats,
    Scala & Paynter (1967) fed BD at 0, 1, 3 or 10% in diet to groups of
    30 male or female weanling Sprague-Dawley rats for two years. The
    changes in body weight, food consumption and pharmacologic effects
    were recorded regularly. The haematologic, clinical, and examinations
    at intervals of four months, and microscopic examination of all
    tissues at one and two years showed no discernable toxic effects in
    rats at any dietary level. The authors, however, noted that some rats
    showed signs of chronic inflammation of lungs, spleen, and kidneys,
    and spontaneous subcutaneous neoplasms in 16 control and 11 test rats.
    Scala & Paynter (1967), however, noted that these effects were common
    in laboratory animals of this strain and age. They concluded that BD
    was nontoxic in rats up to 10% of the diet.

         Dog. Scale & Paynter (1967) fed groups of four animals for each
    sex pure bred beagle dogs BD at 0, 0.5, 1 or 3% in diet for two years.
    Daily or weekly records of food consumption, elimination, appearance,
    signs of pharmacologic effects, body weight changes, and haematologic,
    clinical, and histopathologic examinations showed no discernable toxic
    effects in any dog at any dietary level. The effects such as focal
    chronic nephritis, characterized by radial scarring, mild lymphocytic
    and plasmocytic infiltration, cast formation, tubular atrophy, and
    mild to moderate glomerulitis were seen in some control and test dogs.
    Scale & Paynter (1967), concluded that BD was nontoxic to dogs fed BD
    up to 3% in their diets.

    OBSERVATIONS IN MAN

         In several studies in human volunteers, Tobin et al. (1975) have
    shown that isocaloric substitution of 1,3-butanediol (BD) for starch
    caused less negative nitrogen balance and lower levels of blood
    glucose. On the other hand, in the fasting state and after glucose
    loading, the concentrations of serum insulin and growth hormone were
    significantly increased. In one of the three studies, 12 young men and
    women were allowed a diet which contained 15 g of BD (equivalent to 5%
    of the total caloric intake substituted isocarlorically for starch)
    starch, urea, or urea plus BD. Urea supplied 4 g nitrogen daily. Of
    the mean daily energy intake of 2139 kcal/day, protein provided 5.9%
    of energy, carbohydrates or carbohydrate plus BD provided 64% and fat
    provided 30% of the energy. The daily basal diet for each subject
    consisted of 100 g each of peaches, pears, green beans, tomato juice
    and variable amounts, but constant for any one subject of jelly, hard
    candy, sucrose, starch, butter oil, and carbonated beverages. The diet
    also contained various minerals and vitamins. Blood from each
    individual was analysed for urea, proteins, haematocrit, haemoglobin,
    white blood cells, differential count, glutamic-oxaloacetic
    transaminase, glutomic-pyruvic transaminase, glucose-hydroxybutyrate,
    acetoacetate, lactate, pyruvate, triglycerides, free fatty acids,
    cholesterol, sodium, potassium, chloride, zinc, magnesium, and
    calcium.

         The results of this study showed that feeding of BD caused a
    significant reduction of urinary excretion of nitrogen in BD-fed
    subjects as compared to those fed diet containing starch only, while
    the urinary excretion of nitrogen was slightly elevated in subjects
    fed urea plus BD. The feeding of BD did not affect the faecal
    excretion of nitrogen. The blood glucose levels were significantly
    lowered in BD fed subjects. The blood urea nitrogen was significantly
    elevated in subjects fed BD as compared to those who were fed urea
    only. Feeding of BD did not alter any other biochemical, clinical, or
    haematological parameters. Tobin et al. (1975) hypothesized that
    negative nitrogen balance and the lowering of blood glucose may have
    been caused by (i) decreased gluconeogenesis via negative feedback
    inhibition by BD itself or ketone bodies formed in blood, or (ii)
    better assimilation of BD than of starch, and thereby contributing a
    greater quantity of utilizable energy resulting into decreased

    breakdown of proteins. However, the data from this study did not
    support their hypothesis.

         To determine the cause of hypoglycaemic effect of BD, a separate
    group of 27 women were placed on a diet that contained wheat protein
    as a source of nitrogen providing 4 g N/in2 body surface/day. The
    subjects were provided 40 g BD daily for five days or isocalorically
    equal amounts of sucrose. At the end of the study, their serum was
    analysed for levels of glucose, insulin, triglycerides, cholesterol,
    and growth hormone. Feeding of BD did not alter any of the biochemical
    measures in any subject as compared to feeding sucrose alone.

         The glucose tolerance tests conducted in a separate group of 10
    men and women fed BD equivalent to 10% of the total energy intake for
    five days showed no differences in levels of blood glucose during both
    glucose loading and fasting states, suggesting that humans can utilize
    BD up to 10% of their total caloric intake without any adverse
    effects, except that it may produce hypoglycaemic effect, the cause of
    which remains unknown.

         Altschule et al. (1977) investigated the possible role of alcohol
    in episodic violent behaviour in a young healthy man who showed mild
    brain damage, seemingly related to drinking. After an overnight fast,
    the subject was given 100 ml 95% ethanol in 12 oz of sugar-free
    flavoured beverage. It was consumed within 40 minutes. The subject's
    venous blood was analysed 1, 3, 6, 9 and 12 hours after the ingestion
    of ethanol for metabolites by a gas-liquid chromatographic method, and
    an encymatic method using yeast alcohol dehydrogenase. Food was
    allowed once 9.5 hours after the ingestion of ethanol. The whole
    procedure was repeated the next day. The analyses of venous blood
    showed that it contained a substance whose properties were those of
    1,3-butanediol, suggesting that alcohol may be converted to
    1,3-butanediol in humans. However, the data are insufficient to
    suggest that the bizarre behaviour in the young man with a drinking
    problem was due to 1,3-butanediol in his blood.

    Comments

         Several metabolic tests and acute and chronic feeding studies in
    mice, rats, dogs and cattle have demonstrated that butane-1,3-diol can
    be utilized as a source of energy. At high dietary levels, up to 20%,
    there is a tendency to produce ketosis.

         Short-term metabolic studies in man indicate butane-1,3-diol can
    supply up to 10% of total dietary energy without toxic effects.
    Although the administration of butane-1,3-diol produced hypoglycaemic
    effects in man and rat there appeared no obvious effects on the
    wellbeing of humans ingesting up to 10% of their energy intake as
    butane-1,3-diol for five days, or to rats fed the material at 10% of
    their diets for two years. In a two-year dog feeding study where
    butane-1,3-diol was incorporated into their diets at levels up to 3%
    there was no toxic effect. There are no reproduction studies

    available. There is considerable human data available, but it is not
    long-term. The Committee therefore relied on the long-term animal
    feeding studies.

    EVALUATION

    Level causing no toxicological effect

    Dog: 3% of the diet equivalent to 750 mg/kg bw.

    Estimate of acceptable daily intake for man

    0-4 mg/kg bw.

    FURTHER WORK ON INFORMATION

         It would be desirable to have a multigeneration reproduction/
    teratology study.

    REFERENCES

    Altschule, M. D., Werthessen, N. T. & Miller, S. A. (1977)
         J. Toxicol. Environ. Health., 3, 755

    Dymsza, H. A. (1975) Federation Proc., 34, 2167

    Mackerer, C. R. et al. (1975) Federation Proc., 34, 2191

    Mehlman, M. A., Tobin, R. B. & Mackerer, C. R. (1975) Federation
         Proc., 34, 2182

    Reuzel, P. G. J. et al. (1978) Report "Subchronic (13-week) feeding
         study with 1,3-butanediol in beagle dogs" No. R 5485 by Central
         Institute for Nutrition and Food Research, submitted to WHO,
         dated September 1978

    Rosmos, D. R., Belo, P. S. & Leveille, G. A. (1974) J. Nutr., 104,
         1438

    Rosmos, D. R. Belo, P. S. & Leveille, G. A. (1975) Federation Proc.
         34, 2186

    Scala, R. A. & Paynter, O. E. (1967) Toxicol. Appl. Pharmacol., 10, 160

    Tobin, R. B. et al. (1975) Federation Proc., 34, 2171

    Veech, R. L., Harris, R. L. & Mehlman, M. A. (1974) Toxicol. Appl.
         Pharmacol., 29, 196

    Young, J. W. (1975) Federation Proc., 34, 2177
    


    See Also:
       Toxicological Abbreviations