Chemically, niacin is one of the simplest vitamins, having the empirical formula C6H3O2N (Illus. 13-1). Nicotinic acid and nicotinamide correspond to 3-pyridine carboxylic acid and its amide, respectively. There are antivitamins or antagonists for niacin. These compounds have the basic pyridine structure; two of the important antagonists of nicotinic acid are 3-acetyl pyridine and pyridine sulfonic acid. Nicotinic acid and nicotinamide (niacinamide) generally possess the same activity, although one report with lactating cows suggested that the nicotinamide form has slightly higher activity (Jaster and Ward, 1990). Nicotinic acid is converted to the amide form in the tissues, and Erickson et al. (1991) suggests this occurs in the rumen. Nicotinamide functions as a component of two coenzymes: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).
Both nicotinic acid and nicotinamide are white, odorless, crystalline solids soluble in water and alcohol. They are very resistant to heat, air, light and alkali and thus are stable in feeds. Niacin is also stable in the presence of the usual oxidizing agents. However, it will undergo decarboxylation at a high temperature when in an alkaline medium. An important source of niacin for ruminants is ruminal synthesis. Synthesis of niacin in the rumen has been demonstrated in sheep (Rérat et al., 1959), cattle (Hungate, 1966) and goats (Porter, 1961). This synthesis also has been suggested to be under metabolic control; e.g., more is synthesized when small amounts are provided in the ration and vice versa (Porter, 1961; Abdouli and Schaefer, 1986).
Nicotinic acid and its amide are readily and very efficiently absorbed by diffusion at either physiological or pharmacologic doses. The mechanism by which nicotinamide nucleotides present in animal feeds are absorbed, however, is unknown. Whether the coenzyme is hydrolyzed in the lumen or after it is taken up by the mucosa is unclear.
In animals, absorption from the small intestine seems to be the major route by which niacin is made available to the host. Although direct absorption from the rumen is possible, normally it is thought to be limited because only a small portion (3% to 7%) of the vitamin is in the supernatant fraction of rumen fluid; most is bound within the microbes themselves (Rérat et al., 1959).
Niacin in foods occurs mostly in its coenzyme forms, which are hydrolyzed during digestion, yielding nicotinamide, which seems to be absorbed as such without further hydrolysis in the gastrointestinal tract. The intestinal mucosa is rich in niacin conversion enzymes such as NAD glycohydrolase (Henderson and Gross, 1979). Nicotinamide is released from NAD in the liver and intestines by glycohydrolases for transport to tissues that synthesize NAD as needed. In the gut mucosa, nicotinic acid is converted to nicotinamide (Stein et al., 1994). Nicotinamide is the primary circulating form of the vitamin and is converted into its coenzyme forms in the tissues. Blood transport of niacin is associated mainly with red blood cells. Niacin rapidly leaves the blood stream and enters the kidney, liver and adipose tissues.
The tissue content of niacin and its analogs, NAD and NADP, is a variable factor, dependent on the diet and a number of other factors, such as strain, sex, age and treatment of animals (Hankes, 1984). Although niacin coenzymes are widely distributed in the body, no true storage occurs. The liver is the site of greatest niacin concentration in the body, but the amount stored is minimal.
Urine is the primary pathway of excretion of absorbed niacin and its metabolites. The principal excretory products in humans, dogs, rats, and pigs is the methylated metabolite N1-methylnicotinamide or as two oxidation products of this compound, 4-pyridone or 6-pyridone of N1-methylnicotinamide. On the other hand, in herbivores, niacin does not seem to be metabolized by methylation, but large amounts are excreted unchanged. In the chicken, however, nicotinic acid is conjugated with ornithine as either alpha- or delta-nicotinyl ornithine or dinicotinyl ornithine. The measurement of the excretion of these metabolites is carried out in studies of niacin requirements and niacin metabolism.
The amino acid tryptophan is a precursor for the synthesis of niacin in the body. There is considerable evidence that synthesis can occur in the intestine (Löffler and Petrides, 2003). There is also evidence that synthesis can take place elsewhere within the body. The extent to which the metabolic requirement for niacin can be met from tryptophan depends first on the amount of tryptophan in the diet and second on the efficiency of conversion of tryptophan to niacin (McDowell, 2000). The pathway of tryptophan conversion to nicotinic acid mononucleotide in the body is shown in Figure 13-1. Protein, energy, vitamin B6 and riboflavin nutritional status and hormones affect one or more steps in the conversion sequence shown in Figure 13-1, and hence can influence the yield of niacin from tryptophan. Iron is required by two enzymes for the conversion of tryptophan to niacin with a deficiency reducing tryptophan utilization. At low levels of tryptophan intake, conversion efficiency is high. It decreases when niacin and tryptophan levels in the diet are increased.
Animal species differ widely in ability to synthesize niacin from tryptophan, but all are relatively inefficient. From a variety of experiments, approximately 60 mg tryptophan is estimated to be equivalent to 1 mg niacin in humans, while the rat is more efficient at a conversion rate of 35 to 50 mg tryptophan required. Conversion efficiency of tryptophan to niacin in the chick is estimated to be 45:1 (Baker et al., 1973; Chen and Austic, 1989) and relatively efficient, whereas in the turkey it is inefficient, with conversions ranging from 103:1 to 119:1 (Ruiz and Harms, 1990). Ruminants would be less efficient in this conversion than most species. Conversion efficiency is probably due to inherent differences in liver levels of picolinic acid carboxylase, the enzyme that diverts one of the intermediates (2-amino, 3-acroleylfumaric acid) to the picolinic acid pathway instead of allowing this compound to condense to quinolinic acid, the immediate precursor of nicotinic acid. Picolinic acid carboxylase activity in livers of various species has a positive correlation to experimentally determined niacin requirements. The rat diverts very little of its dietary tryptophan to carbon dioxide and water, and thus is relatively efficient in converting tryptophan to niacin. Picolinic acid carboxylase activity of various species is presented in Table 13-1. The cat has been shown to have 30 to 50 times as much picolinic acid carboxylase activity as the rat. Thus, the cat has so much of this enzyme that it cannot convert any of its dietary tryptophan to niacin. The cat, therefore, has an absolute requirement for niacin itself. The duck has a very high niacin requirement (approximately twice as high as chickens), with considerably higher levels of picolinic acid carboxylase activity (Scott et al., 1982).
The major function of niacin is in the coenzyme forms of nicotinamide, NAD and NADP. Enzymes containing NAD and NADP are important links in a series of reactions associated with carbohydrate, protein and lipid metabolism. They are especially important in the metabolic reactions that furnish energy to the animal. The coenzymes act as an intermediate in most of the H+ transfers in metabolism, including more than 200 reactions in the metabolism of carbohydrates, fatty acids and amino acids. These reactions are of paramount importance for normal tissue integrity, particularly for the skin, the gastrointestinal tract and the nervous system. Like the riboflavin coenzymes, the NAD- and NADP-containing enzyme systems play an important role in biological oxidation-reduction systems due to their capacity to serve as hydrogen-transfer agents. Hydrogen is effectively transferred from the oxidizable substrate to oxygen through a series of graded enzymatic hydrogen transfers. Nicotinamide-containing enzyme systems constitute one such group of hydrogen transfer agents. Important metabolic reactions catalyzed by NAD and NADP are summarized as follows (McDowell, 2000; Kirkland, 2007):
a. Carbohydrate metabolism:
b. Lipid metabolism:
c. Protein metabolism:
e. Rhodopsin synthesis
Niacin, riboflavin and co-enzyme Q10 are associated with poly (ADP-ribose) which is involved in the post-translational modification of nuclear proteins. The poly ADP-ribosylated proteins seem to function in DNA repair, DNA replication and cell differentiation (Carson et al., 1987; Premkumar et al., 2008). Poly (ADP-ribose) is synthesized in response to DNA strand breaks. Rat data have shown that even a mild niacin deficiency decreases liver poly (ADP-ribose) concentrations and that poly (ADP-ribose) levels are also altered by food restriction (Rawling et al., 1994). Zhang et al., (1993) suggest that a severe niacin deficiency may increase the susceptibility of DNA to oxidative damage, likely due to the lower availability of NAD. Turnover rates of protein in Japanese quail have been related to niacin deficiency; a high turnover rate due to the deficiency was primarily attributed to an enhanced degradation rate of protein rather than an enhanced synthesis rate of proteins (Park et al., 1991).
Niacin-dependent poly (ADP-ribose) is involved in the post-translational modification of nuclear proteins. For ruminants, niacin is particularly required for unique features involving protein and energy metabolism, including liver detoxification of portal blood NH3 to urea and liver metabolism of ketones in ketosis. It is apparent that niacin can increase microbial protein synthesis (Girard, 1998). This may result in an increased molar proportion of propionate in rumen volatile fatty acids and may cause an increased rate of flow of material through the rumen. The function of primary interest for lactating dairy cows deals with the role of niacin in fatty acid oxidation and glucose synthesis, particularly as a preventive and possible treatment for clinical and subclinical ketosis.
There is a wide variation in the response of ruminant livestock to supplemental niacin, in part due to variations in: (1) endogenous niacin synthesis from tryptophan; (2) niacin supply and bioavailability in common feedstuffs; and (3) rumen niacin synthesis and degradation. Young, pre-ruminant calves and lambs would be expected to have a dietary requirement for niacin. However, early studies with lambs and calves failed to produce a deficiency by feeding niacin-free diets. The development of a low-tryptophan milk diet enabled researchers to study the situation more clearly. From these studies, it was concluded that a dietary niacin requirement does not exist as long as dietary tryptophan is maintained near 0.2% of dry matter (Hopper and Johnson, 1955). In the absence of dietary tryptophan, 2.5 mg per liter of milk offered ad libitum was required to prevent deficiency symptoms. The minimum niacin level suggested for calf milk replacers is 2.6 mg per kg (1.2 mg per lb) (NRC, 1989). Niacin supplementation of milk replacer would be of more concern when alternative, non-milk protein sources are used as the primary protein source in milk replacer, due to low tryptophan content.
The supply of niacin to the ruminant comes from three main sources: (1) dietary niacin; (2) conversion of tryptophan to niacin; and (3) ruminal synthesis of niacin. Niacin is widely distributed in feedstuffs of both plant and animal origin. Animal and fish by-products, distiller’s grains and yeast, various distillation and fermentation solubles and certain oilseed meals are good sources. The niacin in cereal grains and their by-products is in a bound form, which is largely unavailable, at least to monogastric animals (Luce et al., 1966, 1967). By use of a rat bioassay procedure, it was shown that in eight samples of mature cooked cereals (corn, wheat, rice and milo), only about 35% of the total niacin was available (Carter and Carpenter, 1982). It seems likely that much of this niacin will also be unavailable to rumen microorganisms.
In the calculation of the niacin content of formulated diets, probably all niacin from cereal grain sources should be ignored or at least given a value no greater than one-third of the total niacin. Some bound forms of niacin are biologically available, but the niacin in corn is particularly unavailable and is implicated in the etiology of pellagra in human societies that consume large quantities of the grain. The bioavailability of niacin is 100% in soybean meal but zero in wheat and sorghum and varies from 0 to 30% in corn (McDowell and Ward, 2008).
In immature seeds, niacin occurs as part of biologically available coenzymes necessary for seed metabolism. Binding of niacin to carbohydrate by ester linkages may cause it to be retained in the mature seed until it is utilized; the vitamin availability for man and animal is thus impaired. In rat growth assays for available niacin, corn harvested immaturely (“milk stage”) gave values from 74 to 88 µg per gm, whereas corn harvested at maturity gave assay values of 16 to 18 µg per gm (Carpenter et al., 1988).
Due to conversion of the essential amino acid tryptophan to niacin, the niacin and tryptophan content of the diet are often considered together in expressing niacin values of feeds (the “niacin equivalent”). However, tryptophan is preferably used for protein synthesis (Kodicek et al., 1974), and ruminant feedstuffs tend to be low in tryptophan. Furthermore, the efficiency of the biochemical conversion of tryptophan to niacin in cattle is less than in the pig and chicken (Scott et al., 1982).
There is little doubt that synthesis of niacin can occur in the rumen (Mathison, 1982), but the extent to which it occurs, particularly with commercial feedstuffs, and its contribution to the niacin supply are controversial. Niacin is often present in higher concentrations in rumen dry matter than in the diet, and this has been interpreted as evidence of net synthesis in the rumen (Hollis et al., 1954). Nevertheless, the positive response of ruminants to supplemental niacin in some studies indicated that niacin supply is sometimes sub-optimal.
Niacin is commercially available in two forms, niacinamide and nicotinic acid, with both forms providing about the same biological activity. Positive response to supplementation has been noted with either source. Campbell et al., (1994) noted only minor differences in metabolism of nicotinic acid and niacinamide in dairy cows.
In the pre-ruminant calf, a diet free of niacin and low in tryptophan produced deficiency signs of sudden anorexia, severe diarrhea, ataxia and dehydration, followed by sudden death. Supplementation with 2.5 mg of nicotinic acid per liter of milk, offered ad libitum twice daily, prevented the deficiency (Hopper and Johnson, 1955). On this basis, the daily niacin requirement for calves from all sources would be 10 to 15 mg per day. Niacin may increase microbial protein synthesis, however several studies indicate no effects. Differences between these studies, all of which utilized in vitrosystems, may reflect the amount and availability of niacin in the unsupplemented diet, the niacin status of the microbes, or both (NRC, 2001).
Responses to supplemental niacin in feedlot cattle have been variable. The addition of niacin to beef cattle diets has been shown to significantly improve average daily gain and feed efficiency. Feeder calves responded positively in rate and efficiency of gain in the 29-day adaptation study, gaining an additional 8.3 kg (18.3 lb) with 70 ppm of supplemental niacin (Byers, 1979).
Byers (1979; 1981) summarized 14 beef cattle studies in which niacin supplementation increased gains and feed efficiency by 9.7% and 10.9%, respectively. Niacin supplementation during adaptation of cattle to feedlot diets was beneficial for growth in all studies. Table 13-2 shows the effects of niacin supplementation on gains and feed efficiency of feedlot cattle. Sixteen of the 18 reports showed improved gains and feed efficiency resulting from niacin supplementation.
The large response during the feedlot adaptation phase indicates that supplemental niacin assists in overcoming shipping stress and allows for a more rapid adjustment to feedlot conditions and changing diets, probably because rumen niacin synthesis is reduced by feed deprivation and diet change.
A number of studies have been conducted on the effects of supplemental niacin in dairy cows. The effect of niacin on milk production and composition has been variable (Table 13-3). Under some conditions, supplemental niacin at 6 to 12 g per cow per day has had a beneficial effect on milk production in early lactation and when fed to ketotic cows.
Up to 50% of dairy cows in high-production herds go through borderline ketosis during early lactation (Emery et al., 1964). The concentration of 3-hydroxybutyrate in serum was reduced from 1.24 to 0.74 mmol per liter after five days, when 10 g of niacin was fed to ketotic cows (Flachowsky et al., 1988a). Fronk and Schultz (1979) indicated that supplementing ketotic dairy cows with 12 gm doses of nicotinic acid daily had a beneficial effect on the reversal of both subclinical and clinical ketosis. More recent studies indicate that 6 gm of niacin may be sufficient. Endogenous synthesis of niacin is decreased by ketones and increased by corticosteriods, leading to the hypothesis that part of the beneficial effect of adrenal corticoids on ketosis is derived from increased niacin synthesis. This suggests that niacin may be a useful adjunct to glucocorticoid therapy for ketosis. Supplemental niacin has been reported to increase plasma insulin and glucose response to beta- agonists (Chilliard and Ottou, 1995). Insulin resistance in periparturient ruminants serves to prioritize glucogenic nutrients for vital functions, fetal growth, and lactose production and to enhance mobilization of fatty acids and glycerol from adipose tissue (Bell and Bauman, 1997).
However, exaggerated insulin resistance in adipose tissue can potentially lead to further increases in plasma non-esterified fatty acid (NEFA) concentrations and to the onset of metabolic disorders. Increased plasma NEFA concentration has been associated with insulin resistance in Holstein cows. Reduction of plasma NEFA concentration by nicotinic acid was found to enhance the response to insulin in feed-restricted Holstein cows (Pires et al., 2007). Impaired insulin signaling due to elevated NEFA may affect an array of cell functions in different tissues, with important repercussions on the physiology and productivity of the periparturient dairy cow. Erickson et al. (1990) reported a trend for reduced lipolysis (area under curve for NEFA) in response to epinephrine challenge in cows fed 12 g per day of either nicotinic acid or nicotinamide. Skaar et al. (1989) did not find any effect of niacin on hepatic lipidosis during the periparturient period in dairy cows.
Milk yield was increased after niacin supplementation in some studies, while it was without influence in other trials (Niehoff et al., 2009). The absence of a niacin effect may be explained in that cows were too far into lactation and thus not in a negative energy balance (Ottou et al., 1995). Girard (1998) summarized effects of supplemental niacin on milk production in dairy cows. Some of the individual studies and recent results are discussed below. Many of the more recent studies have tested the possible interaction of feeding niacin with or without supplemental fats.
Daily supplementation of 3 to 6 gm of niacin to early lactation dairy cows resulted in slight increases in milk production. In a study involving six dairy herds, Jaster et al. (1983) found that milk production of niacin-supplemented cows peaked earlier, and milk production of high-producing cows in first lactation was greater when they received supplemental niacin. In these herds there was only a slight increase in milk fat percentage. French et al. (2011) reported that feeding nicotinamide during the close-up period reduced early lactation culling and increased fat-corrected milk yield.
Muller et al. (1986) and Bartlett et al. (1983) both reported that supplemental niacin increased milk yield of cows in early lactation in commercial dairy herds. Muller et al. (1986) noted a 4% increase in milk production over the entire lactation in response to feeding 6 gm of niacin per day.
Horner et al. (1986) reported that feeding whole cottonseed and most other dietary fat sources to dairy cows results in a reduction of milk protein percentage and protein yield. Diets supplemented with niacin (6 gm niacin per 20.45 kg of dry matter) increased milk protein percentage in diets with 15% whole cottonseed. The authors concluded that milk protein depression with whole cottonseed was alleviated by niacin because of stimulation of mammary casein synthesis. A subsequent study reported that supplemental niacin increased milk production by 3% with no effect on dry matter intake (Horner et al., 1988). In another study, there was no beneficial effect of niacin on milk casein synthesis for cows fed whole cottonseed, which may have been due to their late stage of lactation (Lanham et al., 1992). Driver et al. (1990) suggest that feeding niacin to cows receiving heat-treated soybeans corrected a dietary oil-induced milk protein depression. Erickson et al. (1992) reported that feeding cows 12 gm of niacin daily increased milk protein yield and reduced plasma ketones.
More recently, Cervantes et al. (1996), using cows in mid-lactation, found that feeding 12 gm of nicotinamide daily increased milk and milk protein production, decreased milk fat percentage and had no effect on blood glucose or beta-hydroxy butyrate. Madison-Anderson et al. (1997) tested effects of feeding 0 or 12 gm of nicotinic acid daily with or without supplemental fat from extruded soybeans. Milk yield was 3.3 kg per day higher for cows fed niacin, but the difference was not statistically significant. Niacin exerted some effects on fatty acid composition of milk, increasing the proportion of unsaturated and long-chain fatty acids. Milk oleic acid concentration was increased by duodenal infusion of 6 gm of nicotinic acid daily with no other effects on milk yield or composition (Wagner et al., 1997). Minor et al. (1998) tested effects of supplementary niacin (0 or 12 gm per day) fed with either high or moderate levels of nonstructural carbohydrate in the ration, starting 19 days prepartum and continuing through week 40 of lactation. Niacin had no significant effects on production parameters or blood metabolites. In contrast, Drackley et al. (1998), using similar rations with or without supplemental fat (whole soybeans and animal fat), and supplementing either 0 or 12 gm of nicotinic acid daily for weeks four through 43 of lactation, reported increased milk production (6.2% to 7.2%), lower milk casein concentration and a trend toward higher milk protein yield in cows fed niacin.
The variation in response to supplemental niacin in dairy cows is difficult to explain. Interactions of niacin and dietary fat are predicted based on metabolism but have not been observed, although niacin has increased milk yield in diets containing supplemental fat. Tryptophan status of animals may be involved in some of the milk production responses if supplemental niacin is able to spare tryptophan for use by the mammary gland. Horner et al. (1986) reported a trend for elevated plasma levels of free tryptophan in niacin-supplemented cows. Others have noted an apparent effect of niacin in decreasing plasma calcium and increasing plasma phosphorus concentration (Dufva et al., 1983). This has led to speculation that marginal dietary calcium levels may limit the response to supplementary niacin (Harmeyer and Kollenkirchen, 1989). In addition, there are the variable effects of niacin on rumen metabolism and the variations in rumen niacin synthesis and degradation to consider. Girard (1998) concludes that because of its role in energy metabolism, niacin is likely of most value when fed during early lacatation, when body lipid stores are mobilized and when nutrient deficits are most likely to occur. Retrospective analysis of some trial data has led to the theory that cows in heavier body condition, and therefore cows that will mobilize more body fat after calving, are more responsive to supplementary niacin than cows in thin condition. Overall the research results suggest that niacin be considered as a supplemental nutrient at 6 to 12 gm per day in high-producing cows during early lactation, particularly with higher fat diets (>6% fat).
Encapsulated niacin was administered to lactating Holstein cows to study the vitamin’s affect on heat stress (Zimbelman et al., 2007). Cows receiving niacin had increased dry matter intake. Between 11:00AM and 4:00PM average sweating rate for the niacin group was higher than the control (81.1 vs. 68.2 g/M2/hour in shaved areas and 70.6 vs. 62.3 gm/M2/hour in the unshaved area). Vaginal temperatures recorded at 15 minute intervals and averaged over the last 72 hours were lower (38.4 vs. 38.0°C) for cows given niacin compared to control cows. It was concluded that cows given encapsulated niacin, had higher sweating rates and lower core temperatures during acute thermal stress.
Mizwicki et al. (1975) observed that 500 ppm of supplemental niacin improved feed efficiency of lambs fed a high-concentrate diet containing urea. Subsequent studies using 100 ppm niacin fed to growing and finishing lambs showed increased performance (Table 13-4), with evidence that niacin stimulates rumen microbial protein synthesis (Shields et al., 1982). These studies indicate that supplemental niacin: (1) increased nitrogen utilization; (2) improved the percentage of absorbed nitrogen retained; (3) reduced urinary nitrogen excretion; and (4) reduced the percentage of nitrogen found as urea nitrogen. All of these positive responses indicate improved protein metabolism with high-concentrate diets.
Much of the niacin in common feeds (plant sources) is bound in a form that is not readily digestible by animals. Although the bioavailability of niacin is 100% in soybean meal, it is 0 in wheat and sorghum and varies from 0 to 30% in corn. In calculating the niacin content of formulated diets, probably all niacin from cereal grain sources should be ignored or at least given a value no greater than one-third of the total niacin content. Tryptophan, the immediate precursor of niacin in animals, is particularly low in corn. Soybeans and soybean meal and cottonseed meal contain moderate levels (0.5%), while fish meal and blood meal are highest in tryptophan, although these products normally make up only a small portion of the ration. Addition of niacin to a milk replacer is recommended based on lack of synthesis in the pre-ruminant animal. The suggested level is 9 to 18 mg per calf per day (Roche, 1997).
As discussed in the previous section there have been positive responses of cattle and sheep to supplementary niacin. Supplementation appears to be of greatest benefit to stressed animals, such as beef cattle entering the feedlot, feedlot cattle and lambs and dairy cows immediately postpartum, particularly if symptoms of ketosis are present. Recommended supplemental niacin levels are 1 to 2 gm per day for beef receiving cattle or feedlot cattle, 100 to 500 ppm in the diet of feedlot lambs and 3 to 12 gm per day for dairy cattle.
Niacin may be beneficial in the acclimation to non-protein nitrogen (urea) in feedlot rations. However, the stimulation of microbial protein production by niacin was greatest when natural protein rather than non-protein nitrogen was fed (Brent and Bartley, 1984). Kung et al. (1980) reported no interaction between supplemental niacin and protein sources of either soybean meal or urea in lactating dairy cows.
Research has shown some beneficial effects of niacin in preventing or treating ketosis and possibly fat-cow syndrome. For individual cows with positive urinary ketone tests, a level of 12 gm per day is recommended. When used as a general dietary supplementation, a level of 6 gm of niacin per day is suggested, starting two weeks before calving.
Commercially produced niacin is quite stable compared to most other vitamins. Synthetic niacin and niacinamide were stable in premixes with or without minerals for three months (Verbeeck, 1975). Gadient (1986) reports that niacin is stable to heat, oxygen, moisture and light. The retention of niacin activity in pelleted feeds after three months at room temperature and dry storage conditions should be 95% to 100%. Niacin stability is reduced by the presence of trace minerals and choline.
Niacin has a wide margin of safety. Toxic effects of nicotinic acid occur only at levels far in excess of requirements. Limited research indicates that nicotinic acid and nicotinamide are toxic at dietary intakes greater than about 350 mg per kg (160 mg per lb) of body weight per day (NRC, 1987). The intravenious LD50 of niacin in mice is 2.5 gm per kg (1.1 g per lb) of body weight. The oral LD50 and subcutaneous LD50 in mice are 4.5 and 2.8 gm per kg (2.0 and 1.3 gm per lb), respectively. Nicotinamide is two- to three-times more toxic than the free acid (Waterman, 1978). The nicotinic acid and niacinamide tolerance for ruminants has not been determined.
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