Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 107-92-6 Toxicity Effects

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Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • Butyric acid
  • BUTANOIC ACID

Human Toxicity Excerpts

  • SIGNS AND SYMPTOMS: Butyric acid can act as a mild skin irritant in humans ... Application to intact human skin elicits a moderate burning sensation only after 52 min, and erythema is hardly noticeable. Slight epidermal scaling may follow within 24 hr. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:710]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: No sensitization reaction, measured as a change in leukcocyte or eosinophil infiltration, was elicited in human volunteers injected subcutaneously with butyric acid for 2 wk. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:709]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: INHALATION: Sore throat. Cough. Burning sensation. Shortness of breath. Laboured breathing. Symptoms may be delayed. SKIN: Pain. redness. Blisters. Skin burns. EYES: Pain. Redness. Severe deep burns. Loss of vision. INGESTION: Burning sensation. Abdominal pain. Shock or collapse. /from table/ [IPCS, CEC; International Chemical Safety Card on Butyric acid. (November 1998). Available fromhttp://www.inchem.org/documents/icsc/icsc/eics1334.htm as of April 13, 2006. ]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Acute Exposure: After a 90 min exposure to a butyric acid aerosol (40 mg/L), rabbits displayed increased lethargy and dyspnea. Signs of bronchial and capillary dilation and emphysema were evident upon necropsy. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:708]
  • LABORATORY ANIMALS: Acute Exposure: ... No lethalities /were reported/ when rats were exposed for 8 hr to air saturated with butyric acid vapor. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:708]
  • LABORATORY ANIMALS: Acute Exposure: The role of the autonomic innervation in the control of pancreatic endocrine responses to iv infusions of butyrate was investigated in conscious 4-6 month old weaned lambs. IV butyrate produced a small rise in mean arterial plasma pancreatic glucagon concentration which was unlikely to have had any physiological effect and produced no consistent or statistically significant changes in mean plasma pancreatic polypeptide concentration in any of the groups studied. In contrast, butyrate produced an abrupt and substantial rise in mean plasma insulin concentration which rose to a peak incremental value of about 300 pico mol/L in normal control. [Bloom SR, Edwards AV; J Physiol 364: 281-8 (1985) ]
  • LABORATORY ANIMALS: Acute Exposure: ... HbF induction in response to butyrate was dependent on the dose and duration of treatment. Doses of butyrate less than 4 g/kg/d were associated with minimal toxicity (hypokalemia) and significant HbF induction in these nonanemic animals, with 1 g/kg/d producing an increase in HbF-containing reticulocytes (F reticulocytes) from 0.9% to 8.7% and an increase in HbF from 0.8% to 1.4%. A dose of 2 g/kg/d resulted in an increase in F reticulocytes from 2.1% to 27.8% and an increase in HbF from 0.7% to 2.2%. Doses of 4 g/kg/d in another animal produced an increase in F reticulocytes from 1% to 21.6% and in HbF from 1.9% to 5.3%. ... Prolonged infusions of high doses of butyrate (8 to 10 g/kg/d) were associated with peak F reticulocyte percentages reaching 38% to 64.5% and HbF reaching levels in excess of 20%. [Blau CA et al; Blood 81 (2): 529-37 (1993) ] PubMed Abstract
  • LABORATORY ANIMALS: Acute Exposure: ... butyric acid inhibited the TPA-induced mouse skin ODC activity. The effect was dependent on the dose and duration of the butyric acid application. [Gupta KP, Mehrotra NK; Carcinogenesis 8 (11): 1667-70 (1987) ] PubMed Abstract
  • LABORATORY ANIMALS: Acute Exposure: Severe corneal burns were produced in rabbits by an excess of a 5% aqueous solution of butyric acid (unspecified volume). [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:708]
  • LABORATORY ANIMALS: Acute Exposure: Large intravenous doses of butyric acid (sodium salt) caused temporary CNS depression in rabbits (1.6 g/kg) and dogs (0.86 g/kg); similar effects were reported after subcutaneous administration of the acid to cats. /Butyric acid (sodium salt)/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:708]
  • LABORATORY ANIMALS: Acute Exposure: Intravenous application of butyrate (continuous infusion 2.5 mL/min.0.02 mM/kg/min for 10 min) produced an abrupt and substantial rise in mean plasma insulin concentration in lambs. Simultaneous administration but not pretreatment with phentolamine (priming dose 0.2 mg/kg, 10 min later iv infusion of 0.04 mg/kg/min) and propanolol (single iv injection of 0.25 mg/kg) reduced this response as it was either pretreatment with atropine (single iv injection of 0.2 mg/kg 10 min prior to butyrate dosing) or section of the splanchnic nerves. It is concluded, that mediating the release of insulin from the pancreas in response to butyrate in lambs involves adrenoreceptors and muscarine receptors and the full response depends on both sympathetic and parasympathetic influences. [European Chemicals Bureau; IUCLID Dataset, Butyric acid (107-92-6) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of April 20, 2006. ]
  • LABORATORY ANIMALS: Acute Exposure: Butyric acid rated 9 on rabbit eyes./ ... Tested externally on eyes ... and have been rated numerically on a scale of 1-10 according to degree of injury observed after 24 hours, paying particular attention to condition of cornea. Most severe injuries have been rated 10./ [Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 1139]
  • LABORATORY ANIMALS: Acute Exposure: ... It is a moderately strong skin and eye irritant in the guinea pig. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:708]
  • LABORATORY ANIMALS: Acute Exposure: In the closed, rabbit skin patch irritation test, 10 mg butyric acid produced a severe reaction in 24 hr, but in the open test, 500 mg elicited only a moderate response. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:708]
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ... rats, mice and hamsters were fed diet containing 4% propionic or butyric acid for 7 days. Evidence of damage and cellular proliferation in the epithelium of the forestomach and limiting ridge was detected in all three species. [Harrison PT et al; Food Chem Toxicol 29 96): 367-71 (1991) ] PubMed Abstract
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Eleven cows in late lactation were exposed to butyric acid for three weeks. ... Decline in milk yield was clinically recorded in response to butyric acid, while muscle tremor and diarrhea resulted additionally from sodium butyrate. [Dabbagh MN et al; Arch Exp Veterinarmed 44 (6): 819-29 (1990) ] PubMed Abstract
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Male and female rats, mice, and hamsters fed a diet containing 4% butyric acid for 7 days showed evidence of damage and cellular proliferation in the epithelium of the forestomach. These effects were particularly marked in rats. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:709]
  • OTHER TERRESTRIAL SPECIES: ... Topical application of BA immediately after each treatment with 12-0-tetradecanoylphorbol-13-acetate (TPA) promoter-inhibited skin tumors. The effect was dependent on the dose of BA applied. BA showed no marked inhibitory effect on either skin tumor initiation or complete tumorigenesis induced by dimethylbenzanthracene (DMBA). [Gupta KP, Mehrotra NK; Biomed Environ Sci 10 94): 436-41 (1997) ] PubMed Abstract
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Rats (number not specified) fed diets containing butyric acid at concentrations of 25% for up to 35 weeks barely maintained their weights, and histology on 4 rats revealed papillomatosis and hyperkeratosis of gastric tissues. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:709]
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Sprague-Dawley rats were administered butyric acid in corn oil by gavage on gestation days 6 to 15 at dose levels of 100 or 133 mg/kg/day. The dams were allowed to deliver, and their litters were examined through postnatal day 6. Maternal mortalities were high (20 and 47% for the 100- and 133-mg/kg/day groups, respectively), and maternal body weight gain was markedly depressed. Rales and dyspnea were reported for most treated animals. No evidence of effects on progeny were reported. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:709]
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In a frog embryo teratogenesis assay, /investigators/ found that butyric acid caused malformations in 50% of surviving offspring at a concentration of 400 mg/L. Malformations included microcephaly, eye defects, edema, and gut defects. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:710]
  • LABORATORY ANIMALS: Neurotoxicity: The effect of butyrate on cortical blood flow and EEG was studied in cats by iv injections of 1mM/kg. Butyric acid leads to an increased cortical blood flow (up to 100%) in spite of constant blood pressure (reduction of cortical vascular resistance). At the same time slow waves and spindles developed in the EEG. The /investigators concluded that butyric acid blocked the general activating influence of the reticular system upon the cortex. [European Chemicals Bureau; IUCLID Dataset, Butyric acid (107-92-6) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of April 20, 2006. ]
  • GENOTOXICITY: Butyric acid did not induce mutations at concentrations up to 10 mg/plate in an Ames Salmonella typhimurium test with strains TA 92, TA 94, TA 98, TA 100, or TA 1535, and TA 1537 with or without a liver homogenate from rats pretreated with the polychlorinated biphenyl KC-400. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:710]
  • GENOTOXICITY: No clastogenic effects were seen in Chinese hamster fibroblast cells at concentrations up to 1 mg/mL. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:710]
  • OTHER TOXICITY INFORMATION: Prolonged exposure (of unspecified duration) of mice, rats, and rabbits to an atmospheric concentration of 0.1 to 0.2 mg/L butyric acid caused a massive increase in circulating lymphocytes and neutrophils, attributed to the irritant nature of the cmpd. /Chronic and subchronic toxicity/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:709]
  • OTHER TOXICITY INFORMATION: In cattle following a single rapid iv injection of a sodium anion solution, butyrate was toxic at doses above 1 mmole/kg and progressively affected both the rate and progress of bromosulfophthalein clearance as the dose increased. The butyrate effects were accentuated when the anion soln was injected at low pH where a large portion of the /compound/ would be unionized. Levels of butyrate in the rumens of feedlot cattle were high enough to provide toxic doses of these anions. [Bide BW; Can J Comp Med 47 (2): 222-29 (1983) ]
  • OTHER TOXICITY INFORMATION: In ewes, continuous infusion of butyrate decreased ruminal epithelial cell proliferation and caused a thickening of the stratum corneum. Daily short-term infusions produced stimulation of ruminal epithelial cell proliferation. Histological examination revealed parakeratotic changes in the stratum corneum. [Galfi P et al; Zentralbl Veterinaermed, Reihe A 33 (1): 47-52 (1986) ]
  • OTHER TOXICITY INFORMATION: Butyric acid was added to the normal diet of 5 day old chickens at 15 mM/L; the stimulating effect on keratinization was not restricted to ruminal epithelium, but also occurred in the crop. [Galfi P et al; Zentralbl Veterinaermed, Reihe A 32 (2): 146-50 (1985) ]
  • OTHER TOXICITY INFORMATION: The effects of various concentrations of butyrate were examined on a normal embryonic lung fibroblast cell line and its 2 transformed counterparts, a simian virus 40-transformed line and a cell line transformed by gamma-irradiation. The rate of thymidine incorporation into DNA was inhibited by 60-80% in the WI-38 cells, even at butyrate concentrations as low as 5 mM. The two transformed cell lines showed no inhibition of DNA synthesis, even at 75 mM butyrate. Analysis of RNA and protein synthesis revealed that the former was inhibited by + or - 20% at 5-10 mM butyrate in the normal WI-38 cell line, while protein synthesis was not inhibited at these concentrations. The inhibition of RNA synthesis was not dose dependent up to butyrate concentrations of 20 mM, and protein synthesis was inhibited <15% at this concentration. None of these inhibitory effects was observed in the case of the SVWI-38 or CT-1 cell lines. [De Haan JB et al; Cancer Res 46 (2): 713-6 (1986) ]
  • OTHER TOXICITY INFORMATION: Values of the single-hit, multitarget survival curve parameters for non-sodium butyrate-treated clone A cells were n= 17.1, DO(Gy)= 0.81, and DQ(Gy)= 2.31; corresponding parameters for sodium butyrate-treated cells were 1.04, 1.16, and 0.05. For non-sodium butyrate-treated clone D cells, the survival parameters were n= 4.27, DO= 1.05, and DQ= 1.52; corresponding parameters for sodium butyrate-treated cells were 1.19, 1.15, and 0.20. The data indicates that sodium butyrate-induced cell maturation is accompanied by increase in radiation cell kill, particularly in the low-dose region of the survival curve. [Arundel CM; Radiat Res 104 (3): 443-48 (1985) ]
  • OTHER TOXICITY INFORMATION: Small doses of butyric acid have no effect on the cardiovascular system, whereas large doses impair cardiac function and depress blood pressure. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:708]
  • OTHER TOXICITY INFORMATION: The similarity between the effects associated with butyric acid toxicity and the clinical symptoms of diabetic coma suggests that ketone bodies, beta-hydroxybutyrate and acetoacetate, may be responsible for these effects. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:708]
  • OTHER TOXICITY INFORMATION: Short-chain fatty acids, including butyric acid, are metabolic products produced by colonic bacteria and when instilled intrarectally in mice, induce a diffuse colitis. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:709]
  • ALTERNATIVE IN VITRO TESTS: Butyrate induced a marked reduction in the growth rate, colony forming efficiency in soft agar and de novo synthesis of DNA as well as remarkable morphological changes including cell enlargement, flattening, and a decreased number of nucleoli. Secretion of alpha-fetoprotein was reduced during culture with butyrate, while that of albumin was increased. [Nakagawa T et al; Br J Cancer 51 (3): 357-63 (1985) ]
  • ALTERNATIVE IN VITRO TESTS: The effects of butyrate on cellular morphology features and polyamine levels were examined in vitro in glioma F-98 cells. Following exposure to butyrate, the glioma appeared more differentiated and had more characteristics of normal glial cells, such as processes extension, lower nucleocytoplasmic ratio, contact inhibition, and monolayer growth. Butyrate increased glioma intracellular putrescine and spermine levels and decreased spermidine level. [Lin LI, Lin JK; Taiwan I Hsueh Hui Tsa Chih 84 (5): 536-45 (1985) ]
  • ALTERNATIVE IN VITRO TESTS: Treatment of B16-F10 melanoma cells with butyric acid inhibited cell growth and delayed tumor appearance in syngeneic mice. Butyric acid, did not increase melanin content and decreased tyrosinase activity. [Nordenberg J et al; Exp Cell Res 162 (1): 77-85 (1986) ]
  • ALTERNATIVE IN VITRO TESTS: The most effective inducer was butyrate, which caused an essentially linear increase in alkaline phosphatase activity in the concentration range of 2 to 10 mM. Butyrate and related short-chain fatty acids also suppressed 9-1C cell growth. Butyrate appeared to be unique among the various fatty acids in causing an increase in cell protein. Butyrate caused 9-1C cells, which normally grow in a disorganized array with no apparent affinity for each other, to spread out and become organized into parallel tracts through the monolayer. [Reese DH et al; Cancer Res 45 (5): 2308-13 (1985) ]
  • ALTERNATIVE IN VITRO TESTS: Treated murine lymphosarcoma cells were incubated with different amounts of the polyanion heparin, which is known to interact predominantly with chromatin-associated histones. Unlike isolated histone H1, histone H1 in the nuclei of butyrate-treated cells displayed an enhanced affinity for the binding to heparin as compared to histone H1 from control cells. [Stros M, Siroky J; Gen Physiol Biophys 4 (4): 375-81 (1985) ]
  • ALTERNATIVE IN VITRO TESTS: To understand corneal wound healing, in which fibronectin plays an important role, the regulatory mechanism of fibronectin synthesis was studied in cultured rabbit corneal blocks in situ. The amount of fibronectin was detected by ELISA. Butyric acid stimulated fibronectin synthesis in a dose-response fashion, and had a greater stimulatory effect than did any of its derivitives examined. This suggests that butyrate stimulates fibronectin synthesis specifically. Additivity of stimulation by butyrate and by 8-bromo-cAMP was observed at the saturated concentration of each, indicating an independent mechanism of action for these two compounds. [Tanaka H, Nishida T; J Cell Physiol 123 (2): 191-6 (1985) ]
  • ALTERNATIVE IN VITRO TESTS: ... BA-mediated DNA fragmentation and Bax induction were preceded by early stimulation of JNK, and the DNA-binding activities of AP1 and NF-kappaB. BA-induced enhancement of DNA fragmentation and stimulation of Bax promoter activity were blocked by the expression of dominant-negative mutants of JNK1 or AP1 but not NF-kappaB. [Mandal M et al; Gastroenterology 120 (1): 71-8 (2001) ] PubMed Abstract
  • ALTERNATIVE IN VITRO TESTS: ... Untreated P-29 cells formed few nodules while butyric-acid treated cells formed many, the number being duration and dose dependent. ... Treatment with butyric-acid caused them to become flattened but polygonal. Butyric-acid treatment also induced marked increases in plasminogen activator secretion and in total cellular cathepsin-B and cathepsin-L activity. Slight increases in heterotypic adhesion and resistance to trypsin mediated detachment were also observed after butyric-acid treatment. Butyric-acid was more effective than DMSO in enhancing the ability to aggregate homotypically. Treatment with butyric-acid increased markedly the amounts of histones in H4-2, H4-3, and H4-4 with concomitant decreases in H4-0 and H4-1. Alteration in the sub species of histones H3 and H2B was also observed. [Takenaga K; Cancer Res 46 (3): 1244-1249 (1986) ]
  • ALTERNATIVE IN VITRO TESTS: Exposure of HeLa cells to sodium butyrate caused an increase in choleragen (cholera toxin) receptors as measured by increased binding of 125I-choleragen to the intact cells. Maximal increases (over 40-fold) were observed at 48 h and 5 mM sodium butyrate. [Fishman PH, Atikkan EE; J Biol Chem 254 (11): 4342-4 (1979) ] PubMed Abstract
  • ALTERNATIVE IN VITRO TESTS: When tested on isolated cornea, butyric acid esterified with nontoxic salts (i.e., butyrate salts) at a pH between 2 and 6.5 caused slight to moderate loosening of the stratum corneum. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:708]
  • ALTERNATIVE IN VITRO TESTS: Two subpopulations of human colon tumor cells (clones A and D) which differ in their intrinsic sensitivity to X irradiation were grown for several passages in tissue culture medium containing the differentiation-inducing agent sodium butyrate (NaB, 2 mM). Values of the single-hit, multitarget survival curve parameters for non-NaB-treated clone A cells were n = 17.1, D0(Gy) = 0.81, and DQ(Gy) = 2.31; corresponding parameters for NaB-treated cells were 1.04, 1.16, and 0.05. For non-NaB-treated clone D cells, the survival parameters were n = 4.27, D0 = 1.05, and DQ = 1.52; corresponding parameters for NaB-treated cells were 1.19, 1.15, and 0.20. The large reduction in the DQ parameters of both clone A and D cells after NaB treatment indicates that sodium butyrate-induced cell maturation is accompanied by increase in radiation cell kill, particularly in the low-dose region of the survival curve. [Arundel CM; Radiat Res 104 (3): 443-48 (1985) ] PubMed Abstract
  • ALTERNATIVE IN VITRO TESTS: Butyrate reduced by 60 to 80% the rate of thymidine incorporation into DNA by normal embryonic lung fibroblast cells at concentrations as low as 5 mM. /Butyrate/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:710]
  • ALTERNATIVE IN VITRO TESTS: Concentration of 0.1 to 0.5 mM sodium butyrate had a marked inhibitory effect on clonogenicity in soft agar of 1 mouse (B16F-10) and 2 human (SKMEL-28, 6/84) melanoma cell lines without effecting cell viability. The antiproliferative effect of sodium butyrate is accompanied by phenotypic alterations that include morphological and biochemical changes. Sodium butyrate treatment markedly enhanced the activity of the plasma membrane bound enzyme gamma-glutamyltranspeptidase, implicated to participate in amino acid transport, in all 3 cell lines. The treated cells acquired a well-developed rough endoplasmic reticulum and accumulated fat droplets. Also NADPH cytochrome c reductase, a marker enzyme of the endoplasmic reticulum was markedly enhanced. It is suggested that the phenotypic alterations induced by sodium butyrate may serve as markers for the action of this agent on melanoma cells and other tumors. /Sodium Butyrate/ [European Chemicals Bureau; IUCLID Dataset, Butyric acid (107-92-6) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of April 20, 2006. ]
  • ALTERNATIVE IN VITRO TESTS: Cultured HeLa cells were incubated with 5mM sodium butyrate. The treatment caused cessation of growth, morphological differentiation and concomitant increase in lysosomal enzyme activity. The ultrastructure of treated cells seemed more organized, with the occurrence of and extensive internal membranous system including the rough and smooth surface endoplasmic reticulum as well as the appearance of a distinct Gologi apparatus. These ultrastructural results indicate that the inhibition of growth by butyrate is not a toxic process that caused ultrastructral damage to the cell. The lysosomal enzyme increase and cessation of growth were revisable by treating the cells with a butyrate-free media. The histochemical studies showed that a number of lysosomal like structures increased with butyrate treatment and these structures were more randomly distributed throughout the cytoplasm in the treated cells as opposed to the peripheral arrangement in untreated HeLa cells. The results suggest that butyrate treatment may be preventing sublethal autolysis arresting the leakage of the lysosome into the cytosol and thus allowing the cells to chemically and morphologically differentiate. /Sodium Butyrate/ [European Chemicals Bureau; IUCLID Dataset, Butyric acid (107-92-6) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of April 20, 2006. ]
  • ALTERNATIVE IN VITRO TESTS: Exposure of Rat glioma C6 cell line to butyric acid increased levels of L-triiodothyronine (T3) in the nuclear and extranuclear compartment. The increase in nuclear binding was not merely a reflection of the higher cellular hormone content, and the analysis of the T3 binding to isolated nuclei revealed that butyric acid increased receptor number without changing affinity. The effect on the receptor was quantitatively important: a 48 hr incubation with 2 nM butyric acid increased nuclear binding by 2 to 3 fold, and 5 mM butyrate by 35-fold. Butyric acid increased receptor levels by decreasing receptor degradation, since the apparent half-life of receptor disappearance increased by 3-fold in cells incubated with 2 mM butyric acid for 48 hr. Butyric acid had little effect in increasing the level of multiacetylated forms of H3 and H4 histones when studied in acid-urea gels, but it markedly inhibited the turnover of (3H)-acetate from the histone fraction. There was striking similarity in the dose response of butyric acid for increasing receptor levels and inhibiting histone deacetylation. [European Chemicals Bureau; IUCLID Dataset, Butyric acid (107-92-6) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of April 20, 2006. ]

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Rat oral 8.79 g/kg [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 268]**PEER REVIEWED**
  • LD50 Mouse iv 800 mg/kg /From table/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:695]**PEER REVIEWED**
  • LD50 Mouse ip 3180 mg/kg /From table/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:695]**PEER REVIEWED**
  • LD50 Mouse sc 3180 mg/kg /From table/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:695]**PEER REVIEWED**
  • LD50 Rat oral 2940 mg/kg /From table/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:695]**PEER REVIEWED**
  • LD50 Rat oral 2000 mg/kg /From table/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:695]**PEER REVIEWED**
  • LD50 Rabbit skin 6083 mg/kg /From table/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:695]**PEER REVIEWED**
  • LD50 Rabbit skin 530 mg/kg /From table/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:695]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • Butyric acid is readily absorbed from the gastrointestinal tract ... [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:709]**PEER REVIEWED**
  • A pharmacokinetics study was performed by injecting butyric acid as sodium or arginine salts for possible antitumor therapies. In the case of 1-(14)C-labelled butyrate, the appearance of radioactivity in the blood of injected mice is rapid and some of it is maintained for relatively long periods in different organs, mainly the liver. However, no precision can be given about the structure of radioactive compounds in blood and tissues. Using GLC, the metabolism of butyrate in both animals and man were studied. In mice and rabbits, the half-life is less than 5 min. In man, the butyric acid elimination curve can be divided into two parts corresponding to two half-lives: for the first (0.5 min), the slope suggests an accelerated excretion, while for the following (13.7 min), a slow plateau is observed. The rapid elimination of butyrate is a limiting factor for practical applications. However, the lack of toxicity supports its use in human therapy. [Daniel P et al; Clin Chim Acta 181 (3): 255-63 (1989)]**PEER REVIEWED**

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Metabolism/Metabolites

  • Butyric acid is ... rapidly metabolized by the liver. In rats a considerable portion ... is metabolized to acetic acid. Butyric acid metabolism gives rise to ketone bodies (beta-hydroxybutyrate, acetoacetate, acetone) and acetic acid, which may be excreted in the urine or incorporated into normal processes of fat metabolism. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:709]**PEER REVIEWED**
  • The metabolism of carboxyl-labeled butyric acid by liver tissue was investigated in vitro. It was shown that the test substance was converted to ketone bodies mainly by fission into 2-carbon chains with subsequent recombination, and to a lesser extent by direct beta-oxidation. [European Chemicals Bureau; IUCLID Dataset, Butyric acid (107-92-6) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of April 20, 2006. ]**PEER REVIEWED**
  • In isolated animal tissues butyric acid was oxidized to acetoacetic and beta-hydroxybutyric acid. The formation of carbohydrate and complete oxidation were also reported. Besides the formation of beta-hydroxybutyric acid the formation of ketone bodies represents possibly an alternative path after oxidation at the beta-carbon atom of butyric acid. [European Chemicals Bureau; IUCLID Dataset, Butyric acid (107-92-6) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of April 20, 2006. ]**PEER REVIEWED**
  • ... Following butyraldehyde intake ... it is oxidized by aldehyde dehydrogenase, largely in the liver but also in other tissues. Butyric acid undergoes further oxidation via the Krebs cycle, or it may be conjugated with glutathione. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:978]**PEER REVIEWED**

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TSCA Test Submissions

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.

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Web page last updated on May 14, 2008