Preservative Chemicals

Thompson D, Moldeus P, Biochem Pharmacol 1988 Jun 1;37(11):2201-7
"...Using isolated rat liver mitochondria we observed that both BHA and BHT inhibited respiratory control primarily by stimulating state 4 respiration and thus acting as membrane uncouplers. BHA and BHT also effectively dissipated membrane potential across the mitochondrial membrane and caused the release of calcium and mitochondrial swelling. These mitochondrial effects were reflected by a rapid decrease in ATP levels in intact hepatocytes which preceded cell death...."
Takami M, Preston SL, Toyloy VA, Behrman HR., The American Journal of Physiology 1999 Apr;276(4 Pt 1):E684-8
Reproductive Biology Section. . . Yale University School of Medicine
" We previously showed that the cell-permeant antioxidant 2(3)-tert-butyl-4-hydroxyanisole (BHA) inhibited germinal vesicle breakdown (GVBD) in oocyte (egg)-cumulus complexes (OCC) of the rat. . . . Spontaneous GVBD in OCC incubated for 2 h was significantly inhibited . . .by . . . NDGA . . . BHA . . . octyl gallate . . . ethoxyquin . . . . . . BHT . . . Antioxidants that had no effect on oocyte maturation at the same concentration . . . included ascorbic acid, vitamin E, and Trolox. . . . Oocyte maturation was induced by incubation of follicles for 3 h with human chorionic gonadotropin (hCG), and this response was inhibited by BHA or NDGA. These findings support the conclusion that cell-permeant antioxidants inhibit spontaneous resumption of meiosis (special cell division for eggs or sperms), which may implicate a role of oxygen radicals in oocyte maturation"
However, BHA induces in animals tumours of the forestomach, which are dose dependent, wherease BHT induces liver tumours in long-term experiments.
Zoccarato F, Pandolfo M, Deana R, Alexandre A, Biochem Biophys Res Commun 1987 Jul 31;146(2):603-10
"...While the Ca2+ uptake observed under non depolarizing conditions is not affected by these agents, the depolarization induced Ca2+ uptake is strongly inhibited. ..."
Stokes JD, Scudder CL, Dev Psychobiol 1974 Jul;7(4):343-50
"The chronic ingestion of .5% butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) by pregnant mice and their offspring resulted in a variety of behavioral changes. Compared to controls, BHA-treated offspring showed increased exploration, decreased sleeping, decreased self-grooming, slower learning, and a decreased orientation reflex. BHT-treated offspring showed decreased sleeping, increased social and isolation-induced aggression, and a severe deficit in learning." Cited here.
Stolze K, Nohl H., Free Radical Research 1999 Apr;30(4):295-303
" . . . tBHQ significantly increased the amount of high molecular weight degradation products of erythrocyte membrane constituents. These changes were only observed when incubations were performed in the presence of oxygen. . . These observations can be interpreted in terms of metabolic activation of the antioxidant BHA via tBHQ . . . thereby leading to harmful effects on erythrocyte (red blood cell) membrane structures. Moreover, deleterious effects on other biological membranes are also likely to occur. "
Vorhees CV, Butcher RE, Brunner RL, Wootten V, Sobotka TJ, Neurobehav Toxicol Teratol 1981 Fall;3(3):321-9
"Comparison of the present results to a similar study using BHT clearly indicates that BHA at equivalent dietary doses is considerably less toxic than BHT. The present results also suggest that BHA is not a potent behavioral toxin, although it is developmentally toxic using non-behavioral measures."
Sarafian TA, Kouyoumjian S, Tashkin D, Roth MD, Toxicol Lett 2002 Jul 21;133(2-3):171-9
" ... BHA alone, at concentrations of 10-200 microM, produced limited cell toxicity but significantly enhanced the necrotic death resulting from concurrent exposure to THC. ... The combination was synergistic in this respect, reducing ATP levels to <15%>
Tryphonas H, Lacroix F, Lok E, Jee P, Clayson DB, Hayward S, Miller D, Mehta R, Food Chem Toxicol 1999 Jul;37(7):671-81
"...The induction of EAF and/or 0.5% BHT treatment resulted in a significant reduction in the natural killer (NK) cell activity of splenocytes...."
Osmundsen PE, Contact Dermatitis 1980 Dec;6(7):452-4
"...In one of the patients contact with plastic articles also provoked urticaria. A 20-min patch test with several articles of plastic (polyethylene and PVC) and with butylhydroxytoluene (BHT) 1% in ethanol elicited urticarial reactions. BHT is used as an antioxidant in plastic..."
Siman CM, Eriksson UJ, Toxicol Lett 1996 Oct;87(2-3):103-8
"The results show that BHT has adverse effects in the liver. BHT is metabolized by the cytochrome P450 system in the liver and may be converted to prooxidative compounds during this process. "
McFarlane M, et al., Food Chem Toxicol 1997 Aug;35(8):753-67
"...Dams [mother rats] receiving BHT at a nominal dose of 500 mg/kg body weight/day showed liver enlargement accompained by induction of pentoxyresorufin O-depentylase and glutathione S-transferase, and proliferation of the endoplasmic reticulum. Pups from these dams were of the same weight at birth as controls but lost weight during the lactation period. This deficit was not recovered by the time the experiment was terminated. ..."
Umemura T, Kodama Y, Hioki K, Nomura T, Nishikawa A, Hirose M, Kurokawa Y. Jpn J Cancer Res. 2002 Aug;93(8):861-6.
" We have demonstrated the utility of a 9-week in vivo two-stage assay for lung cancer initiating agents, using transgenic mice ...and butylhydroxytoluene (BHT) as a potent lung promoter .... Additionally, use of BHT was validated for promotion of urethane (UR) carcinogenesis in male and female rasH2 mice.... In a dose-response study, effects were dose-dependent, the dose of 400 mg/kg causing eight-fold elevation as compared to the control.... "
Malkinson, AM, Crisp Data Base National Institutes Of Health 1999
"...The food additive, butylated hydroxytoluene (BHT), encourages the development of tumors from previously initiated cells. ...Chronic administration of BHT to inbred mice down-regulates the pulmonary concentrations of the alpha isozyme of protein kinase C (PKCa) and calpain in promotion-sensitive strains ... " The researchers are searching for the gene responsible.
Kovaleva ES, Prilipko LL, Muranov KO, Kagan VE, Biull Eksp Biol Med 1983 Oct;96(10):55-7
"..All free radical scavengers used inhibited 3T-hydroxytryptamine uptake and stimulated 3H-hydroxytryptamine release, with the efficacy being reduced in the following order: 7-hydroxyaminazine greater than butylated hydroxytoluene greater than paginol-2-methyl-6-ethyl-3-hydroxypyridine greater than alpha-tocopherol..."
Tanaka T, Oishi S, Takahashi O. Toxicology Letters 1993 Mar;66(3):295-304
" Butylated hydroxytoluene (BHT) was administered to mice, . . . in the diet at levels of 0 (control), 0.015, 0.045, 0.135, and 0.405%, . . . .The body weight of the pups of the 0.015% BHT group was increased at birth and during the lactation period for each generation. . . In the neurobehavioural parameters, a few parameters were increased in treatment groups; i.e., surface righting . . . and negative geotaxis . . . "
Meyer O, Hansen E, Toxicology 1980;16(3):247-58
"...The applied dose of BHT [500 mg/kg to rats] exerted a significant adverse effect on body weight in both F0 and F1-animals and on several developmental parameters in F1-animals. The effects arose during the lactation period."
Safer AM, al-Nughamish AJ, Histol Histopathol 1999 Apr;14(2):391-406
"BHT resulted in a significant increase in liver weight. The liver cells presented gradual vacuolization, cytoplasmic disintegration, "moth-eaten" appearance, ballooning degeneration, hepatocellular necrosis, aggregation of chromatin material around the periphery of the nuclear envelope, SER proliferation, RER clumping with broken cisternae, withered and autolyzed mitochondria, augmentation of lipid droplets and glycogen depletion. "
Ohno Y, Takuma T, Asahi K, Isono K, FEBS Lett 1984 Jan 9;165(2):277-9
"Butylated hydroxytoluene (BHT) ... has been found to induce the differentiation of murine erythroleukemia cells. BHT also amplifies the differentiation inducing activity of DMSO."
Faine LA, Rodrigues HG, Galhardi CM, Ebaid GM, Diniz YS, Fernandes AA, Novelli EL. Exp Toxicol Pathol. 2006 Jan;57(3):221-6. Epub 2005 Dec 9
"The heart of BHT animals showed alteration of antioxidant defenses and increased concentrations of lipid hydroperoxides, indicating elevated lipoperoxidation. TG concentrations and lactate dehydrogenase activities were elevated in the cardiac muscle of BHT animals. Thus, long-term administration of BHT is capable to induce oxidative and metabolic alterations similarly to some pathological disorders, constituting an efficient experimental model to health scientific research."

Blaszczyk A, Toxicol Lett. 2006 May 5;163(1):77-83. Epub 2005 Nov 2
"This compound was recently found to cause not only many unfavourable side-effects in animals fed with feeds containing it, but also adverse effects in people exposed to it at work. "
Blaszczyk A, Skolimowski J. Acta Pol Pharm. 2005 Mar-Apr;62(2):111-5
"It was shown that EQ induced apoptosis in cultured human lymphocytes, especially at 0.25 and 0.5 mM concentrations."
Blaszczyk A, Osiecka R, Skolimowski J. Mutat Res. 2003 Dec 9;542(1-2):117-28.
"The results of the chromosome aberration assay showed that EQ induces chromosome aberrations: gaps and breaks as well as dicentrics and atypical translocation chromosomes."
"However, after recently completing a scientific review of a voluntarily-submitted study from the Monsanto company, CVM has reason to believe that the 150 ppm level may not provide an adequate margin of safety in lactating female dogs and possibly puppies. The results from this study show that ethoxyquin levels above the current tolerance in dog foods produced no adverse reproductive effects. There was, however, an increase in a dark, reddish-brown pigment in the liver of female dogs immediately after completing a 6-week lactation. The liver pigment was identified as protoporphyrin IX, a normal intermediate in the synthesis of heme. This pigment was also associated with elevations in liver-related enzymes in the serum of a few animals. "
MSDS Sheet:
"May be harmful by ingestion, inhalation and through skin contact."
"Ethoxyquin was originally developed as a rubber stabilizer. The Monsanto corporation later refined it for use as a preservative in animal feeds. Most dog foods contained very little of the chemical. But in the late 1980s, many companies that were making high performance foods began adding extra ethoxyquin. The foods contain more fat than regular dog foods, and the companies found the chemical to be a cheaper, more effective way to extend the shelf-life of their product. Not long after, some breeders were finding their dogs were developing unusual disorders."

Propyl Gallate:
D. Muñoz, M. Audicana, G. Gastaminza and E. Fernández. Allergology and Clinical Immunology Service, “Santiago Apóstol” Hospital, Vitoria-Gasteiz, Spain Contact dermatitis due to gallates
"Gallates are antioxidant compounds that are used in the food, cosmetics and
drug industries. Even though they behave as powerful antigens in animal models,
only a rather limited number of cases of gallate-induced contact dermatitides
has been reported in humans. This phenomenon has been attributed to immunologic
tolerance through oral exposure, as described in experimental animal
Kraus AL, Stotts J, Altringer LA, Allgood GS, Procter and gamble Company, Cincinnati, Ohio 45241.
"The antioxidant propyl gallate, in a deodorant product, caused an allergic contact dermatitis in 1 subject during developmental controlled use testing. Subsequent dose response elicitation studies with this subject revealed a differing threshold of sensitivity to propyl gallate dependent upon application method."
Bojs G, Nicklasson B, Svensson A, Contact Dermatitis 1987 Nov;17(5):294-8
"The antioxidant propyl gallate in a moisturizing cream caused an allergic contact dermatitis in a patient previously sensitized to gallates while working in a bakery."
Hausen BM, Beyer W, Contact Dermatitis 1992 Apr;26(4):253-8
"A literature review revealed that the frequency of reports of allergic contact dermatitis from antioxidants of the gallate type has increased in the last 4 years. In most cases, the moderate sensitizer propyl gallate was the source of sensitization."

Sodium Benzoate: See Benzoic Acid toxicity under "Cranberries" above.

Peters MM, Rivera MI, Jones TW, Monks TJ, Lau SS.
" 3-tert-Butyl-4-hydroxyanisole and tert-butyl-hydroquinone (TBHQ) are antioxidants known to promote renal and bladder carcinogenesis [cancer] in the rat, although the mechanisms of these effects are unclear....Because some chemicals may induce carcinogenesis by a mechanism involving cytotoxicity followed by sustained regenerative hyperplasia, our results suggest that the toxicity of GSH conjugates of TBHQ to kidney and bladder may contribute to the promoting effect of 3-tert-butyl-4-hydroxyanisole and TBHQ in these tissues. "
Patrick E, Juberg DR, O'Donoghue J, Maibach HI. Food Chem Toxicol 1999 Feb-Mar;37(2-3):169-75
" tert-Butyl hydroquinone (TBHQ) has important and functional uses in consumer and commercial applications, some of which involve human exposure primarily through dermal (skin) contact. . . . . Repetitive exposure to concentrations of 1.0% and 5.0% TBHQ and HQ were slightly to moderately irritating, while 0.1% of each of these test materials produced only weak irritant responses. . . . this study showed that TBHQ causes depigmentation in black guinea pigs at concentrations of 1% or greater. . . "