Bisphenol A

Indirect Food Additives and Polymers: Migration and Toxicology 30mar00

BISPHENOL A
Molecular Formula. C₁5H₁₆O₂
M = 228.29
CAS No 80-05-7
RTECS No SL6300000
Abbreviation. BPA.

Synonyms. Bis(p-hydroxyphenyl)propane; Diane; 4,4'-Dihydroxydiphenylolpropane; 4,4'-Dimethylmethylenediphenol; Diphenylolpropane; 4,4'-Isopropylidenediphenol.

Properties. Grayish or colorless, crystalline powder. Water solubility is 0.04%. Readily soluble in alcohol, insoluble in oils. Odor perception threshold is 50 mg/l, taste perception threshold is 0.25 mg/l (astringent).¹ BPA forms chlorophenol odors (threshold concentration 0.01 mg/l).

Applications. Monomer in the production of numerous chemical products including polycarbonates and epoxy, phenolic, ethoxylene, ion-exchange resins, corrosion-resistant unsaturated polyester-styrene resins, reinforced pipes, food packaging materials and vulcanizates intended for use in contact with food or drink. A thermal stabilizer of polyvinyl chloride.

Migration of BPA to food from molded discs prepared from a composite of BPA-derived poly-carbonate resins was determined using food-simulating solvents and time and temperature conditions recommended by FDA. The study demonstrated that no detectable BPA was found in the extracts obtained under FDA's most severe default testing condition.

The potential dietary exposure to BPA from use of polycarbonate resins was determined to be less than 0.25 ppb.² Migration into water from epoxy coatings (exposure 7 days, 37°C) was 0.004 mg/l.³ Migration of BPA from baby feeding bottles made of polycarbonate was not detectable in infant feed using a very sensitive method of liquid chromatography with fluorescence detection with a 0.03 mg/kg detection limit.⁴

Acute Toxicity. Oral LD₅₀ values were reported to range from 4.24 to 12.0 g/kg BW in rats, and from 2.4 to 12 g/kg BW in mice. In rabbits and guinea pigs, LD₅₀ is 4.0 g/kg BW.¹ Alcohol enhances toxicity of BPA. Poisoning is characterized by a transient agitation followed by CNS inhibition and labored respiration, coordination disorder, and convulsions.⁵

Repeated Exposure failed to reveal cumulative properties. Two rats out of 10 died after oral exposure to 1.0 g/kg BW for 10 days. Histology examination revealed fatty dystrophy of the liver, parenchymatous dystrophy of the renal tubular epithelium, and irritation of the spleen pulp.⁵

Rats and rabbits were given a dose of 0.5 g BPA/kg BW for 2 months. The treatment led to a reduction in BW gain, and to an increase in the acid resistance of erythrocytes and in the content of oxidized glutathione. The level of free phenols in the urine was increased. Rabbits displayed erythropenia and elevated liver and spleen weights.^'

Short-term Toxicity. Male and female B6C3F₁ mice received BPA at dose levels of 0.2 to 4.0% in the diet for 13 weeks. It was concluded that the maximum tolerated dose (MTD) is 0.2% in diet, because the dose level of 0.5% proved to exert significant hematological toxicity.⁶

Long-term Toxicity. A 6-month study in rats and rabbits revealed signs of anemia. The treatment affected the NS, activity of SH-groups of tissue proteins, and detoxication system of the body.¹

Reproductive Toxicity.

Embryotoxicity. CD-l mice received 0.25 to l.0% BPA in the diet for 18 weeks. The treatment caused a decrease in mean number of litters per pair and in mean number of live pups per litter in 0.5% and 1.0% treated groups.⁷ Sprague-Dawley rats and CD-l mice were dosed by gastric intubation with 160 to 640 mg/kg and 500 to 1250 mg/kg BW, respectively, on days 6 to 15 of gestation. Higher doses produced fetal toxicity in mice, but not in rats and did not alter fetal morphological development in either species.⁸ Rats were treated s/c with 300 mg BPA/kg BW from postnatal day 1 to 5. All male and female rats showed normal reproductive function and no histopathologic abnormalities of reproductive organs. These results indicated that treatment with BPA at a fairly high dose was ineffective if given postnatally to male and female rats.⁹

Teratogenic effect is reported in rats, but not in mice. Administration of BPA to pregnant animals resulted in hydrocephaly and impaired ossification in the offspring.¹⁰

Gonadotoxicity. BPA has an estrogenic effect. The xenoestrogen BPA has been shown to mimic estrogen both in vivo and in vitro. Treatment of F344 rats with approximately 0.3 mg BPA/kg BW for 3 days resulted in hypertrophy, hyperplasia, and mucus secretion in the uterus and hyperplasia and cornification of the vaginal epithelium. Continuous exposure to mg levels of BPA is sufficient for exerting estrogenic actions.¹¹ Han-Wistar albino rats were exposed to drinking water that contained 0.01, 0.l, l.0, or 10 ppm BPA, 7 days per week, for a total of 10 weeks. No treatment-related effects on growth or reproductive endpoints were observed in adult females exposed to any concentration of BPA. Similarly, no treament-related effects were observed on the growth, survival, or reproductive parameters (including testes, prostate and preputial gland weights, sperm count, daily sperm production, or testes histopathology) of male offspring from dams exposed to BPA during gestation and lactation.¹² These results do not confirm the previous low-dose observations reported as preliminary results by Sharpe et al. ¹³

In vitro genotoxicity. BPA is reported to be negative in Salmonella mutagenicity bioassay and mouse lymphoma assay; it did not cause CA in cultured mammalian cells.0¹⁶, ⁰²⁵

For assessment of in vitro carcinogenicity and related activity of BPA, the abilities of this compound to induce cellular transformation and genetic effects were examined simultaneously using the Syrian hamster embryo (SHE) cell model. BPA showed marked cell-transforming and genotoxic activities in cultured mammalian cells and potential carcinogenic activity.¹⁴

Carcinogenicity. In a long-term carcinogenicity bioassay rats were given 1000 and 2000 ppm in their diet, mice were given 1000 or 5000 ppm (males) and 5000 or 10000 ppm (females). BPA did not appear to be carcinogenic, however, increased incidence of leukemia in male rats and lymphoma in male mice was associated with the test chemical.¹⁵

Carcinogenicity classification.
NTP: E - N - N - N (feed).

Chemobiokinetics. BPA metabolism occurs through partial conversion into phenols, increasing their urinary content in a free and bound form. BPA is passed from the body unaltered in the urine and feces in the form of glucuronides.¹⁶

Administration of a single or multiple dose of 200 mg BPA/kg BW to CD-l male rats produced two major and several minor adducts in the liver DNA. BPA is oxidized to BPA-o-quinone in the the presence of activation system. It is capable of binding covalently to DNA. One of the DNA-binding metabolites may be BPA-o-quinone. ¹⁷

EU (1990). BPA is available in the List of authorized monomers and other starting substances which shall be used for the manufacture of plastic materials and articles intended to come into contact with food-stuffs (Section A).

U.S. FDA (1998) approved the use of BPA in the manufacture of 4,4'-isopropylidenediphenolepichlorohydrin thermosetting epoxy resin (finished articles containing the resins shall be thoroughly cleansed prior to their use in contact with food) in accordance with the conditions specified in the 21 CFR part 177.1440.

Great Britain (1998). BPA is authorized without time limit for use in the production of polymeric materials and articles in contact with food or drink or intended for such contact. The specific migration of this substance shall not exceed 3.0 mg/kg.

EU (1990). SML: 3.0 mg/kg.

Russia (1995). MAC and PML: 0.01 mg/l (organolept., taste).

1. Fedyanina, V. N., Study of the Effect of Epichlorohydrin and Diphenylolpropane upon the Body, Author's abstract of thesis, Novosibirsk, 1970, 22 (in Russian).
2. Howe, S. R. and Borodinsky, L., Potential exposure to bisphenol A from food-contact use of polycarbonate resins, Food Addit. Contam., 15, 370, 1988.
3. Krat, A. V., Kesel'man, I. M., and Sheftel', V. O., Sanitary-chemical evaluation of polymeric articles in water-supply constructions, Gig. Sanit., 10, 18, 1986 (in Russian).
4. Mountfort, K. A, Kelly, J., Jickells, S. M., and Castle, L., Investigations into the potential de-gradation of polycarbonate baby bottles during sterilization with consequent release of bisphenol A, Food. Addit. Contam., 14, 737, 1997.
5. Stasenkova, K. P., Shumskaya, N. I., Greenberg, A. Ye., et al. Comparative evaluation of toxicity of bisphenol A and its derivatives, in Hygiene and Toxicology of High-Molecular-Mass Compounds and of the Chemical Raw Material Used in Their Synthesis, Proc. 4^th All-Union Conf., S. L. Danishevsky, Ed., Khimiya, Leningrad, 1969, 180 (in Russian).
6. Furukawa, F., Nishikawa, A., Mitsui, M., Sato, M., Suzuki, J., Imazawa, T., and Takahashi, M., A 13-week subchronic study of bisphenol A in B6C3F₁ mice, Abstract, Eisei Shikenjo Hokoku, 112, 89, 1994 (in Japanese).
7. Reel, J. R., George, J. D., Lawton, A. D., et al., Bisphenol A: Reproduction and Fertility Assessment in CD-I Mice when Administered in the Feed, Final study report, NTP/NIENS contract No ES-2-504, NTIS Accession N PB86103207, 1985.
8. Mor^rissey, R. E., George, J. D., Price, C. J., et al., The developmental toxicity of bisphenol A in rats and mice, Fundam. Appl. Toxicol., 8, 571, 1987.
9. Nagao, T., Saito, Y., Usumi, K ., Kuwagata, M., and Imai, K., Reproductive function in rats exposed neonatally to bisphenol A and estradiol benzoate, Reprod. Toxicol., 13, 303, 1999.
10. Bond, G. P. et al., Reproductive effects of bisphenol A, Toxicol. Appt Pharmacol., 23, 1980.
11. Steinmetz, R., Mitchner, N. A., Grant, A., Allen, D. L., Bigsby, R. M., and Ben-Jonathan, N., The xenoestrogen bisphenol A induces growth, differentiation, and c-fosgene expression in the female reproductive tract, Endocrinology, 139, 2741, 1998.
12. Cagen, S. Z., Waechter J. M., Jr, Dimond, S. S., Breslin, W. J., Butala, J. H., Jekat, F. W., Joiner, R. L., Shiotsuka, R. N., Veenstra, G. E., and Hams, L. R., Normal reproductive organ development in wistar rats exposed to bisphenol A in the drinking water, Regul. Toxicol. Pharmacol., 30, 130, 1999.
13. Sharpe, R. M., Majdic, G., Fisher, J., Parte, P., Millar, M., and Saunders, P. T. K., Effects on testicular development and function, 10th Int. Congress Endocrinol,, S23, 1996.
14. Tsutsui, T., Tamura, Y., Yagi, E., Hasegawa, K., Takahashi, M., Maizumi, N., Yamaguchi, F., and Barrett, J. C., Bisphenol A induces cellular transformation, aneuploidy and DNA adduct formation in cultured Syrian hamster embryo cells, Int. J. Cancer, 75, 290, 1998
15. Carcinogenesis Bioassay of Bisphenol A in F344 Rats and B6C3F₁ Mice (Feed Study), NTP Technical Report Series No 215, Litton Bionetics, Inc., 1982.
16. Knaak, J. and Sullivan, L., Metabolism of bisphenol A in the rat, Toxicol. Appt Pharmacol., 8, 175, 1966.
17. Atkinson, A. and Roy, D., In vivo DNA adduct formation by bisphenol A, Environ. Molec. Mutagen., 26, 60, 1995.