Formaldehyde: The Food and Drug Administration's Perspective

16 Formaldehyde: The Food and Drug Administration’s Perspective ROBERT J. S C H E U P L E I N

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Office of Toxicological Sciences, Bureau of Foods, Food and Drug Administration, Washington, D C 20204 Formaldehyde is used in mostly minor quantities of foods, drugs, and cosmetics. It has recently been found to be carcinogenic in rats when inhaled continuously at high doses (>2 ppm) for a lifetime. Formaldehyde has not been found to be carcinogenic in rodents when orally ingested at high doses (~5%) for a lifetime. A great deal of biological and chemical findings corroborate the view that the results from ingestion studies are more relevant to food use. Aside from the similarity in the route of administration, support for this view includes the short biological half-life of formaldehyde, the anomalous effects of locally high concentrations, and the highly curvilinear shape of the inhalation dose-response curve. On the basis of the data now available, the Food and Drug Administration does not believe that the very low levels that are used in food or cosmetics present a significant safety concern.

F O R M A L D E H Y D E is O N E O F T H E M O S T W I D E L Y USED of all synthetic chemi-

cals. In 1979 the U.S. production reported in terms of formalin (37% aqueous solution) was 2900 million kg, or over 12 kg for every person in the country. The Food and Drug Administration's (FDA) interest in formaldehyde's safety is derived from formaldehyde's use in foods, drugs, and cosmetics. Compared to its major uses in plastics, resin manufacture, and production of chemical intermediates, formaldehyde's direct use in foods, drugs, and cosmetics is very small. Following the announcement in January 1980 that the inhalation of formaldehyde apparently induced tumors in the nasal passages of rats, FDA took a good look at its inventory of approved uses of formaldehyde. On the basis of the exposure levels and the routes of administration, F D A concluded that no regulatory action against the use of formaldehyde in the products it regulates was necessary at that time to protect the public health (I). Since then the Chemical Industry Institute of Toxicology (CUT) study has been completed, published (2), and confirmed in a similar study conducted by Albert et al. (3). Formaldehyde is now generally recognized to This chapter not subject to U.S. copyright. Published 1985 American Chemical Society

In Formaldehyde; Turoski, V.; Advances in Chemistry; American Chemical Society: Washington, DC, 1985.

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FORMALDEHYDE: A N A L Y T I C A L CHEMISTRY A N D TOXICOLOGY

be carcinogenic in rats, or more accurately to rat nasal turbinates when inhaled at high-dose levels for 5 days per week for the lifetime of the animals. FDA's regulatory position on the safety of food, drug, and cosmetic uses of formaldehyde remains the same. In this chapter I will try to explain the toxicological basis of that position, but first I will give an overview of formaldehyde's major FDA-regulated uses.


Drags In human drug products, formaldehyde (HCHO) is used as a densensitizing agent in dentifrices at concentrations of 1.4 % and as a preservative at concentrations of 0.1 % or lower (4). It is also used in the manufacture of various vaccines to inactivate bacteria or viruses or to detoxify bacterial toxins. Depending on the intended use of the vaccines, the H C H O content may vary from less than 2 ppm to more than 100 ppm. Cosmetics (5) Perhaps formaldehyde's widest use, in terms of amount, is mainly as a preservative in shampoos and other hair products. H C H O is an excellent preservative against Gram-negative microorganisms, particularly Pseudomonas aeruginosa, a potentially pathogenic microorganism. According to voluntarily registered product formulation data, approximately 35% of the marketed cosmetic shampoos, 23% of bubble bath formulations, and 20% of hair rinses and hair conditioners contain H C H O as an antimicrobial preservative. The typical concentration of H C H O in preservative use is approximately 0.1%. Formaldehyde is a popular preservative, and attempts to replace it on a wide scale have not yet been successful. A few years ago a manufacturer replaced H C H O in his shampoo with paraben preservatives. Almost a half million bottles of shampoos were recalled because of contamination with Pseudomonas. The other effective preservatives against Gram-negative microorganisms are organic mercurials. However, the use of mercury compounds in cosmetics is limited by regulation to use as preservatives in eye-area cosmetics because they are absorbed through the skin on topical application and tend to accumulate in the body and are capable of causing neurotoxic effects. The agency's concern about the safety of H C H O and H C H O donors is threefold, namely, irritation, sensitization, and systemic effects. The carcinogenicity issue is subsumed in systemic effects. Skin irritation is of concern when H C H O is present in a product at relatively high concentrations, as, for example, in nail hardeners. F D A has not officially objected to its use in nail hardeners provided the product contains no more than 5 % H C H O , provides the user with nail shields that restrict application to the nail tip, furnishes adequate direction for safe use, and warns the user about the consequences of misuse and the potential for causing allergic reactions in already sensitized users. F D A does not endorse the use of formaldehyde for



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239

this purpose, but insufficient evidence is available to indicate that any sig nificant risk is present when used with care. FDA's concern about the possi ble harmfulness of H C H O as a skin sensitizer is directed more toward the elicitation of allergic reactions and less toward induction of allergenicity. When used as a preservative its concentration is usually too low and the exposure too short to induce sensitization; however, it may elicit a skin re action in some HCHO-sensitive consumers. Sensitivity to H C H O is not un common in the United States; it is ranked among the 10 most prominent skin contact sensitizers. Nonetheless, millions of people can use a H C H O preserved cosmetic without ever showing any sign of sensitization. Foods Formaldehyde is used in the food industry in several important ways but always under conditions that result in very small amounts of formaldehyde in food. It has never been a popular food additive in the United States prob ably because of its association with embalming and its strong odor. It has been cleared for use as a preservative in defoaming agents containing si methicone, in an amount not to exceed 1.0% of the simethicone content or 100 ppb in ready-to-eat food (6). It is also used as a component in adhesives intended for use in packaging food. In such use the adhesive is either sepa rated from the food by a functional barrier except for possibly at seams and edges which can contribute only trace amounts at most (J). Formaldehyde is used in the animal feed industry in ruminant feeds to improve the handling characteristics of animal fat in combination with certain oilseed meals. As formalin (37 % solution), it is added to the mixture at a level of 4% . This mixture on drying contains less than 1 % formalde hyde, and the feed is limited to contain less than 25 % of the mixture. Thus, animals may ingest as much as 0.25% formaldehyde in their diet (8). The animals appear to thrive on it, and no evidence indicates that tissue levels of formaldehyde are any higher in these animals than in animals that do not ingest added formaldehyde. The metabolic capacity of ruminant ani mals seems quite sufficient to catabolize even rather high levels of formal dehyde. Paraformaldehyde, which liberates formaldehyde when dissolved in water, is approved for controlling fungal growth in maple tree tapholes (9). It is used such that the maple syrup produced from the sap of treated maple trees does not contain more than 2 ppm of formaldehyde. A typical portion of syrup might then contain 50 μ g of formaldehyde. Hexamethylenetetramine (HMT), a complex of formaldehyde and ammonia that decomposes slowly to its constituents under acidic condi tions, has been used for many years as a food additive in the Scandinavian countries. It is used in fish products such as herring and caviar that are generally prepared by hand. H M T has the advantage of exerting a good antimicrobial effect without influencing the taste and odor. Its effect is due


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FORMALDEHYDE: A N A L Y T I C A L CHEMISTRY A N D TOXICOLOGY

to the gradual liberation of formaldehyde. It is permitted as a food additive in Norway at levels of 0.1-0.05%, corresponding to a daily ingestion of approximately 2.5 mg/day (10).


Discussion How do these ingested use levels of formaldehyde compare to established clinical or toxicological effect levels? The major adverse effects of formaldehyde and the corresponding doses are given in Table I. The first four entries show generally that human adverse effects of increasing severity occur as the dose increases to a vapor concentration greater than 30 ppb. In 1976 the National Institute of Occupational Safety and Health (NIOSH) recommended lowering industrial exposures to 1.0 ppm on the basis of formaldehyde's irritation potential. The last five entries are results from animal studies. By dividing the human oral lethal doses by human body weight, the animal and human oral L D values are reasonably comparable. The most sensitive animal adverse effects are teratogenic effects in 5 0

Table I. Summary of Toxicity Data on Formaldehyde

Concentration 30 ppb (vapor) ~ 1 . 2 ppm (vapor) 4-5 ppm (vapor) 50 ppm (vapor) ~ 30 ppm (aqueous) 1-100 g formalin, ingestion 0.8 g/kg 15 mg/kg, ingestion 0.15 mg/kg 500 mg/kg 14 ppm (vapor)

17.

Clinical Symptoms and Toxicological End Points no observed acute effects threshold of human response (irritation to nose, eyes) becoming intolerable, difficulty in breathing (humans) pulmonary edema, pneumonitis (humans) threshold of sensitization in sensitized human subject some human fatalities oral L D in rats no effect level, fetotoxicity in dogs estimated ADI in humans (17) no-effect level, long term feeding in rodents carcinogenic in rat nasal mucosa by inhalation 5 0

NOTE: Table is compiled from data in Refs. 2 , 3 , 1 1 , 13, 16, and



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dogs, and the fetoxic no-effect level is used as the basis for setting the Acceptable Daily Intake (ADI) for food use. The application of a 100-fold safety margin to this teratogenic no-effect level in dogs yields an ADI of 0.15 mg/kg or approximately 9 mg/day (11). Repeated subcutaneous injections on a weekly basis over IV2 to 2 years in rats produce local sarcomas at the site of injections (Table II) (12). Finally, the recent positive inhalation studies in rats indicate a highly nonlinear carcinogenic response that is detectable in 100 rats at 5.6 ppm and increases approximately cubically with increasing dose (2, 3, 13). Table III shows several oral studies that have been conducted on formaldehyde or H M T (14). H M T breaks down gradually to formaldehyde and N H under acidic conditions or in the presence of proteins, and is considered equivalent to formaldehyde for toxicological purposes. These longterm studies point to a dietary level of 5% H M T as causing no effect in rodents. On a weight percent basis a very similar no-effect level would be true for formaldehyde monomer (15). Collectively these studies indicate that formaldehyde may be potentially carcinogenic to humans when inhaled at high levels. Generally when faced with both positive and negative data obtained from equally well-conducted bioassays, F D A usually will elect to err on the side of prudence and regulate on the basis of the positive study or studies. Our food laws require that a substance be shown to be safe for its intended use (to a reasonable certainty), and when studies disagree and are of equal quality and significance, a reasonable question of safety can be said to remain. But in the case of formaldehyde as a food ingredient, ingestion studies, inhalation studies, and injection studies are not of comparable biological significance or relevance. Although production of local sarcomata occurs in rats at the site of repeated injections, and neoplastic lesions develop in the nasal passages and trachea of rats exposed to high vapor concentrations of formaldehyde, the probability of carcinogenic potential in food-additive use appears to be excluded on the basis of adequate ingestion studies. A great deal of biological and chemical findings corroborate the view that the ingestion studies are probably correct and more relevant to food use. First, aside from the similarity in route of administration between the animal ingestion studies and formaldehyde's use as a food additive, formaldehyde is highly reactive. It is very rapidly converted to formic acid upon ingestion and has a biological half-life of approximately 1 min in a variety of species (11). Thus, one might expect that if high local concentrations are persistently applied to tissue, then conversion kinetics to formate may be overwhelmed. This situation would result in the retention of formaldehyde and the consequences of high concentrations of a highly reactive, irritating, and toxic substance. The results of subcutaneous injection studies using formaldehyde, in addition to the usual difficulties with their interpretation 3



41-163 ppm formaldehyde 10 ppm formaldehyde 2.0-14.3 ppm formaldehyde

Mouse

Rat

Rat

Rat

Rat

Mouse

Rat

2.0-14.3 ppm formaldehyde 14.7 ppm formaldehyde, 10.6 ppm HC1 14.3 ppm formaldehyde, 10.0 ppm HC1 14.1 ppm formaldehyde, 9.5 ppm HC1 14.2 ppm formaldehyde

3% formalin

Rabbit

Hamster

subcutaneous subcutaneous

0.4% formalin 9-4% H M T

Rat Rat

inhalation

inhalation

inhalation

inhalation

inhalation

inhalation

inhalation

direct application to palate inhalation

Route

Compound

Species

588 days

588 days

588 days

lifetime

2.5 years

2.5 years

lifetime

35-70 weeks

15 months until tumor formation 10 months

Length of Study

10/100

6/100

12/100

2, 13, 16

103/200 at 14.3 ppm, 2/214 at 5.6 ppm 2/240 at 14.3 ppm 25/99

1

1

1

1

2, 13, 16

19

20

21

12 22

Ref.

negative

1/6 "carcinoma in situ" negative

2/10 7/20

Tumor Incidence

Table II. Formaldehyde Carcinogenicity Studies with Laboratory Animals


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Table III. Formaldehyde Carcinogenicity Oral Studies with Laboratory Animals Species


Rat Mouse Rat Rat Rat

Compound 0.4 g H M T 0.5-5.0% H M T 1.0-5.0% H M T 1.0% H M T 5.0% H M T

Length of Study

Ref.

333 days 110-30 weeks 156 weeks 3 generations 2 years

23 14 24 24 14

NOTE: Tumor incidence was negative in all studies.

and significance, would be particularly difficult to extrapolate to lower doses. In the nasal passages of the rat a similar effect may be enhanced by a concomitant inhibition of mucociliary function as has been reported to occur at concentrations greater than 2 ppm (16). Higher concentrations also are accompanied in the rat inhalation studies by greater cell proliferation in response to increased cytotoxicity. This result may offer increased opportunity for the formation of DNA-protein cross-links which appear to occur linearly at concentrations greater than 6 ppm in some studies (16). Furthermore, higher local concentrations may also inhibit DNA repair and could potentiate the effects of DNA damage caused by formaldehyde or other agents. Also no convincing evidence for systemic tumors (i.e., those that occur in parts of the body remote from the site of application) has been reported in animals exposed subcutaneously or by inhalation. Finally, formaldehyde at low concentrations is a normal biological intermediate that appears to be present in all biological tissues. Cells have developed specific enzymatic pathways for its removal. In the form of "active formaldehyde" (i.e., N ,N -methylenetetrahydrofolate) it is used in mammals in the biosynthesis of purines, thymine, methionine, and serine. Table IV shows the amount of formaldehyde that might be absorbed systemically each day by the average American adult. As can be seen from this table, the use of food additives containing the low levels of formaldehyde that I have described make very little contribution to the formaldehyde that we breathe, drink, or find naturally in ordinary food. 5

10

Conclusions For the reasons just discussed and on the basis of the data now available, F D A believes that the low levels of formaldehyde used in food or cosmetics do not present a significant safety issue. Perhaps the most important issue raised is a scientific one. Namely, significant distinctions in the various uses of a substance can have a crucial bearing upon the possible carcinogenic risk. The very purpose of the toxico-


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F O R M A L D E H Y D E : A N A L Y T I C A L CHEMISTRY A N D T O X I C O L O G Y

Table IV. Reported Human Exposures to Formaldehyde


Source Water Rain water Food Tomatoes Apples Cabbage Spinach Green onion Carrots Tobacco smoke 1 cigarette Air Outside, New Jersey (1977) Outside, Los Angeles (1980) Indoor, conventional Indoor, particle board

Amount Present 0.15 mg/kg

Daily Exposure Ref. 0.2 mg

25

varies varies varies varies varies varies

18 18 18 18 18 18

0.005 mg

1.0 mg

26

5 ppb 15 ppb 50 ppb 1000 ppb

0.03 mg 0.1 mg 0.3 mg 6.0 mg

27 28 29 29

0.6 mg/100 2.0 mg/100 0.5 mg/100 0.5 mg/100 2.0 mg/100 0.8 mg/100

g g g g g g

0

"These levels are higher than anticipated lifetime average doses because they have not been corrected for the intermittency of exposure.

logical art is to identify, refine, and predict the consequences of significant biological and chemical distinctions between such uses. As our chemical detection methods improve and more carcinogens at smaller levels are found in more places in the marketplace, in the workplace, and in our envi ronment, the need for more discriminating science will increase. It is im portant for everyone that regulatory agencies are supported by adequate funding for their research and by scientifically sophisticated policy direc tion that encourages the best possible science as a basis for regulatory decisions. Literature Cited 1. FDA Talk Paper "Formaldehyde" (T82-27), May 21, 1980 and (T82-40), June 17, 1982. 2. Pavkov, K. L.; Mitchell, R. I.; Donofrio, D. J.; Kerns, W. D . ; Connell, M . M.; Harroff, H . H.; Fisher, G . L.; Joiner, R. L.; Thake, D . C . "Final Report on Chronic Inhalation Toxicology Study in Rats and Mice Exposed to Formal dehyde," conducted by Battelle Columbus Laboratory for Chemical Indus try Institute of Toxicology, December 31, 1981. 3. Albert, R.; Sellakumar, Α.; Laskin, S.; Kuschner, M.; Nelson, N.; Synder, C . J. Natl. Cancer Inst. 1982, 68, 597-603. 4. Fed. Regist. 1980, 47 (101) 22753. 5. Eiermann, H. J., “The Safety of Formaldehyde as a Regulatory Issue,”pre sented on May 23, 1983, in Washington, D . C . 6. “Code of Federal Regulations,”Title 21, Part 173.340, 1982. 7. “Code of Federal Regulations,”Title 21, Parts 175.105 and 178.3120, 1982. 8. “Code of Federal Regulations,”Title 21, Part 573.460, 1982. 9. “Code of Federal Regulations,”Title 21, Part 193.330, 1982.



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10. Natuig,H.;Anderson, J.; Rasmusso, E . Wulff Food Cosmet. Toxicol. 1971, 9, 491-500. 11. WHO Food Addit. Ser. 1972 1, 17-18; also Hurni, H.; Ohder, H. Fd. Cisnet. Tixucik. 1973,11,459. 12. Watanabe, F . ; Matunaga, T.; Iwata, Y. Gann 1954, 45, 451. 13. Kerns, W . D.; Pavkov, K. L.; Donofrio, D . J.; Gralla, E . J.; Swenberg, J. A . Cancer Res. 1983, 43, 4382-92. 14. Dellaporta, G.; Colnaghi, M . J.; Parmiani, G . Food Cosmet. Toxicol. 1968, 6, 707-15. 15. Hollingsworth, R. S. “Summary on Formaldehyde,”Internal Division of Toxi cology memorandum F D A - B E , March 11, 1980. 16. Swenberg, J. Α.; Barrow, C . S.; Boreiko, C . J.; Heck, H. d’A.; Levine, R. J.; Morgan, K. T.; Starr, T. B. Carcinog. 1983, 4, 943-52. 17. WHO Food Addit. Ser. 1974, 5, 63-73. 18. IARC Monogr. Eval. Carcinog. Risk Chem. Man 1982, 358, 345. 19. Dalbey, W . E . “Toxicology in Review,”1981, OSHA Formaldehyde Docket H-225. 20. Horton, A. W . ; Type, R.; Stemmer, K. L. J. Natl. Cancer Inst. 1963, 30, 31-43. 21. Mueller, R.; Raabe, G.; Schumann, D . Exp. Pathol. 1978, 16, 36-42. 22. Watanabe, F . ; Sugimoto, S. Gann 1955, 46, 365-67. 23. Brendel, R. Arzneim. Forsch. 1964, 14, 51-53. 24. Dellaporta, G . ; Cabral, J. R.; Tarmiani, G . Tumori 1970, 56, 325. 25. Environmental Protection Agency “Investigation of Selected Potential Envi ronmental Contaminants: Formaldehyde”by Kitchens, J. F.; Casner, R. E . ; Edwards, G . S.; Harvard, W . Ε., III; Macri, B. J., Government Printing Office: Washington, 1976; pp. 5, 85-110, 126-32; EPA 560/2-76-009. 26. Mansfield, C . T.; Hodge, B. T.; Hege, R. B., Jr.; Hamlin, W . C . J. Chromatogr. Sci. 1977, 15, 301-2. 27. Cleveland, W . S.; Graedel, T. E.; Kleiner, B. Atmos. Environ. 1977,11,35760. 28. Environmental Protection Agency “Human Exposure to Formaldehyde,” Draft report (contract no. 68-01-5791) by Versar, Inc. for Office of Pesti cides and Toxic Substances, 1980, pp. 70-72, 103, 107. 29. Anderson, I.; Lundgrist, G . R.; Molhave, L . Atmos. Environ. 1975, 9, 1121-27. RECEIVED

for review October 16, 1984.

ACCEPTED

April 1, 1985.


Formaldehyde: The Food and Drug Administration's Perspective

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