Mercury Compounds in Drugs and Food (TXT)

April 28, 2002

CBER - Mercury Compounds in Drugs and Food

You will not believe this FDA report!

- http://www.fda.gov/cber/genadmin/merclst.htm -

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Mercury Compounds In Drugs And Food

Under section 413(a) of the Food and Drug Administration Modernization Act

of 1997 (FDAMA) (Pub. L. 105- 115), entitled “Food and Drug Administration

Study of Mercury Compounds in Drugs and Food,Ethe Food and Drug

Administration (FDA) is required to: (1) Compile a list of drugs and foods

that contain intentionally introduced mercury compounds, and (2) provide a

quantitative and qualitative analysis of the mercury compounds in this list.

The statute did not differentiate between mercury as an active or an

inactive ingredient.

In the FEDERAL REGISTERs of December 14, 1998 (63 FR 68775) and April

29,1999 (64 FR 23083), FDA published requests for data and information on

mercury compounds in drugs and food. The agency asked all manufacturers of

any food, including dietary supplements, and human and veterinary drug

products (prescription or over-the-counter (OTC)) containing any

intentionally introduced mercury compounds, whether used as an active or

inactive ingredient, to provide information about the products to the

agency. The agency requested the following information for each product: (1)

its commercial name, (2) the chemical name of the mercury compound present

in the product, the Chemical Abstract Service (CAS) registry (Reg.) Number

(No.) and the CAS preferred chemical name of the mercury compound(s), (3)

the quantitative amount present in the product, (4) the purpose of the

mercury compound in the product, (5) a copy of the product’s labeling, and

(6) an estimate of the amount of the mercury compound used annually in

manufacturing the product. - General comments on the subject could also be

submitted.

The agency received 41 responses to the request-for-data notices; 38 from

manufacturers of products, 1 from an association of homeopathic pharmacists,

and 2 from consumers. Of the 38 responses from manufacturers, 15 were from

manufacturers of homeopathic drug products, and 23 were from manufacturers

of drug and/or biologic products (13 drug manufacturers, 8 biologic

manufacturers, and 2 manufacturers of both types of products). Five of the

drug manufacturers informed the agency that they had no products containing

any mercury compounds. One drug manufacturer was an animal health

corporation providing information on a veterinary drug product, and two

manufacturers of homeopathic products included information on five

veterinary drug products as well as human drug products. The product

information submitted with the comments is summarized below in separate

sections based on the types of products: Human drug products (nonhomeopathic

and homeopathic), veterinary drug products (nonhomeopathic and homeopathic),

biological products, food and dietary supplement products, and other

products (where the type of product could not be determined from the

information that was submitted).

I. Information from the Responses

Human Drug Products (nonhomeopathic):

The nine manufacturers of human drug products submitted information on a

total of 32 products, half of which are prescription products and half of

which are OTC products. The prescription products included 7 ophthalmic, 4

otic, 3 injectable (1 bacteriostatic water for injection and 2 hyaluronidase

for injection), and 2 topical (for treating candidiasis) products. The OTC

products included 14 nasal spray/drop and 2 ophthalmic products. None of the

products contained any mercury compounds as active ingredients.

The 32 products contained the following mercury compounds as inactive

ingredients used as a preservative: 27 contained thimerosal , 4

contained phenylmercuric acetate (PMA), and 1 contained phenylmercuric

nitrate (PMN). TM was used in the 13 ophthalmic and otic products at the

following concentrations: 0.001% (5 products), 0.002% (1 product), 0.004% (2

products), 0.005% (2 products), and 0.01% (3 products). TM was used in 10

nasal spray/drop products at 0.00025% (3 products), 0.001% (6 products), and

0.002% (1 product). The 2 topical products contained 0.01% TM, and the 2

hyaluronidase injection products contained 0.075 or 0.1 milligram (mg) TM

per 150 United States Pharmacopeia (USP) units of drug (0.01%).

PMA was used in 4 nasal spray/drop products at 0.002%. One manufacturer

reported subsequently that its product had been reformulated to delete the

PMA. (This reduced the total number of products to 31). PMN was used in the

bacteriostatic water for injection at 0.01%.

The manufacturers reported estimated annual amounts of TM used as 1,086

grams (g) for 10 nasal spray/drop products, 1,123 g for 9 ophthalmic

products, 6,015 g for 4 otic products, 40 g for 2 topical products, and 192

g for the 2 hyaluronidase injection products. The manufacturers estimated

annual amounts used were 482 g for PMA for the 4 nasal spray/drop products

and 1.6 g for PMN for the 1 bacteriostatic water for injection product.

Human Drug Products (homeopathic):

The agency considers homeopathic products as drugs. These drugs may be

either prescription or OTC products. Mercury compounds are used in very

dilute concentrations in homeopathic products for a variety of purposes.

Homeopathic dosages are based on principles of serial dilution, and

homeopathic products are marketed in strengths that indicate the number of

dilutions that the substance has undergone in the manufacturing process.

Homeopathic products are marketed with either “XEor “CEpotencies.

“XEpotencies are prepared by 1 to 10 dilutions, and “CEpotencies are prepared

by 1 to 100 dilutions.

For example, a mercury compound is completely dissolved in solvent/diluent

in a ratio of 1 part mercury compound to 10 parts or 100 parts solution. The

resulting solution is known as the 1X or 1 C dilution. To manufacture the 2X

or 2C dilution, one part of the 1X solution is mixed with 9 parts of the

solvent/diluent and one part of the 1C solution is mixed with 99 parts of

the solvent/diluent. The 3X or 3C dilution is made from one part of the 2X

or 2C dilution plus 9 or 99 parts, respectively, of the solvent/diluent.

This dilution is repeated as many times as desired.

For substances that are insoluble in alcohol and water, the insoluble

substance is mixed with 9 times its weight of lactose. This process is

repeated until the substance has been diluted to at least a 6X potency, at

which point it is sufficiently diluted to allow solubility in a fluid, and

the process can be continued to the desired dilution.

A homeopathic product marketed at a 6X potency would contain 0.000001 g of

mercury compound per 1 g of tablet or pellet. This represents 1 part per

million (ppm) by weight. The American Association of Homeopathic Pharmacists

stated that a typical dose of a 6X dilution of a mercury compound contains

from 0.000066 to 0.000495 mg of elemental mercury. Mercury concentrations in

submitted products generally ranged from 6X to 200X.

The 15 manufacturers of homeopathic products submitted information on 494

human products containing 22 different mercury compounds, as follows:

Homeopathic nameCAS Preferred or

Chemical NameNumber of

Products

Aethiops antimonialis antimony sulfide/mercury mixture 2

Aethiops mercurialis-mineralis black mercuric sulfide 8

Mercurius aceticus mercurous acetate 4

Mercurius auratus mercury and gold amalgam3

Mercurius biniodatus mercuric iodide 3

Mercurius bromatus mercurous bromide 3

Mercurius corrosivus mercuric chloride 80

Mercurius cum kali iodatus potassium tetraiodomercurate 3

Mercurius cyanatus mercuric cyanide 20

Mercurius dulcis mercurous chloride 21

Mercurius iodatus flavus mercurous iodide 23

Mercurius iodatus ruber mercuric iodide 28

Mercurius methylenus dimethylmercury 3

Mercurius nitricus mercuric nitrate 4

Mercurius praecipitatus albus ammoniated mercury (chloride) 11

Mercurius praecipitatus ruber red mercuric oxide 31

Mercurius protoiodatus mercurous iodide 2

Mercurius solubilis [Hahnemann's] soluble mercury 126

Mercurius sulphocyanatus mercuric thiocyanate 3

Mercurius sulphuratus ruber red mercuric sulfide 10

Mercurius sulphuricus mercuric sulfate 13

Mercurius vivus [Quicksilver] mercury 72

Combination products 18

Due to the large number of dilutions in the manufacture of homeopathic

products, the amount of mercury compounds used annually in manufacturing

these products is minimal. One manufacturer stated that 1 g of a mercury

compound provides enough active ingredient for 1,000 kilograms (kg) of 6X

tablets or pellets. Thus, most manufacturers annual requirements for any

mercury compound used in manufacturing a homeopathic drug product should not

exceed 1 g.

Veterinary Drug Products (nonhomeonathic and homeonathic):

Three manufacturers submitted information on six products. One manufacturer

of nonhomeopathic veterinary drug products stated that it marketed one

ophthalmic ointment for dogs containing a mercury compound (0.002% PMN) as a

preservative. Two of the veterinary homeopathic drug products contained

mercurius corrosivus or mercurius dulcis, both at a 15X potency. The other

three veterinary homeopathic drug products contained mercurius corrosivus,

mercurius cyanatus, or mercurius vivus and are marketed in 1 OX, 30X, and

100X potencies.

Biological Products:

The ten manufacturers of biological products submitted information on a

total of 38 products: 30 vaccines, 7 other biological products, and 1

diluent for a vaccine. Eight of the 30 vaccines were variations of

diphtheria (D or d) and tetanus (T) toxoids; 6 were tetanus toxoids (TT); 2

were DTaP (diphtheria and tetanus toxoids and acellular pertussis); 1 was

DTP (diphtheria and tetanus toxoids and whole cell pertussis); and 2 were

DTP or DTaP combined with Haemophilus influenzae type b (DTP-HIB or

DTaP-HIB). The other vaccines were 5 influenza, 2 hepatitis B, 2 HIB, 1

pneumococcal, and 1 Japanese encephalitis. The 7 other biological products

were 3 antivenins, 2 human immune globulins, 1 mumps skin test antigen, and

1 normal horse serum. The final product was a diluent for a meningococcal

vaccine. None of the products contained any mercury compounds as active

ingredients.

The 38 products all contained TM as the mercury compound used as a

preservative. TM was present at a 0.01% concentration in 29 of the products;

0.003% in 3 products (1 Td and 2 immune globulins); 0.005% in 5 products (2

hepatitis B, 2 antivenins, and 1 normal horse serum), and 0.007% in 1

Japanese encephalitis virus vaccine. For products containing 0.01% TM, the

amount of TM per 0.5 milliliters (mL) of product is 50 micrograms, and the

amount of elemental mercury per 0.5 mL dose is approximately 25 micrograms.

The manufacturers reported estimated annual amounts of TM used as 3,125 g

for the 19 products containing any form of D and T, 24,408 g for the other

11 vaccine products (one manufacturer estimated 20,000 g for a hepatitis B

vaccine), 60 g for 2 human immune globulins, 7 g for the 3 antivenins, 4 g

for 1 mumps skin test antigen, 1 g for the 1 normal horse serum product, and

50 g for the diluent for 1 meningococcal vaccine. The total estimated amount

for the 38 products is 27,655 g of TM.

Food and Dietary Supplement Products:

No manufacturer of any food or dietary supplement products submitted any

information in response to the agency’s requests.

Other Products:

One consumer provided some information about the mercury content of some

herbal pills from China that had been sold to her by an acupuncturist as

part of acupuncture treatment for a sinus condition. The consumer had the

pills analyzed and they were found to contain 62 ppm (0.0062%) mercury. The

information provided did not enable the agency to determine the ingredients

these pills contain, whether the product would be considered a drug or

dietary supplement, or what the exposure to mercury would be from its use.

II. Information from Other Sources

Human Drug Products (nonhomeopathic):

The agency has reviewed information from its Drug Registration and Listing

System (DRLS) and other sources to identify additional drug products that

contain intentionally introduced mercury compounds. All but one of the 32

submitted drug products (see section I. A. above) were included in the DRLS

files. These 31 products are not discussed in this section.

The agency identified 138 additional nonhomeopathic products containing

mercury compounds. Of these, 13 contained mercury compounds as an active or

bulk chemical ingredient and 125 contained mercury compounds as a

preservative (124) or inactive ingredient (1).

Eleven of the 13 products contained mercury compounds (TM (8), merbromin(2),

and mercuric oxide yellow (1)) as a bulk chemical ingredient, and only 2

products (merbromin (mercurochrome) solution) had active drug uses. The

agency does not believe either of these products that had active drug uses

is currently marketed because of a final rule that the agency issued on

April 22, 1998 (63 FR 19799). In that final rule, the agency declared

merbromin (and other mercury active ingredients) as not generally recognized

as safe and effective as an active ingredient for OTC first aid antiseptic

and antimicrobial diaper rash uses. Products containing these ingredients

for these uses could no longer be initially introduced or initially

delivered for introduction into interstate commerce after October 19, 1998.

Of the 124 products containing mercury compounds as a preservative, 52 were

nasal solutions/sprays, 41 were ophthalmic solutions/ointments, 18 were otic

solutions, 8 were topical products, and 5 were injectable products. The 124

products contained TM (62), PMA (54), mercuric acetate (believed to be PMA)

1, PMN (5), and mercuric nitrate (believed to be PMN) (2). The agency

believes that the 7 ointment or suppository products containing PMN as a 9

preservative are no longer marketed because the PMN was present in a product

that contained live yeast cell derivative (LYCD). The agency declared LYCD

as not generally recognized as safe and effective for OTC anorectal use in a

final rule issued on September 2, 1993 (58 FR 46746). Products containing

LYCD for anorectal use could no longer be initially introduced or initially

delivered for introduction into interstate commerce after September 2, 1994.

Based on current product information and information about similar products

that were previously marketed, the agency believes that when these products

were reformulated to remove the LYCD, the PMN preservative was also removed

from the products. One topical ointment listed mercury as an inactive

ingredient at less than 0.02 ppm.

When preservative concentration information was provided in the DRLS files,

TM was present at 0.0005 to 0.01% (about 75% of the products) in the

ophthalmic solutions and at 0.002 to 0.01% (over 75% of the products) in the

otic solutions. PMA was present in most of the nasal solutions/sprays at

0.002% and at 0.0008% in 1 ophthalmic ointment. Mercuric acetate was listed

at 0.002% in one nasal solution/spray product.

The agency is able to estimate only the amounts of mercury compounds used

annually as a preservative in these products. Based on

manufacturersEinformation provided for submitted products (see section I. A.

above), 1,086

g of TM is used annually to manufacture 10 nasal spray/drop products. For 2

additional nasal spray/drop products, the estimated amount would be

approximately an additional 217 g (0.2 times 1,086), making a total of 1,303

g. The agency is unable to determine the accuracy of this proration because

it cannot correlate the 10 and 2 product quantities in terms of total number

of products sold. But the calculation provides an estimate that

approximately 1,300 g of TM would be used annually as a preservative in the

10 manufacture of approximately 12 nasal spray/drop drug products. The

agency believes that this number will be less for these products in the

future because many manufacturers of these products have reformulated or are

currently reformulating the products to replace TM as the preservative with

another (nonmercury compound) preservative, e. g., benzalkonium chloride.

Manufacturers estimated 1,123 g of TM used annually as a preservative for 9

ophthalmic products. Using the same type of calculation as above, 4,492 g (4

times 1,123) would be used for 36 additional products, making a total

estimate of 5,615 g for 45 products. Similarly, 6,015 g of TM was estimated

for 4 otic products. This would estimate as 27,068 g (4.5 times 6,015) for

18 additional products, making a total estimate of 33,083 g for 22 products.

The agency believes this estimate is high because of the large quantity used

for 1 of the 4 submitted products. The agency does not believe that many of

the other 18 products have the same volume of sales; thus, the actual amount

used would be much lower.

Manufacturers estimated 192 g of TM are used for 2 injectable products and

40 g are used for 2 topical products. The 5 injectable products and the 1

topical ointment product containing TM that were identified in the DRLS are

significantly different types of products than the submitted products for

which estimates of annual use were made. Therefore, the agency is not able

to make an estimate for these 6 products in the DRLS.

Manufacturers estimated 482 g of PMA are used annually in 4 nasal spray/drop

products. This would estimate as 6,025 g (12.5 times 482) for 50 additional

products, making a total of 6,507 g for 54 products. No ophthalmic products

containing PMA were included in the submissions. Therefore, the agency has

no estimate for the 5 ophthalmic products containing PMA that were

identified in the DRLS. Manufacturers provided an estimate of 1.6 g for only

1 manufacture of approximately 12 nasal spray/drop drug products. The agency

believes that this number will be less for these products in the future

because many manufacturers of these products have reformulated or are