[Federal Register Volume 60, Number 90 (Wednesday, May 10, 1995)]
[Proposed Rules]
[Pages 24808-24811]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-11526]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 500, 582, and 589
[Docket No. 94G-0239]
GRAS Status of Propylene Glycol; Exclusion of Use in Cat Food
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations to exclude from generally recognized as safe (GRAS)
status the use of propylene glycol (PG) in or on cat food. This
proposed action is based on FDA's review of currently available
information which has raised significant questions about the safety of
this use. Semimoist pet foods containing PG were not in existence when
the GRAS status for use in animal feeds was established, thus this GRAS
determination does not apply to the newly intended uses of PG. FDA is
proposing that PG in or on cat food is a food additive and is not prior
sanctioned for this use, and subject to certain provisions of the
Federal Food, Drug, and Cosmetic Act (the act).
DATES: Written comments by July 24, 1995.
ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),
Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville,
MD 20857.
FOR FURTHER INFORMATION CONTACT: David A. Dzanis, Center for Veterinary
Medicine (HFV-222), Food and Drug [[Page 24809]] Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-1728.
SUPPLEMENTARY INFORMATION:
I. Background
Propylene glycol has been used worldwide in the preparation of
human foods, pet foods, pharmaceuticals, and cosmetics. It was first
used in human foods in 1920, and in pet foods in the early 1960's. In
pet foods, PG functions as a humectant, plasticizer, and
microbiological preservative.
In the Federal Register of November 20, 1959 (24 FR 9368), the
agency published a final rule establishing PG as generally recognized
as safe (GRAS) in 21 CFR 121.101(h) as a general purpose food additive.
PG's use in animal food and feed was recodified to 21 CFR 582.1666 in
the Federal Register September 10, 1976 (41 FR 38618 at 38657).
In the Federal Register of June 17, 1977 (42 FR 30865), the agency
proposed to affirm PG as GRAS as a direct and indirect human food
ingredient. Subsequently, in the Federal Register of June 25, 1982 (47
FR 27810), a final rule was published affirming the GRAS status of PG.
The agency's conclusions were based upon a review of scientific
literature from 1920 to 1977. A total of 282 abstracts on the additive
were reviewed and 68 particularly pertinent reports from the literature
survey were summarized in a scientific literature review. The results
of this scientific review were discussed in the June 17, 1977,
document.
II. Prior Sanction
A substance that is added to food is not a food additive if it is
the subject of a prior sanction (section 201(s)(4) of the act (21
U.S.C. 321(s)(4)). ``Prior sanction'' means an explicit approval
granted with respect to use of a substance in food prior to September
6, 1958, by FDA or the United States Department of Agriculture (USDA)
pursuant to the act, the Poultry Products Inspection Act, or the Meat
Inspection Act (21 CFR 570.3(1)). A prior sanction applies to the
specific use of a substance in food, i.e., the level, condition,
product, etc., for which there was explicit approval by FDA or USDA.
Moreover, the existence of a prior sanction exempts the sanctioned use
from the food additive provisions of the act but not from the other
adulteration or the misbranding provisions of the act (see 21 CFR
181.5(a) and (b)).
If, at the time that FDA proposes to determine that a substance is
not GRAS and is a food additive under 21 CFR 570.38, the agency is
aware of any prior sanction for use of the substance, it will
concurrently propose a separate regulation covering such use of the
ingredient under part 582 (21 CFR part 582). If the agency is unaware
of any such applicable prior sanction, the proposed regulation (as to
the substances GRAS or food additive status) will so state and will
require any person who intends to assert or rely on such sanction at
any later time (21 CFR 570.38(d)).
FDA is not aware of any prior sanctions for the use of propylene
glycol in or on cat food, that meet the criteria described above. No
party has claimed a prior sanction for this use of propylene glycol in
or on cat food. Accordingly, based on the information that is available
to it, the agency concludes that no prior sanction exists for the use
of propylene glycol in or on cat food.
III. FDA's Concerns
Following review of a number of studies conducted since 1982
concerning the use of PG in cat food, the agency has concluded that
there are significant questions about the safety of PG in cat food. In
1976, because the safety of PG was being questioned, the European
Economic Community (EEC) initiated a review of additives used in pet
foods. In response to this initiative, studies were funded by several
pet food companies to verify the safety of PG in semimoist dog and cat
foods (these studies include Ref. 1). Clinical tests included the
measurement of a blood parameter called Heinz bodies, a test which had
not been performed in previous PG studies. Heinz bodies are small
clumps of denatured protein in the red blood cells. Cats offered food
containing PG at levels used in semimoist food were found to develop
Heinz bodies. Although Heinz bodies were known to be indicative of red
blood cell damage, the studies did not provide evidence that PG caused
anemia or other adverse clinical effects in cats.
Because of the questions raised by the European cat studies, a U.S.
pet food industry research group (IRG), composed of interested pet food
companies and PG manufacturers, was formed in early 1978. The IRG's
purpose was to investigate the significance of linking PG and Heinz
body formation, especially PG's effect on the health of the cat. In
August 1978, representatives of the IRG met with FDA to provide the
results of the EEC tests and describe the research being conducted to
determine the significance of Heinz body formation. Since this first
meeting, additional pertinent research data have been provided to FDA.
The results of the IRG studies were published in peer-reviewed
scientific journals (Refs. 2 and 3). In the first study, adult cats
were fed diets containing 0, 6, or 12 percent PG on a dry matter basis
over a 16-week period. Cats fed PG had a dose-related increase in Heinz
bodies, and a dose-related decrease in mean red blood cell survival
time. In the 12 percent group, there was also an increase in punctate
reticulocytes, and slight changes in the packed cell volume, hemoglobin
concentration, and red blood cell counts. These results indicate that
red blood cells are more susceptible to destruction due to PG.
Periportal liver glycogen accumulation, splenic nodules, and heart and
kidney lesions were observed in some of the cats in the 12 percent
group, and the same splenic lesions were seen in some cats in the 6
percent group. In the second study, 12-to 14-week-old kittens were fed
diets containing 0, 6, or 12 percent PG on a dry matter basis for 13
weeks. Findings followed a pattern similar to those of the adult cat
study, but the increase in reticulocyte count and reduction in red
blood cell lifespan were greater in kittens than in adults. This
difference was attributed to higher consumption of PG on a per weight
basis in kittens.
Other reports in the scientific literature confirmed and expanded
on the IRG findings. In a retrospective study, a direct relationship
between Heinz body formation and lower packed cell volumes and lower
erythrocyte reduced glutathione concentrations were found in cats (Ref.
4). Another study found dose-dependent increases in Heinz body
formation and decreases in red blood cell lifespans in cats fed diets
containing 12 and 41 percent PG (Ref. 5). A dose-dependent increase in
iron pigment in liver and splenic tissue was also observed. Cats fed 41
percent PG diets had a significantly lower mean packed cell volumes, a
decreased mean erythrocyte reduced glutathione concentration, punctate
reticulocytosis, and bone marrow erythroid hyperplasia. This suggests
that although the bone marrow was attempting to compensate for
increased red blood cell destruction, the marrow could not produce
enough red blood cells to compensate for the rate of destruction.
Increased Heinz body formation and decreased red blood cell
survival time were observed in kittens fed diets containing 5 or 10
percent PG for 12 weeks in a study by Hickman and others (Ref. 6).
Purified experimental diets containing nitrate, histamine, histamine
plus nitrate, or vitamin A failed to induce Heinz body formation. After
cessation of treatment with PG- [[Page 24810]] containing diets, the
Heinz body percentage returned to pretreatment levels in 6 to 8 weeks.
Thus, PG was identified as the causative factor, and these other
possible components of cat food were ruled out as causes of Heinz body
formation. Another study found cats fed a commercial diet containing
8.3 percent PG were more susceptible to red blood cell oxidant stress
from acetaminophen administration than cats fed a control diet (Ref.
7). Thus, acetaminophen, a common pain reliever for human use but
poisonous to cats, was even more dangerous if cats were fed diets
containing PG.
Despite the lack of overt clinical anemia in cats in these studies,
the data establishes clearly that PG taxes the red blood cell
production system. The lack of reports from the veterinary profession
of clinically obvious consequences of PG ingestion is an inappropriate
criterion to judge the safety of PG, as the indirect impacts of a
toxicant are not often readily associated with the compound. FDA
believes that cats consuming PG-containing diets would be less able to
compensate for other oxidative stresses, such as those induced by
infections, drugs, or toxins. Heinz bodies induced by PG may interfere
with the proper diagnosis of diabetes mellitus, hyperthyroidism,
lymphoma, and other diseases in cats associated with Heinz body
formation. Consumption of PG-containing diets may also contribute to
the severity of anemia from a variety of causes. Thus, FDA concludes
that the findings of the studies of IRG and others constitute adverse
effects on the health of cats.
Based on data derived from the FDA master file on PG, the no-
observed-effect-level (NOEL) in cats with respect to Heinz body
formation is 80 milligrams (mg) PG per kilogram (/kg) body weight (Ref.
1). Assuming typical consumption rates, this level translates to
approximately 4,900 to 5,700 mg PG/kg food dry matter (0.49 to 0.57
percent dry matter) for adult, nonreproducing cats, and 0.135 to 0.16
percent dry matter for growing kittens. These levels are far below what
has historically been used as a humectant in semimoist cat foods (6
percent to 13 percent dry matter). At levels below 3 percent, PG no
longer has any technical or functional effect in the food as a
humectant. Effects are seen in adult as well as growing animals. Thus,
FDA cannot conclude that a limited use of PG, e.g., a reduced level of
use, or a diet intended for certain lifestages of cats only is GRAS.
In 1992, FDA informed industry through a letter to the IRG of its
concern regarding the safety of PG in cat foods. Subsequent to that
action, the majority of cat food manufacturers removed PG from their
formulations. However, a portion of the products on the market,
including some imported products, continue to contain PG.
IV. Conclusions
On the basis of the foregoing, the agency has concluded that PG is
not GRAS as an ingredient of cat food nor is this use subject to a
prior sanction. Under these circumstances PG is deemed to be a food
additive, subject to section 409 of the act (21 U.S.C. 348), and its
use in cat food must be in accordance with a published food additive
regulation.
V. Environmental Impact
The agency has carefully considered the potential environmental
effects of this action. FDA has concluded that the action will not have
a significant impact on the human environment, and that an
environmental impact statement is not required. The agency's finding of
no significant impact and the evidence supporting that finding,
contained in an environmental assessment, may be seen in the Dockets
Management Branch (address above) between 9 a.m. and 4 p.m., Monday
through Friday.
VI. Analysis of Impacts
FDA has examined the impacts of this proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the proposed
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
This assessment analyzes the economic effects of the proposed rule
to exclude from GRAS status the use of PG in or on cat food. PG is used
as a humectant, plasticizer, and microbiological preservative in
semimoist cat food. Semimoist cat foods containing PG did not exist
when the GRAS status for its use in animal feeds was established, and
this GRAS determination does not apply to the newly intended use of PG.
Currently available information on the effects of PG demonstrates
serious concerns about its safety in cats.
FDA requested that pet food manufacturers discontinue the use of PG
as an ingredient in semimoist cat foods in 1992. The majority of
manufacturers in the industry have complied with this request. Agency
experts estimate that PG is currently used in at most 5 percent of
semimoist cat foods and at most 10 percent of cat snacks, which are
similar in texture and content to semimoist foods. These usage rates
continue to decline.
FDA estimates of 1993 sales of semimoist cat foods and snacks to
U.S. households are $85,000,000 and $53,000,000, respectively (Neilsen
Marketing Research data). Those sales representing semimoist cat foods
and cat snacks which contain PG are approximately $9,550,000 (5 percent
of $85,000,000 plus 10 percent of $53,000,000). The effect of the
proposed rule would be to replace these sales with other cat foods and
cat snacks not containing PG. Most of the industry has already
substituted glycerin for PG in semimoist foods and snacks. It is likely
that the remaining portion of the industry would make the substitution
of glycerin for PG rather than surrender their share of the semimoist
cat food and cat snack market. The cost of this substitution to the
production process is expected to be small.
Purchases of PG by semimoist cat food and cat snack manufacturers
represent a very small percentage of total PG sales, estimated at less
than 1 percent. Demand for semimoist cat foods has declined
considerably since 1987. Although demand for cat snacks continues to
grow, its sales are still a small part of the total pet food industry.
Thus, the effect of the proposed rule to PG manufacturers would also be
small.
The effects of the proposed rule on small businesses would not be
substantial. Although more small-sized companies are involved in
manufacturing cat snack foods than in semimoist foods, their costs of
compliance would not be significant.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. For the above reasons, the agency certifies that the
proposed rule will not have a significant economic impact on a
substantial number of small entities. Therefore, under the Regulatory
Flexibility Act, no further analysis is required.
VII. References
The following references have been placed on display in the Dockets
[[Page 24811]] Management Branch (address above) and may be seen by
interested persons between 9 a.m. and 6 p.m., Monday through Friday.
1. Quast, J. F., C. G. Humiston, C. E. Wade, et al. Results of a
Toxicology Study in Cats Fed Diets Containing Propylene Glycol for
up to Three Months, FDA Master File Report No. 12, 1979.
2. Bauer, M. C., D. J. Weiss, V. Perman, ``Hematologic
Alterations in Adult Cats Fed 6 or 12% Propylene Glycol,'' American
Journal of Veterinary Research, 53:69-72, 1991.
3. Bauer, M. C., D. J. Weiss, V. Perman, ``Hematological
Alterations in Kittens Induced by 6 and 12% Dietary Propylene
Glycol,'' Veterinary and Human Toxicology, 34:127-130, 1992.
4. Christopher, M. M., ``Relation of Endogenous Heinz Bodies to
Disease and Anemia in Cats: 120 Cases (1978-1987),'' Journal of the
American Veterinary Medical Association, 194:1089-1095, 1989.
5. Christopher, M. M., V. Perman, J. W. Eaton, ``Contribution of
Propylene Glycol-Induced Heinz Body Formation to Anemia in Cats,''
Journal of the American Veterinary Medical Association, 194:1045-
1055, 1989.
6. Hickman, M. A., Q. R. Rogers, J. G. Morris, ``Effect of Diet
on Heinz Body Formation in Kittens,'' American Journal of Veterinary
Research, 50:475-478, 1990.
7. Weiss, D. J., C. B. McClay, M. M. Christopher, M. Murphy, V.
Perman, ``Effects of Propylene Glycol-Containing Diets on
Acetaminophen-Induced Methemoglobinemia in Cats,'' Journal of the
American Veterinary Medical Association, 196:1816-1819, 1990.
VIII. Comments
Interested persons may, on or before July 24, 1995, submit to the
Dockets Management Branch (address above) written comments regarding
this proposal. Two copies of any comments are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Received comments may be seen in the office above between 9
a.m. and 4 p.m., Monday through Friday.
List of Subjects
21 CFR Part 500
Animal drugs, Animal feeds, Cancer, Labeling, Polychlorinated
biphenyl's (PCB's).
21 CFR Parts 582 and 589
Animal feeds, Animal foods, Food additives.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 500, 582, and 589 be amended as follows:
PART 500--GENERAL
1. The authority citation for 21 CFR part 500 continues to read as
follows:
Authority: Secs. 201, 301, 402, 403, 409, 501, 502, 503, 512,
701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331,
342, 343, 348, 351, 352, 353, 360b, 371).
2. New Sec. 500.50 is added to subpart B to read as follows:
Sec. 500.50 Propylene glycol in or on cat food.
The Food and Drug Administration has determined that propylene
glycol in or on cat food is not generally recognized as safe and is a
food additive subject to section 409 of the Federal Food, Drug, and
Cosmetic Act (the act). The Food and Drug Administration also has
determined that this use of propylene glycol is not prior sanctioned.
PART 582--SUBSTANCES GENERALLY RECOGNIZED AS SAFE
3. The authority citation for 21 CFR part 582 continues to read as
follows:
Authority: Secs. 201, 402, 409, 701 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).
4. Section 582.1666 is amended by revising paragraph (b) to read as
follows:
Sec. 582.1666 Propylene glycol.
* * * * *
(b) Conditions of use. This substance is generally recognized as
safe (except in cat food) when used in accordance with good
manufacturing or feeding practice.
PART 589--SUBSTANCES PROHIBITED FROM USE IN ANIMAL FOOD OR FEED
5. The authority citation for 21 CFR part 589 continues to read as
follows:
Authority: Secs. 201, 402, 409, 701, of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).
6. New Sec. 589.1001 is added to subpart B to read as follows:
Sec. 589.1001 Propylene glycol in or on cat food.
The Food and Drug Administration has determined that propylene
glycol in or on cat food has not been shown by adequate scientific data
to be safe for use. Use of propylene glycol in or on cat food causes
the feed to be adulterated and in violation of the Federal Food, Drug,
and Cosmetic Act (the act), in the absence of a regulation providing
for its safe use as a food additive under section 409 of the act,
unless it is subject to an effective notice of claimed investigational
exemption for a food additive under Sec. 570.17 of this chapter, or
unless the substance is intended for use as a new animal drug and is
subject to an approved application under section 512 of the act or an
effective notice of claimed investigational exemption for a new animal
drug under part 511 of this chapter.
Dated: May 2, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-11526 Filed 5-9-95; 8:45 am]
BILLING CODE 4160-01-F