[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