Food Additives Permitted for Direct Addition to Food for Human Consumption; 1,3-Butylene Glycol

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. 87G-0351]

Food Additives Permitted for Direct Addition to Food for Human

Consumption; 1,3-Butylene Glycol

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the food

additive regulations to provide for the safe use of 1,3-butylene glycol

as a formulation and processing aid in the manufacture of edible

sausage casings. This action is in response to a petition filed by

Teepak, Inc.

DATES: Effective May 13, 1997; written objections and requests for a

hearing by June 12, 1997. The Director of the Office of the Federal

Register approves the incorporation by reference in accordance with 5

U.S.C. 552(a) and 1 CFR part 51 of a certain publication listed in new

Sec. 172.712, effective May 13, 1997.

ADDRESSES: Submit written objections to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: James C. Wallwork, Center for Food

Safety and Applied Nutrition (HFS-215), Food and Drug Administration,

200 C St. SW., Washington, DC 20204-0001, 202-418-3078.

SUPPLEMENTARY INFORMATION:

I. Background

In accordance with the procedures described in Sec. 170.35 (21 CFR

170.35), Teepak, Inc., 915 North Michigan Ave., Danville, IL 61832-

0597, submitted a petition (GRASP 7G0332) requesting that 1,3-butylene

glycol be affirmed as generally recognized as safe (GRAS) for use in

food as a formulation and processing aid, when used in accordance with

current good manufacturing practice.

FDA published a notice of filing of this petition in the Federal

Register of November 23, 1987 (52 FR 44936), and gave interested

parties an opportunity to submit comments concerning the petition to

the Dockets Management Branch (address above). FDA received no comments

in response to that notice.

After the petition was filed, the petitioner amended the petition

to limit the scope of the requested GRAS affirmation. As amended, the

petition asks FDA to affirm 1,3-butylene glycol as GRAS for use only as

a formulation and processing aid in the manufacture of edible sausage

casings.

II. Standard for Evaluation of Petition

Under Sec. 170.30 (21 CFR 170.30), general recognition of safety

may be based only on the views of experts qualified by scientific

training and experience to evaluate the safety of substances added to

food. The basis of such views may be either: (1) Scientific procedures,

or (2) in the case of a substance used in food prior to January 1,

1958, experience based on common use in food (Sec. 170.30(a)). General

recognition of safety based upon scientific procedures requires the

same quantity and quality of scientific evidence as is required to

obtain approval of the substance as a food additive and ordinarily is

to be based upon published studies, which may be corroborated by

unpublished studies and other data and information (Sec. 170.30(b)). In

its petition, Teepak, Inc., has not claimed a history of common use in

food before 1958, but rather has relied upon scientific procedures,

primarily published scientific papers, to support its claim that 1,3-

butylene glycol is GRAS.

In reviewing the data in the petition and other relevant material,

FDA noted that the published studies on the safety of 1,3-butylene

glycol are of varying quality. As discussed in section IV. of this

document, the agency believes that the available data, taken together,

establish the safety of 1,3-butylene glycol for the limited use

requested in the petition. However, FDA does not believe that the data

are sufficient to show that the basis for such a safety determination

is generally recognized by experts in the field.

Thus, in accordance with 21 CFR 170.35(c)(5) and 170.38, the agency

has determined that the requested use of 1,3-butylene glycol cannot be

considered GRAS based upon scientific procedures and that the compound

is a food additive subject to section 409 of the Federal Food, Drug,

and Cosmetic Act (the act) (21 U.S.C. 348). FDA notified the petitioner

of this conclusion and the firm agreed that 1,3-butylene glycol could

be evaluated as a food additive rather than as a GRAS ingredient.

III. Introduction

A. Identity

1,3-Butylene glycol

(CH2OHCH2CHOHCH3, CAS Reg. No.

[[Page 26226]]

107-88-0, and molecular weight 90.12) is the common name for 1,3-

dihydroxybutane or 1,3-butanediol. It is a clear, colorless,

hygroscopic, viscous liquid almost without odor.

B. Regulated Food and Packaging Uses

1,3-Butylene glycol is regulated for use under 21 CFR 173.220 1,3-

Butylene glycol as a solvent for natural and synthetic flavoring

substances, except where food standards preclude its use. Also, 1,3-

butylene glycol is regulated for use in polyester formation under 21

CFR 175.320 Resinous and polymeric coatings for polyolefin films and as

a reactant under 21 CFR 177.1680 Polyurethane resins in the preparation

of resins for use in contact with dry bulk foods.

IV. Safety

A. Manufacturing Process

1,3-Butylene glycol is produced through the controlled aldol

condensation of acetaldehyde in the presence of dilute aqueous sodium

hydroxide. The first reaction product, a trimer of acetaldehyde, is

decomposed to a dimer, acetaldol (3-hydroxy-butyraldehyde), during the

neutralization of the excess sodium hydroxide with dilute acetic acid.

The unreacted acetaldehyde is removed by distillation. Acetaldol is

then reduced to butylene glycol by hydrogenation in the presence of a

nickel catalyst. 1,3-Butylene glycol thus produced is purified in a

series of vacuum distillation towers. The product is manufactured to

conform to the identity and specifications listed in the monograph

entitled ``1,3-Butylene Glycol'' in the Food Chemicals Codex, 4th ed.

(1996), p. 52.

B. Proposed Use in Food

The petition contains data demonstrating that 1,3-butylene glycol

is effective in reducing breakage in manufactured sausage casings. The

petition also contains data demonstrating that the petitioned substance

is most effective at levels of 5 to 15 percent of the liquid phase of

the casing (equivalent to 2 to 6 percent of the total casing weight).

Included in the petition are data demonstrating that at levels higher

than 6 percent, 1,3-butylene glycol sausage casings become more

susceptible to breakage. Thus, the petition provides data demonstrating

that the proposed ingredient is technologically self-limiting.

C. Consumer Exposure

Using sausage intake data from the Market Research Corp. of America

(Ref. 1) and assuming from information submitted with the petition that

1 percent of the weight of sausage is casing made with 6 percent 1,3-

butylene glycol, FDA estimates that exposure to the proposed ingredient

is 6.0 milligrams/person/day (mg/p/d) (mean) and 12 mg/p/d (90th

percentile) for the 2+ years age group. For the 2- to 5-year-old age

group subcategory, FDA estimates that exposure is 4.5 mg/p/d (mean) and

8.5 mg/p/d (90th percentile).

D. Toxicology

To provide evidence of the safety of 1,3-butylene glycol for the

petitioned use, the petitioner provided published and unpublished

reproduction and chronic feeding studies in rats and dogs, as well as a

number of published short-term nutrition and metabolism studies. In

addition, an agency-initiated literature search identified a

reproduction study with 1,3-butylene glycol published in 1990.

A published 2-year dietary feeding study (Ref. 2) in beagle dogs

reported no visible adverse effects on appearance, behavior, growth,

food intake, urinalysis, hematology or serum biochemistry that could be

attributed to treatment with 1,3-butylene glycol. The diets of male and

female dogs were treated with the petitioned substance at 118, 228, and

613 mg/kilogram body weight/day (mg/kg bw/d) for males and 101, 228,

and 732 mg/kg bw/d for females. Although microscopic lesions were

observed in testes and lymph nodes of males after 1 and 2 years'

treatment, FDA concludes that the lesions do not appear to be of

pathological significance. Lesions of the type and severity observed

are frequent incidental findings in dogs. Moreover, no significant

difference in appearance between lesions in control and treated animals

could be derived from the histopathological descriptions of the tissues

examined. Therefore, the agency finds that the incidence of gross

pathological lesions is unrelated to treatment and that this study

supports a no-effect level of 700 mg/kg bw/d, the highest dose in the

study.

The agency concludes that data from a published 2-year dietary

feeding study (Ref. 2) in Sprague-Dawley rats cannot be used to

establish the safety of 1,3-butylene glycol. The study had insufficient

statistical power to detect an adverse response to 1,3-butylene glycol

because an inadequate number of rats was used and widespread disease

killed most of the rats during the second year of the study.

A published reproduction study (Ref. 3) in Long-Evans rats, treated

by gavage with 1,3-butylene glycol (0, 706, 4,236, and 7,060 mg/kg bw/

d) during days 6 to 15 of gestation, also reported no treatment-related

effects on a variety of reproduction parameters (litter weight and

size, crown-rump length, corpora lutea, implantation sites, sex

distribution, intrauterine deaths, total malformed pups or incidence of

litters with malformed pups). However, the researchers reported an

increased incidence of low body weights and sternebral anomalies in

pups from high-dose mothers, indicating a possible teratogenic effect

from exposure to 1,3-butylene glycol. The full significance of the

effects of the treatment of rats with 1,3-butylene glycol, though,

cannot be determined from the available data. FDA finds that the data

are insufficient to determine whether the observed anomalies were

caused by the treatment-related reductions in birth weight or by a

teratogenic effect of the additive. However, because the observed low

body weights and sternebral anomalies occurred only in high-dose

groups, the agency concludes that a no-effect level can be set from

doses employed with mid-dose rats at 4,200 mg/kg bw/d.

A number of published and unpublished nutritional and metabolic

studies with 1,3-butylene glycol were also provided (Refs. 4 through

21). Within the limited scope of those studies no significant

toxicological effects were reported except in a human clinical study

(Ref. 21). In that study, 1,3-butylene glycol fed to young male and

female subjects (250 mg/kg bw/d in bread for four separate 7-day

periods) was reported to significantly depress blood glucose (lowered

by 12 percent relative to controls). The 1,3-butylene glycol-induced

glucose reduction did not involve insulin or growth hormone, although

its mechanism could not be determined. As discussed in section IV.D.1.

of this section, the reduction in blood glucose would not be expected

to occur at the low levels estimated for human dietary exposure from

the proposed use of 1,3-butylene glycol.

Ordinarily, chronic studies in rodent and nonrodent species are

needed to establish the safety of direct food ingredients (Ref. 22).

Although the petitioner did not submit an acceptable chronic dietary

rodent study, FDA concludes that the toxicological data submitted are

adequate to establish the safety of the use of 1,3-butylene glycol in

edible sausage casings, for the following reasons:

1. The metabolism of 1,3-butylene glycol is well understood. In the

rat, 1,3-butylene glycol is metabolized in the liver cytosol in a

manner similar to ethanol (Refs. 13 and 16). In the intact rat and in

tissue slices, it is converted

[[Page 26227]]

to acetoacetate and -hydroxybutyrate, which are normal

intermediates in fat metabolism. In the kidney, 1,3-butylene glycol

blocks gluconeogenesis at the conversion of 3-phosphoglycerate to

glyceraldehyde-3-phosphate (Ref. 14). This metabolic blockage is

responsible for the reduction in serum glucose that occurs when 1,3-

butylene glycol is consumed at sufficiently high levels. At consumption

levels that would be expected from the proposed use, however, 1,3-

butylene glycol would not be expected to inhibit gluconeogenesis in the

kidney. In addition, from an examination of the scientific literature

on the metabolism of 1,3-butylene glycol, which is well understood and

documented (Refs. 16 and 21), there is no indication that 1,3-butylene

glycol would be expected to have any carcinogenic potential. Therefore,

FDA concludes that a chronic rodent study is not necessary to support

the safety of the proposed use of 1,3-butylene glycol.

2. To ensure an adequate margin of safety, FDA applied a 1,000-fold

safety factor (rather than the normal 100-fold safety factor) to the

no-effect level from the dog study (Ref. 2) to compensate for the lack

of an acceptable chronic rodent study for 1,3-butylene glycol. Applying

a 1,000-fold safety factor to the no-effect level from the dog study

gives an acceptable daily intake (ADI) for 1,3-butylene glycol of 0.7

mg/kg bw. Although an adverse metabolic effect (decreased serum

glucose) was reported in humans consuming 250 mg 1,3-butylene glycol/kg

bw, it is unlikely that any such metabolic effects would be observed at

the ADI, which is 350-fold lower. Furthermore, for 1,3-butylene glycol,

the ADI (0.7 mg/kg bw) is greater than the daily exposure estimates of

0.1 mg/kg bw (mean) and 0.2 mg/kg bw (90th percentile) for adults,

assuming a bw of 60 kg, and 0.3 mg/kg bw (mean) and 0.6 mg/kg bw (90th

percentile) for 2- to 5-year-olds, assuming a body weight of 15 kg.

Therefore, the agency concludes that the level of exposure resulting

from the petitioned use of 1,3-butylene glycol is safe.

V. Conclusion on Safety

FDA has evaluated the data in the petition and other relevant

material regarding the use of 1,3-butylene glycol as a formulation and

processing aid in sausage casings and concludes that the substance

produces the intended technical effects and is safe under the proposed

conditions of use. Therefore, the agency is amending the food additive

regulations to provide for the requested use.

In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), the petition

and the documents that FDA considered and relied upon in reaching its

decision to approve the petition are available for inspection at the

Center for Food Safety and Applied Nutrition by appointment with the

information contact person listed above. As provided in Sec. 171.1(h),

the agency will delete from the documents any materials that are not

available for public disclosure before making the documents available

for inspection.

VI. 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.

VII. Objections

Any person who will be adversely affected by this regulation may at

any time on or before June 12, 1997, file with the Dockets Management

Branch (address above) written objections thereto. Each objection shall

be separately numbered, and each numbered objection shall specify with

particularity the provisions of the regulation to which objection is

made and the grounds for the objection. Each numbered objection on

which a hearing is requested shall specifically so state. Failure to

request a hearing for any particular objection shall constitute a

waiver of the right to a hearing on that objection. Each numbered

objection for which a hearing is requested shall include a detailed

description and analysis of the specific factual information intended

to be presented in support of the objection in the event that a hearing

is held. Failure to include such a description and analysis for any

particular objection shall constitute a waiver of the right to a

hearing on the objection. Three copies of all documents shall be

submitted and shall be identified with the docket number found in

brackets in the heading of this document. Any objections received in

response to the regulation may be seen in the Dockets Management Branch

between 9 a.m. and 4 p.m., Monday through Friday.

VIII. References

The following references have been placed on display in the Dockets

Management Branch (address above ) and may be seen by interested

persons between 9 a.m. and 4 p.m., Monday through Friday.

1. Memorandum from M. DiNovi, Chemistry Review Branch, to R. L.

Martin, Direct Additives Branch, dated November 8, 1988.

2. Scala, R. A., and O. E. Paynter, ``Chronic Oral Toxicity of

1,3-Butanediol,'' Toxicology and Applied Pharmacology, 10:160-164,

1967.

3. Mankes, R. F., V. Renak, J. Fieseher, and R. LeFevre,

``Birthweight Depression in Male Rats Contiguous to Male Siblings in

Utero Exposed to High Doses of 1,3-Butanediol During

Organogenesis,'' Journal of the American College of Toxicology,

5:189-196, 1986.

4. Dymsza, H. A., ``Nutritional Application and Implication of

1,3-Butanediol,'' Federation Proceedings, 34:2167-2170, 1975.

5. Giron, H. M., ``Some Aspects of the Utilization of 1,3-Diols

as Synthetic Dietary Energy Sources'' (thesis for master of science

degree), Massachusetts Institute of Technology, August 1968.

6. Food and Drug Research Laboratories, Inc., Morgareidge, K.,

``Utilization of 1,3-Butylene Glycol in Dogs,'' November 1, 1972.

7. Mehlman, M. A., ``Synthetic Food Additives as a Source of

Calories: 1,3-Butanediol,'' Federation Proceedings, 34:2166, 1975.

8. Miller, S. A., and H. A. Dymsza, ``Utilization by the Rat of

1,3-Butanediol as a Synthetic Source of Dietary Energy,'' Journal of

Nutrition, 91:79-88, 1967.

9. Stoewsand, G. S., H. A. Dymsza, M. A. Kilmore, and S. M.

Swift, ``Plasma Lipid Changes in Exercised Dogs Fed 1,3-

Butanediol,'' Federation Proceedings, 25:608, 1966 (abstract).

10. Young, J. W., ``Use of 1,3-Butanediol for Lactation and

Growth in Cattle,'' Federation Proceedings, 34:2177-2181, 1975.

11. Mackerer, C. R., R. N. Saunders, J. R. Haettinger, and M. A.

Mehlman, ``Influence of 1,3-Butanediol on Blood Glucose

Concentration and Pancreatic Insulin Content of Streptozotocin-

Diabetic Rats,'' Federation Proceedings, 34:2191-2196, 1975.

12. Mehlman, M. A., R. B. Tobin, and J. B. Johnston, ``Metabolic

Control of Enzymes in Normal, Diabetic and Diabetic Insulin Treated

Rats Utilizing 1,3-Butanediol'' (undated).

13. Mehlman, M. A., R. B. Tobin, H. K. J. Hahn, V. DeVore, and

L. Kleager, ``Metabolic Fate of 1,3-Butanediol (BD) in the Rat,''

Omaha, NE (undated).

14. Mehlman, M. A., R. B. Tobin, and J. B. Johnston, ``Influence

of Dietary 1,3-Butanediol on Metabolites and Enzymes Involved in

Gluconeogenesis and Lipogenesis in Rats,'' Journal of Nutrition,

100:1341-1346, 1970.

15. Mehlman, M. A., R. B. Tobin, and C. R. Mackerer, ``1,3-

Butanediol Catabolism in the Rat,'' Federation Proceedings, 34:2182-

2185, 1975.

16. Nahapetian, A., ``Metabolism in Vivo of 1,3-Butanediol in

the Rat'' (thesis for doctor of science degree), Massachusetts

Institute of Technology, September 1971.

17. Parker, M. M. (under the supervision of Myron A. Mehlman),

``Metabolic Effects of 1,3-Butanediol,'' Omaha, NE, August 1972.

[[Page 26228]]

18. Romsos, D. R., P. S. Belo, and G. A. Leveille, ``Butanediol

and Lipid Metabolism,'' Federation Proceedings, 34:2186-2190, 1975.

19. Tate, R. L., M. A. Mehlman, and R. B. Tobin, ``The

Metabolism of 1,3-Butanediol'' (undated).

20. Tate, R. L., M. A. Mehlman, and R. B. Tobin, ``Metabolic

Fate of 1,3-Butanediol in the Rat: Conversion to -

Hydroxybutyrate,'' Journal of Nutrition, 101:1719-1726, 1971.

21. Tobin, R. B., M. A. Mehlman, C. Kies, H. M. Fox, and J. S.

Soeldner, ``Nutritional and Metabolic Studies in Humans With 1,3-

Butanediol,'' Federation Proceedings, 34:2171-2176, 1975.

22. ``Toxicological Principles for the Safety Assessment of

Direct Food Additives and Color Additives Used in Food'' in

``Redbook,'' Center for Food Safety and Applied Nutrition, Food and

Drug Administration, 1982. Available through National Technical

Information Service (NTIS), 5285 Port Royal Rd., Springfield, VA

22161, order number PB-83-170696. Revised draft is available from

the Office of Premarket Approval (HFS-206), 200 C St. SW.,

Washington, DC 20204-0001.

List of Subjects in 21 CFR Part 172

Food additives, Incorporation by reference, Reporting and

recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs and

redelegated to the Director, Center for Food Safety and Applied

Nutrition, 21 CFR part 172 is amended as follows:

PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR

HUMAN CONSUMPTION

1. The authority citation for 21 CFR part 172 continues to read as

follows:

Authority: Secs. 201, 401, 402, 409, 701, 721 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 348, 371,

379e).

2. New Sec. 172.712 is added to subpart H to read as follows:

Sec. 172.712 1,3-Butylene glycol.

The food additive 1,3-butylene glycol (CAS Reg. No. 107-88-0) may

be safely used in food in accordance with the following prescribed

conditions:

(a) It is prepared by the aldol condensation of acetaldehyde

followed by catalytic hydrogenation.

(b) The food additive shall conform to the identity and

specifications listed in the monograph entitled ``1,3-Butylene Glycol''

in the Food Chemicals Codex, 4th ed. (1996), p. 52, which is

incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR

part 51. Copies are available from the Office of Premarket Approval,

Center for Food Safety and Applied Nutrition, 200 C St. SW.,

Washington, DC 20204-0001, or may be examined at the Center for Food

Safety and Applied Nutrition's Library, Food and Drug Administration,

200 C St. SW., rm. 3321, Washington, DC, or at the Office of the

Federal Register, 800 North Capitol St. NW., suite 700, Washington, DC.

(c) It is used in the manufacture of sausage casings as a

formulation aid as defined in Sec. 170.3(o)(14) of this chapter and as

a processing aid as defined in Sec. 170.3(o)(24) of this chapter.

Dated: April 14, 1997.

Fred R. Shank,

Director, Center for Food Safety and Applied Nutrition.

[FR Doc. 97-12461 Filed 5-12-97; 8:45 am]

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