TOXICOLOGY AND WORLDWIDE REGULATIONS CONCERNING USE

V. TOXICOLOGY AND WORLDWIDE REGULATIONS CONCERNING USE

There are two sources of international food standards, the Codex Alimentarius standards under the auspices of the Food and Agricultural Organization/World Health Organization (FAO/WHO) on a worldwide basis and the European Economic Community (EEC) direc- tives applicable to the member states within the European Economic Community (Gnauck, 1978). In the United States the Food and Drug Administration (FDA) is the primary source of regulation on food, particularly for food additives.

Recommendations for the Codex Alimentarius Committee come from the Joint Ex- pert FAO/WHO Committee on Food Additives (JEFCA), for the EEC from the Scientific Committee on Food (SCF), and in the United States from within the FDA. Opinions from the SCF and the JEFCA are provided to legislative bodies in interested countries either in Europe or elsewhere in the world. The Scientific Committee on Food is a committee of scientists nominated by the Commission of the European Communities to advise the Commission:

on any problem relating to the protection of the health and safety of persons arising from the consumption of food, and in particular on the composition of food, processes which are liable to modify food, the use of food additives and other processing aids, as well as the presence of contaminants. (Haigh, 1978)

Evaluations of emulsifiers and recommendations for their limiting concentrations in food and their acceptable daily intake (ADI) are then provided to the Commission by the SCF.

The Joint FAO/WHO Codex Alimentarius Commission, which consists of member nations and associate members of FAO and/or WHO, was established to implement the Joint FAO/WHO Food Standards Program (FAO/WHO, 1979). The Joint FAO/WHO Food Standards Program was established to promulgate international standards for foods The Joint FAO/WHO Codex Alimentarius Commission, which consists of member nations and associate members of FAO and/or WHO, was established to implement the Joint FAO/WHO Food Standards Program (FAO/WHO, 1979). The Joint FAO/WHO Food Standards Program was established to promulgate international standards for foods

The JEFCA recommended that food additives be used only after authorization by the appropriate authorities and that legal control be based on a system of permitted or positive lists. Two key criteria, technological efficacy and safety, must be satisfied before

a substance can be formally accepted as a food additive. Principles of evaluation and procedures for the toxicological analysis of food addi- tives were dealt with in four separate Committee reports (JEFCA, 1973,1994). The first stage of a toxicological evaluation is the collection of relevant data, while the second is the interpretation and assessment of the data in order to arrive at a decision about the acceptability of the substance as a food additive.

If sufficient data exist, an acceptable daily intake is recommended. The JEFCA may make one of several recommendations: a specific amount in milligrams per kilogram of body weight; an upper limit of ‘‘not specified;’’ ‘‘decision postponed’’ (pending clarifica- tion of matters related to technological use); ‘‘no ADI allocated’’ (in the absence of suffi- cient data for established safety or of adequate specifications); or ‘‘not to be used’’ (where there is sufficient information on which to base such a decision). The JEFCA definition of the acceptable daily intake for man, expressed on a body weight basis, ‘‘is the amount of a food additive that can be taken daily in the diet, even over a lifetime, without risk’’ (JEFCA, 1973,1994). In the Seventeenth Report, Annex 3 (JEFCA, 1973), the general procedures for the testing of food additives are provided. For example, recommendations are given for acute toxicity studies, biochemical studies, short-term studies, long-term toxicity, and several additional special studies including embryotoxicity, teratogenicity, and carocinogenicity.

No acute or chronic toxic effects have been observed with either lecithin or mono- and diglycerides at normal dosage levels (JECFA, 1974). There was also no evidence of acute or chronic toxic effects with fatty acid salts (JEFCA, 1970). Similarly, there were no observable acute and chronic toxicological effects from acetic, citric, lactic, tartaric, mixed tartaric, or acetic and diacetyltartaric acid esters of mono- and diglycerides (JEFCA, 1974). Sucrose fatty acid esters have shown no toxic effects at a practical dose level. In addition, both long-term and short-term studies indicate no significant organ changes and no adverse effects due to sucrose fatty acid esters. No toxic effects were seen in rats due to high doses of calcium stearoyl-2-lactylate over a short term, while the short-term studies on sodium stearoyl-2-lactylate were conflicting in terms of growth rates and relative organ weights with rats.

Both polyoxethylene (polysorbate 20) sorbitan monolaurate and polyoxethylene (polysorbate 20) sorbitan monooleate have an oral LD 50 level in excess of 30 g/kg for Both polyoxethylene (polysorbate 20) sorbitan monolaurate and polyoxethylene (polysorbate 20) sorbitan monooleate have an oral LD 50 level in excess of 30 g/kg for

80 incorporated in rat diets showed no abnormalities attributable to the diet. The same study over a 3-year period showed no evidence of abnormalities in growth rates and gross or histological analysis. Polyoxethylene (polysorbate 20) sorbitan monopalmitate (poly- sorbate 40) did not show any acute or chronic toxicological effects in rats. Neither polyoxe- thylene (polysorbate 20) sorbitan monostearate (polysorbate 60) nor polyoxethylene (poly- sorbate 20) sorbitan tristearate (polysorbate 65) showed any acute or chronic toxicological effects in test animals (JEFCA, 1974). Five percent levels in the diet of rats showed no significant toxicological effects for both polyoxethylene (polysorbate 8) stearate and poly- oxethylene (40) stearate. Neither sorbitan monolaurate, or monooleate, or monopalmitate showed any toxicological effects in rats over a 2-year period at the 5% level. The absence of toxicity for sorbitan monostearate and tristerate has also been established. Stearyl tar- trate has shown no long- or short-term toxicity based on work done with animal studies. Most of this toxicological information has also been summarized in the EFEMA (1976). Annex 4 lists the ADI for several food additives including emulsifiers.

The FDA issues ‘‘Proposed Rules’’ in the Federal Register and solicits input from the public regarding the proposed regulation changes. After due consideration, the pro- posed changes are issued as Final Rules, initially in the Federal Register and finally in the Code of Federal Regulations (CFR).

The CFR (1997) list concentrations allowed in food, while the Codex Alimentarius Commission (1995) lists both allowable concentrations in foods and the acceptable daily intakes. Table 3 was compiled from both these sources. The limitations imposed by the CAC are based on toxicological evaluations provided by the Joint FAO/WHO Expert Committee on Food Additives published in FAO Nutrition Meetings Reports. The limita- tions set for concentrations in food in the United States are published yearly in the CFR, while the limitations promulgated by the CAC (1979) are published in the Guide to the Safe Use of Food Additives . For specific applications the appropriate reference should be consulted.

In 1974 the Council of the European Communities issued Council Directive No. 74/329 to facilitate trade among countries within the European community. Food emulsi- fiers, as defined in the directive, are ‘‘those substances which, when added to a foodstuff, make it possible to form or maintain a uniform dispersion of two or more immiscible substances.’’ The emulsifiers, as authorized in 1974 by the European Economic Council (EEC), and as amended in 1978, 1980, and 1985, are those emulsifiers listed in Table 4 with an EEC number. A second category, Annex II, published in 1980 by the EEC, is that of emulsifiers that may be authorized for use by member states for a limited time.

In the United States a list of the emulsifiers approved for use has been published in the Code of Federal Regulations, Part 172 of Title 21 (1997). The CFR covers food emulsifiers under two categories: those permitted only under specific conditions and those generally recognized as safe. The emulsifiers covered are in the Code of Federal Regula- tions, Title 21, Part 182, subpart E. Included in this table is lecithin, covered in Part 184 but also listed as GRAS. Both of these groups are listed in Table 4. As one can see from Table 4, there are several emulsifiers that are allowed in the United States but not in Europe and vice versa.

Most of the approved uses for food additives as food emulsifiers as listed in the CFR (1997) are in Table 5 . The CFR also discusses the limiting concentrations for the emulsifiers and the methods approved for their production. A list of the approved uses

Table 3 Limitations for Emulsifiers List from the U.S. Code of Federal Regulations and the Codex Alimentarius Commission

CAC b

CFR a ML c ADI d

Lecithin GRAS e 5–20 g/kg f Not specified g Na phosphate derivatives of mono- and diglycerides of fatty acids

Not specified Hydroxylated lecithin h

GRAS

No ADI i Na, K, and Ca salts of fatty acids j

Not specified Mono- and diglycerides of fatty acids

2.5–15 g/kg Not specified k Acetic acid esters of mono- and diglycerides of fatty acids l,m

GRAS

10–20 g/kg (oil) Not specified k Lactic acid esters of mono- and diglycerides of fatty acids l,m

10–20 g/kg (oil) Not specified k Citric acid esters of mono- and diglycerides of fatty acids l

10–20 g/kg (oil) Not specified k Mixed acetic and tartaric acid esters of mono- and diglycerides of fatty acids l

200 ppm

10–20 g/kg (oil) Not specified k Mono- and diacetyltartaric acid esters of mono- and diglycerides of fatty acids

10–20 g/kg (oil) 0–50 mg/kg n Tartaric acid esters of mono- and diglycerides of fatty acids l

GRAS

Not specified k Sucrose esters of fatty acids h,m

10–20 g/kg 0–2.5 mg/kg Sucroglycerides

10–20 g/kg 0–2.5 mg/kg Polyglycerol esters of fatty acids m

5–20 g/kg 0–25 g/kg Na stearoyl-2-lactylate

0–20 mg/kg Ca stearoyl-2-lactylate

0.2–0.5% p

20 g/kg

0–20 mg/kg Stearyl citrate

0.05–0.5% p

20 g/kg

0–50 mg/kg

0–25 mg/kg Polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40) q

Polyoxyethylene (20) sorbitan monolaurate (polysorbate 20) e —

0–25 mg/kg Polyoxyethylene (20) sorbitan monostearate (polysorbate 60) q

0–25 mg/kg Polyoxyethylene (20) sorbitan tristearate (polysorbate 65) q

15–20 g/kg 0–25 mg/kg Polyoxyethylene (20) sorbitan monooleate (polysorbate 80) q

20 g/kg (oil) 0–25 mg/kg Polyoxyethylene (8) stearate

0–25 mg/kg r Polyoxyethylene (40) sorbitan

0–25 mg/kg r Ammonium phosphatides

0–30 mg/kg Thermally oxidized soybean oil interacted with mono- and diglycerides of fatty acids

0–0.3 mg/kg Lactylated fatty acid esters of glycerol and propylene glycol l

Not specified k Dioctyl sodium succinate

0–0.1 mg/kg Stearyl monoglyceridyl citrate j

25 ppm (cocoa fat)

5 g/kg

Not specified k

0–25 mg/kg Copolymer condensates of ethylene oxide and propylene oxide

Stearyl propylene glycol hydrogen succinate (succistearin) h —

0–25 mg/kg Methyl glucoside–coconut oil ester

0.5% (flour)

— Oxystearin

320 ppm (molasses)

— Sodium lauryl sulfate

0.125% (oil)

125–1000 ppm (egg

whites) 25 ppm (fruit juice drink)

Sodium stearoyl fumarate

0.5–1.0% (bakery products)

0.2% (starch thickened foods)

Succinylated monoglycerides

3.0% (shortening)

0.5% (flour)

Ethoxylated mono- and diglycerides

0.2–0.5% (flour, dairy

substitutes, etc.)

Polyglycerol polyricinoleate

0–7.5 mg/kg Propylene glycol esters of fatty acids l

5–20 g/kg

0–25 mg/kg Propylene glycol alginate p (limited by GMP t )

20 g/kg

0–25 mg/kg Sorbitan esters of monostearate

5–10 g/kg

10–20 g/kg 0–25 mg/kg u Sorbitan esters of tristearate

10–20 g/kg 0–25 mg/kg u Sorbitan esters of monopalmitate

10–20 g/kg 0–25 mg/kg u Sorbitan esters of monolaurate

0–25 mg/kg u Sorbitan esters of monooleate

0–25 mg/kg u a Code of Federal Regulation gives the concentrations allowed in food.

b Codex Alimentarius Commission. c ML is the designation for the maximum limit, which is product specific. d Acceptable daily intake (ADI) is in milligrams of emulsifier per kilogram of body weight. e Generally recognized as safe.

f Grams of emulsifier per kilogram of food product. g An ADI of ‘‘not specified’’ is allocated to substances which do not constitute a toxicological hazard to man except under the most gross conditions of overexposure. h Must be used in accordance with good manufacturing practices (GMP).

i No ADI indicates no ADI allocated. j Must be used as outlined in the Code of Federal Regulations. k As sum of the total mixed glycerol fatty acids and acetic, citric, lactic, and tartaric acids, provided that the total amount of emulsifier does not exceed 100 mg/kg. l As sum of the total glycerol fatty acids and acetic, citric, lactic, and tartaric acids, provided that the total additive intake of tartaric acid does not exceed 30 mg/kg. m Must not be used in excess of the amount reasonably required to produce its effect in food. n Milligrams of emulsifier per kilogram of body weight. o Calculated as the palmitate ester. p Concentration is dependent on both the food products the emulsifier is used in and the other emulsifiers used (refer to CFR, Title 21). q As the sum of the polyoxyethylene (20) sorbitan esters. r As the sum of polyoxyethylene (20) sorbitan and polyoxyethylene (8) stearate. s As propylene glycol. t The additive in question is self-limiting in food for technological, organoleptic, or other reasons and that, therefore, the additive need not be subject to legal maximum limits. It also means that the food additives must be used according to good manufacturing practice and in accordance with the General Principles for the Use of Food Additives. u As the sum of all the sorbitan esters.

Table 4 Emulsifiers Authorized for Use by the EEC Emulsifier designation

EEC no. CFR no. Lecithins

E322 184.1400 Sodium phosphate derivatives of mono- and diglycerides of edible oils

— 182.4521 Stearyl monoglyceride citrate

— 172.755 Stearoyl propylene glycol hydrogen succinate (succistearin)

— 172.765 Copolymer condensates of ethylene oxide and propylene oxide

— 172.808 Hydroxylated lecithins

— 172.814 Methyl glucoside–coconut oil ester

— 172.816 Oxystearin

— 172.818 Sodium lauryl sulfate

— 172.822 Sodium stearoyl fumarate

— 172.826 Na, K, and Ca salts of fatty acids

E470 172.863 Succinylated monoglycerides

— 172.830 Ethoxylated mono- and diglycerides

— 172.834 Mono- and diglycerides of fatty acids

E471 182.4505 Acetic acid esters of mono- and diglycerides of fatty acids

E472(a) 172.828 Lactic acid esters of mono- and diglycerides of fatty acids

E472(b) 172.852 Citric acid esters of mono- and diglycerides of fatty acids

E472(c) 172.832 Tartaric acid esters of mono- and diglycerides of fatty acids

E472(d) — Mono- and diacetyltartaric acid esters of mono- and diglycerides of

E472(e) 182.4101 fatty acids Mixed acetic and tartaric acid esters of mono- and diglycerides of

E472(f ) — fatty acids Sucrose esters of fatty acids

E473 172.859 Sucroglycerides

E474 — Polyglycerol esters of fatty acids

E475 172.854 Propane-1,2-diol esters of fatty acids (or propyleneglycol esters of

E476 172.856 fatty acids) Propylene glycol alginate

— 172.858 Na stearoyl-2-lactylate

E481 172.846 Ca stearoyl-2-lactylate

E482 172.844 Stearyl tartrate

E483 — Polyoxyethylene (20) sorbitan monolaurate (polysorbate 20)

Annex II 172.515 Polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40)

Annex II 172.515 Polyoxyethylene (20) sorbitan monostearate (polysorbate 60)

Annex II 172.836 Polyoxyethylene (20) sorbitan tristearate (polysorbate 65)

Annex II 172.838 Polyoxyethylene (20) sorbitan monooleate (polysorbate 80)

Annex II 172.840 Polyoxyethylene (8) stearate

Annex II — Polyoxyethylene (40) sorbitan

Annex II — Ammonium phosphatides

Annex II — Thermally oxidized soybean oil interacted with mono- and diglycer-

Annex II — ides of fatty aids Lactylated fatty acid esters of glycerol and propylene glycol

— 172.850 Lactylic esters of fatty acids

— 172.848 Dioctyl sodium sulfosuccinate

Annex II 172.810 Polyglycerol polyricinoleate

Annex II — Sorbitan esters of monostearate

Annex II 172.842 Sorbitan esters of tristearate

Annex II — Sorbitan esters of monolaurate

Annex II —

Table 5 Approved Uses for Food Additives as Emulsifiers Additive

Approved uses or functions Stearyl monoglyceridyl citrate

Emulsion stabilizer in shortenings

Succistearin oil Shortenings and edibles used in baked products, e.g., pastries Copolymer condensates of

Yeast-leavened products and flavor concentrates ethylene oxide and propy- lene oxide

Dioctyl sodium sulfosuccinate Emulsifier in cocoa fat for noncarbonated beverages Hydroxylated lecithin a Methyl glucoside–coconut oil

Surfactant in molasses

ester Oxystearin

Inhibition of crystallization of vegetable oils Sodium lauryl sulfate

To facilitate product formulation with egg whites Sodium stearoyl fumarate