INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
SAFETY EVALUATION OF CERTAIN FOOD
ADDITIVES AND CONTAMINANTS
WHO FOOD ADDITIVES SERIES: 44
Prepared by the Fifty-third meeting of the Joint FAO/WHO
Expert Committee on Food Additives (JECFA)
World Health Organization, Geneva, 2000
IPCS - International Programme on Chemical Safety
ANNEX 4
ACCEPTABLE DAILY INTAKES, OTHER TOXICOLOGICAL INFORMATION, AND
INFORMATION ON SPECIFICATIONS
1. Food additives
Substance Specificationsa ADI and other toxicological
recommendations
Glazing agent
Hydrogenated poly 1-decene R No ADI allocatedb
Sweetening agent
Erythritol N ADI 'not specified'c
Thickener
Curdlan N ADI 'not specified'
(temporary)c,d
Miscellaneous substances
gamma-Cyclodextrin R ADI 'not specified'c
Sodium iron EDTA R Considered to be safe in
food fortification
programmese
Sodium sulfate N,T ADI not specifiedc,f
a New specifications prepared; R, existing specifications revised; T, the
existing, new or revised specifications are tentative and information
is needed.
b Data were insufficient for establishing an ADI.
c ADI 'not specified' is applied to a food substance of very little
toxicity which, on the basis of the available chemical, biological,
toxicological, and other data and the total dietary intake of
the substance arising from its use at the levels necessary to
achieve the desired effect and from its acceptable background level
in food, does not, in the opinion of the Committee, represent a
hazard to health. For this reason and for reasons stated in the
individual evaluations, the establishment of an ADI in numerical
form is deemed unnecessary.
d Applies to food additive uses
e The Committee concluded that sodium iron EDTA (ethylene diamine
tetraacetate) could be considered to be safe when used in
supervised food fortification programmes in response to a need
for iron supplementation of the diet of a population as determined
by public health officials. Such programmes would provide a daily
iron intake of approximately 0.2 mg/kg bw.
f Temporary ADI pending consideration of the 'tentative' qualification
of the specifications
2. Substances evaluated by the procedure for the safety
evaluation of flavouring agents
Flavouring agent No. Specificationsa Conclusions based
on current intake
Aliphatic and aromatic sulfides and thiols
Subgroup i: Simple sulfides (thioethers)
Methyl sulfide 452 N No safety concern
Methyl ethyl sulfide 453 N No safety concern
Diethyl sulfide 454 N No safety concern
Butyl sulfide 455 N No safety concern
(1-Butenyl-1)methyl sulfide 457 N,T No safety concern
Bis(methylthio)methane 533 N,T No safety concern
Allyl sulfide 458 N,T No safety concern
Methyl phenyl sulfide 459 N No safety concern
Benzyl methyl sulfide 460 N No safety concern
Subgroup ii: Acyclic sulfides with oxidized side-chains
3-(Methylthio)propanol 461 N,T No safety concern
4-(Methylthio)butanol 462 N,T No safety concern
3-(Methylthio)-1-hexanol 463 N No safety concern
2-Methylthioacetaldehyde 465 N,T No safety concern
3-(Methylthio)propionaldehyde 466 N,T No safety concern
3-(Methylthio)butanal 467 N,T No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
4-(Methylthio)butanal 468 N,T No safety concern
3-Methylthiohexanal 469 N No safety concern
2-(Methylthio)methyl-2-butenal 470 N,T No safety concern
2,8-Dithianon-4-ene-4-carboxaldehyde 471 N,T No safety concern
Methyl 3-methylthiopropionate 472 N No safety concern
Methylthiomethyl butyrate 473 N,T No safety concern
Methyl 4-(methylthio)butyrate 474 N No safety concern
Ethyl 2-(methylthio)acetate 475 N,T No safety concern
Ethyl 3-methylthiopropionate 476 N No safety concern
Ethyl 4-(methylthio)butyrate 477 N No safety concern
3-(Methylthio)propyl acetate 478 N,T No safety concern
Methylthiomethyl hexanoate 479 N,T No safety concern
Ethyl 3-(methylthio)butyrate 480 N,T No safety concern
3-(Methylthio)hexyl acetate 481 N,T No safety concern
1-Methylthio-2-propanone 495 N,T No safety concern
1-(Methylthio)-2-butanone 496 N No safety concern
4-(Methylthio)-2-butanone 497 N,T No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
4-(Methylthio)-4-methyl-2-pentanone 500 N,T No safety concern
Di(butan-3-one-1-yl) sulfide 502 N,T No safety concern
ortho-(Methylthio)phenol 503 N,T No safety concern
4-(Methylthio)-2-oxobutanoic acid 501 N No safety concern
2-(Methylthiomethyl)-3-phenyl propenal 505 N No safety concern
Subgroup iii: Cyclic sulfides
2,5-Dimethyl-2,5-dihydroxy-1,4-dithiane 562 N,T No safety concern
2,5-Dihydroxy-1,4-dithiane 550 N No safety concern
2-Methyl-4-propyl-1,3-oxathiane 464 N,T No safety concern
4,5-Dihydro-3(2H)thiophenone 498 N,T No safety concern
2-Methyltetrahydrothiophen-3-one 499 N,T No safety concern
1,4-Dithiane 456 N,T No safety concern
2-Methyl-1,3-dithiolane 534 N No safety concern
Trithioacetone 543 N,T No safety concern
Subgroup iv: Thiols
Methyl mercaptan 508 N,T No safety concern
Propanethiol 509 N,T No safety concern
2-Propanethiol 510 N,T No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
1-Butanethiol 511 N No safety concern
2-Methyl-1-propanethiol 512 N,T No safety concern
3-Methylbutanethiol 513 N,T No safety concern
2-Pentanethiol 514 N,T No safety concern
2-Methyl-1-butanethiol 515 N No safety concern
3-Methyl-2-butanethiol 517 N No safety concern
1-Hexanethiol 518 N,T No safety concern
2-Ethylhexanethiol 519 N,T No safety concern
Prenythiol 522 N No safety concern
Thiogeraniol 524 N,T No safety concern
Cyclopentanethiol 516 N,T No safety concern
2,3, and 10-Mercaptopinane 520 N,T No safety concern
Allyl mercaptan 521 N,T No safety concern
1-para-Menthene-8-thiol 523 N,T No safety concern
Benzenethiol 525 N No safety concern
Benzyl mercaptan 526 N No safety concern
Phenylethyl mercaptan 527 N No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
ortho-Toluenethiol 528 N,T No safety concern
2,6-Dimethylthiophenol 530 N No safety concern
2-Naphthalenethiol 531 N,T No safety concern
2-Ethylthiophenol 529 N,T No safety concern
Subgroup v: Thiols with oxidized side-chains
2-Mercaptopropionic acid 551 N No safety concern
Ethyl 2-mercaptopropionate 552 N,T No safety concern
Ethyl 3-mercaptopropionate 553 N No safety concern
3-Mercaptohexyl acetate 554 N No safety concern
3-Mercaptohexyl butyrate 555 N No safety concern
3-Mercaptohexyl hexanoate 556 N,T No safety concern
1-Mercapto-2-propanone 557 N,T No safety concern
3-Mercapto-2-butanone 558 N,T No safety concern
2-Keto-4-butanethiol 559 N,T No safety concern
3-Mercapto-2-pentanone 560 N,T No safety concern
3-Mercapto-3-methyl-1-butanol 544 N,T No safety concern
3-Mercaptohexanol 545 N No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
2-Mercapto-3-butanol 546 N,T No safety concern
alpha-Methyl-beta-hydroxypropyl 547 N No safety concern
alpha-methyl-beta-mercaptopropyl sulfide
4-Methyoxy-2-methyl-2-butanethiol 548 N,T No safety concern
3-Methyl-3-mercaptobutyl formate 549 N No safety concern
para-Mentha-8-thiol-3-one 561 N,T No safety concern
Sodium 3-mercapto-oxopropionate 563 N No safety concern
Subgroup vi: Dithiols
1,2-Ethanedithiol 532 N No safety concern
1,3-Propanedithiol 535 N No safety concern
1,2-Propanedithiol 536 N,T No safety concern
1,2-Butanedithiol 537 N No safety concern
1,3-Butanedithiol 538 N No safety concern
2,3-Butanedithiol 539 N No safety concern
1,6-Hexanedithiol 540 N No safety concern
1,8-Octanedithiol 541 N No safety concern
1,9-Nonanedithiol 542 N No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
Subgroup vii: Simple disulfides
Dimethyl disulfide 564 N No safety concern
Methyl propyl disulfide 565 N,T No safety concern
Propyl disulfide 566 N No safety concern
Diisopropyl disulfide 567 N No safety concern
Methyl 1-propenyl disulfide 569 N,T No safety concern
Propenyl propyl disulfide 570 N,T No safety concern
Methyl 3-methyl-1-butenyl disulfide 571 N,T No safety concern
Allyl methyl disulfide 568 N,T No safety concern
Allyl disulfide 572 N,T No safety concern
Dicyclohexyl disulfide 575 N,T No safety concern
Methyl phenyl disulfide 576 N No safety concern
Methyl benzyl disulfide 577 N No safety concern
Benzyl disulfide 579 N,T No safety concern
Phenyl disulfide 578 N No safety concern
Subgroup viii: Disulfides with oxidized side-chains
2-Methyl-2-(methyldithio) propanal 580 N,T No safety concern
Ethyl 2-(methyldithio) propionate 581 N,T No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
Subgroup ix: Trisulfides
Dimethyl trisulfide 582 N,T No safety concern
Methyl ethyl trisulfide 583 N,T No safety concern
Methyl propyl trisulfide 584 N,T No safety concern
Dipropyl trisulfide 585 N,T No safety concern
Allyl methyl trisulfide 586 N,T No safety concern
Diallyl trisulfide 587 N,T No safety concern
Diallyl polysulfide 588 N,T No safety concern
Subgroup x: Heterocyclic disulfides
3,5-Dimethyl-1,2,4-trithiolane 573 N,T No safety concern
3-Methyl-1,2,4-trithiane 574 N,T No safety concern
Subgroup xi: Thioesters
S-Methyl thioacetate 482 N,T No safety concern
Ethyl thioacetate 483 N No safety concern
Methyl thiobutyrate 484 N,T No safety concern
Propyl thioacetate 485 N No safety concern
S-Methyl 2-methylbutanethioate 486 N,T No safety concern
S-Methyl 3-methylbutanethioate 487 N,T No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
S-Methyl 4-methylpentanethioate 488 N,T No safety concern
S-Methyl hexanethioate 489 N,T No safety concern
Allyl thiopropionate 490 N,T No safety concern
Prenyl thioacetate 491 N No safety concern
Methylthio 2-(acetyloxy)propionate 492 N No safety concern
Methylthio 2-(propionyloxy)propionate 493 N No safety concern
3-Acetyl-3-mercaptohexyl acetate 494 N No safety concern
S-Methyl benzothioate 504 N,T No safety concern
cis-and trans-Menthone-8-thioacetate 506a N No safety concern
and
506b
Subgroup xii--Sulfoxides
Methylsulfinylmethane 507 N,T No safety concern
Aliphatic primary alcohols, aldehydes, carboxylic acids, acetals and esters containing additional
oxygenated functional groups
2-Oxobutyric acid 589 N,T No safety concern
Methyl 2-hydroxy-4-methylpentanoate 590 N,T No safety concern
Methyl 2-oxo-3-methylpentanoate 591 N,T No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
Citronelloxyacetaldehyde 592 N,T No safety concern
3-Oxobutanal dimethyl acetal 593 N No safety concern
Ethyl 3-hydroxybutyrate 594 N,T No safety concern
Ethyl acetoacetate 595 N No safety concern
Butyl acetoacetate 596 N,T No safety concern
Isobutyl acetoacetate 597 N,T No safety concern
Isoamyl acetoacetate 598 N,T No safety concern
Geranyl acetoacetate 599 N,T No safety concern
Methyl 3-hydroxyhexanoate 600 N,T No safety concern
Ethyl 3-hydroxyhexanoate 601 N No safety concern
Ethyl 3-oxohexanoate 602 N No safety concern
Ethyl 2,4-dioxohexanoate 603 N,T No safety concern
3-(Hydroxymethyl)-2-heptanone 604 N,T No safety concern
1,3-Nonanediol acetate (mixed esters) 605 N,T No safety concern
Levulinic acid 606 N No safety concern
Ethyl levulinate 607 N No safety concern
Butyl levulinate 608 N No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
1,4-Nonanediol diacetate 609 N,T No safety concern
Hydroxycitronellol 610 N,T No safety concern
Hydroxycitronellal 611 N No safety concern
Hydroxycitronellal dimethyl acetal 612 N No safety concern
Hydroxycitronellal diethyl acetal 613 N,T No safety concern
Diethyl malonate 614 N No safety concern
Butyl ethyl malonate 615 N,T No safety concern
Dimethyl succinate 616 N No safety concern
Diethyl succinate 617 N No safety concern
Fumaric acida 618 R,T No safety concern
(-)-Malic acid 619 R,T No safety concern
Diethyl malate 620 N,T No safety concern
Tartaric acid (+-,-, ±, meso-) 621 R No safety concern
Diethyl tartrate 622 N No safety concern
Adipic acid 623 R No safety concern
Diethyl sebacate 624 N No safety concern
Dibutyl sebacate 625 N No safety concern
2. (continued)
Flavouring agent No. Specificationsa Conclusions based
on current intake
Ethylene brassylate 626 N No safety concern
Aconitic acid 627 N,T No safety concern
Ethyl aconitate (mixed esters) 628 N,T No safety concern
Triethyl citratea 629 R,T No safety concern
Tributyl acetylcitrate 630 N,T No safety concern
3-Methyl-2-oxobutanoic acid and 631 N,T No safety concern
sodium salt
3-Methyl-2-oxopentanoic acid and 632 N,T No safety concern
sodium salt
4-Methyl-2-oxopentanoic acid and 633 N,T No safety concern
sodium salt
2-Oxopentandioic acid 634 N No safety concern
3-Hydroxy-2-oxopropionic acid 635 N No safety concern
N, new specifications prepared; R, existing specifications revised; T, the existing new or revised
specifications are tentative and information is needed.
a The ADI for this substance was maintained.
3. Peanut and soya bean oils
The Committee reviewed available information on the potential
allergenicity of peanut and soya bean oils. It concluded that distinct
processes that would consistently yield safe products have not been
defined, since:
* the processes by which the peanut and soya bean oils tested
clinically in humans were refined were not clearly described;
* data on the protein content of those oils that had been
clinically tested were not available; and
* the quality of the analytical procedures, including validation,
for the determination of the concentration of residual protein in
the oils was not clearly described.
Further information is required.
4. Contaminants
4.1 Lead
The provisional tolerable weekly intake (PTWI) of 25 µg/kg bw was
maintained. The Committee considered the results of a quantitative
risk assessment and concluded that the concentrations of lead found
currently in food would have negligible effects on the
neurobehavioural development of infants and children. It noted,
however, examples of foods with high levels of lead remain in
commerce. The simulation model that is presented in the report could
be used to evaluate the effects of potential intervention procedures.
A complete risk assessment of lead should also take into account other
sources of exposure.
4.2 Methylmercury
The PTWI of 3.3 µg/kg bw was maintained. The Committee considered
data on intake, quantitative relationships between daily intake of
methylmercury and concentrations in blood and hair, and
epidemiological studies in progress. The information available was
insufficient to evaluate neurodevelopmental effects on the children of
mothers who had a low intake of methylmercury. No clear indication of
consistent risk was detected in the epidemiological studies. The
Committee noted that fish, the major source of methylmercury in the
diet, is an important component of nutrition, especially in certain
regions and ethnic groups, and recommended that the nutritional
benefits of fish be weighed against the possibility of harm when
limits on the concentration of methyl-mercury in fish or on fish
consumption are being considered.
4.3 Zearalenone
A PMTDI of 0.5 µg/kg bw was established.
5. Food additives considered for specifications only
Food additive Specificationsa
alpha-Acetolactate decarboxylase from Bacillus R
brevis expressed in B. subtilis
Adipic acid R
alpha-Amylase from B. megaterium expressed R
in B. subtilis
alpha-Amylase from B. stearothermophilus expressed R
in B. subtilis
Argon N
Calcium hydrogen sulfite W
Carob bean gum R
Carotenes, algae S
Carotenes, vegetable S
Chymosin A from Escherichia coli K-12 containing the R
prochymosin A gene
Chymosin B from Aspergillus niger var. awarmori R
containing the prochymosin B gene
Chymosin B from Kluyveromyces lactis containing R
the prochymosin B gene
Citric acid R
Ferrous gluconate R
Ferrous sulfate R
Ferrous sulfate, dried N
Fumaric acid R
Guar gum R
Helium N
Magnesium gluconate R
(±)-Malic acid R
Maltogenic amylase from B. stearothermophilus R
expressed In B. subtilis
5. (continued)
Food additive Specificationsa
Nitrogen R
Oxygen N
Potassium metabisulfite R
Potassium sulfite R
Riboflavin from B. subtilis R
Sodium hydrogen sulfite R
Sodium metabisulfite R
Sodium sulfite R
Sodium thiosulfate R
Sucrose esters of fatty acids R
(±)-Tartaric acid R
(-)-Tartaric acid R
Thaumatin R
Xanthan gum R
a N, new specifications prepared; R, existing specifications
revised; S, specifications exist, revision not considered or
required; W, existing specifications withdrawn
6. Food additives considered for evaluation of national
intake assessments
Substance Conclusions
Annatto extracts (bixin) Intake estimates based on levels proposed in the draft General
Standard for Food Additivesa and the range of foods in which
use is allowed integrated with national food consumption data
exceeded the ADI of 0-0.065 mg/kg bw (expressed as bixin).
Intake assessments based on national standards did not exceed
the ADI for most population groups. Data from Brazil, however,
provided evidence that 28% of the population consume annatto
as a condiment and have a chronic intake of about 150% of the ADI.
The Committee recommended that populations that have a high intake
of annatto extracts continue to be monitored and recommended that
annatto extracts be re-evaluated in 2001.
Canthaxanthin Intake estimates based on levels proposed in the draft General
Standard for Food Additivesa and the range of foods in which use
is allowed integrated with national food consumption data exceeded
the ADI of 0-0.03 mg/kg bw.
Indirect exposure through the use of canthaxanthin as a feed
additive for food animals is the major source of intake of
canthaxanthin in food.
Long-term intake based on national standards is unlikely to
exceed the ADI.
Erythrosine The intake of erythrosine could exceed the ADI of 0-0.1 mg/kg
bw if the levels proposed in the draft General Standard for
Food Additivesa are widely adopted at the national level.
Non-food sources of erythrosine, such as pharmaceutical
products, should be included in intake assessments.
On the basis of national assessments, the long-term intake of
erythrosine is unlikely to exceed the ADI.
6. (continued)
Substance Conclusions
Iron oxides Iron oxides are permitted for use in foods in the draft General
Standard for Food Additivesa under conditions of Good
Manufacturing Practice.
Intake of iron oxides assessed on the basis of national
standards is unlikely to exceed the ADI of 0-0.5 mg/kg bw.
a Intake estimates based on food additive levels in the draft General Standard for Food Additives
(GSFA) being developed by the Codex Committee on Food Additives and Contaminants integrated
with national food consumption data will give gross overestimates of actual intakes in any
one country because the levels proposed in the draft GSFA are generally compiled by adopting
the highest level of use of any one food category submitted by Member States or nongovernmental
organizations. The range of food uses specified in the draft GSFA is also usually
much wider than in national standards.
See Also:
Toxicological Abbreviations