973. Simple aliphatic and aromatic sulfides and thiols (WHO Food Additives Series 44)

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

SIMPLE ALIPHATIC AND AROMATIC SULFIDES AND THIOLS

First draft prepared by Dr A. Mattia¹ and Professor A.G. Renwick²

¹Division of Product Policy, Office of Premarket Approval, Center for
Food Safety and Applied Nutrition, US Food and Drug Administration,
Washington DC, United States; ²Clinical Pharmacology Group,
University of Southampton, Southampton, United Kingdom

Evaluation
Introduction
Estimated daily intake
Metabolic considerations
Application of the Procedure for the Safety Evaluation of
Flavouring Agents
Consideration of combined intakes
Conclusions
Relevant background information
Explanation
Additional considerations on intake
Biological data
Absorption, distribution, metabolism, and excretion
Simple sulfides (thioethers)
Acyclic sulfides with oxidized side-chains
Cyclic sulfides
Simple thiols
Thiols with oxidized side-chains
Dithiols
Simple disulfides
Disulfides with oxidized side-chains
Trisulfides
Heterocyclic disulfides
Thioesters
Sulfoxides
Toxicological studies
Acute toxicity
Short-term studies of toxicity
Ninety-day studies of toxicity
Long-term studies of toxicity and carcinogenicity
Genotoxicity
Developmental toxicity
Chemoprevention
Observations in humans
References

1. EVALUATION

1.1 Introduction

The Committee evaluated a group of 137 flavouring agents that
includes aliphatic and aromatic sulfides and thiols, with and without
an additional oxygenated functional group (see Table 1), using the
Procedure for the Safety Assessment of Flavouring Agents (Figure 1, p.
122). The Committee has not previously evaluated any member of the
group.

1.2 Estimated daily intake

The total annual volume of the 137 sulfides and thiols in this
group is approximately 6000 kg in Europe and 5300 kg in the United
States. Approximately 51% and 52%, respectively, of the total annual
volume in Europe and in the United States is accounted for by methyl
sulfide (No. 452). The estimated daily intake, modified for use to
calculate the intake of flavouring agents and for 'eaters only' (see
introduction to this section), of methyl sulfide is 10 µg/kg bw in
Europe and 9 µg/kg bw in the United States; the intake of the
remaining substances in this group is lower. The estimated modified
daily intake of methyl 3-methylthiopropionate (No. 472) in Europe and
of bis(methylthio)methane (No. 533) in the United States is 2 µg/kg
bw. The estimated modified intake of four substances in Europe,
3(methylthio)propional-dehyde (No. 466), ethyl 3-methyl-thiopropionate
(No. 476), methyl mercaptan (No. 508), and allyl disulfide (No. 572),
and two substances in the United States, benzenethiol (No. 525) and
3-methyl-1,2,4-trithiane (No. 574), is estimated to be 0.0003-0.2
µg/kg bw per day. The values for the intake of each substance in the
group in Europe and in the United States are reported in Table 1.

Sulfides and thiols have been detected in a variety of foods,
including onion, garlic, beer, cabbage, tea, and coffee. Of the
substances in this group, 106 have been reported to occur naturally in
foods. Quantitative data on the natural occurrence of 19 substances in
the group demonstrate that they are consumed predominantly from
traditional foods, with the exception of methyl 3-methylthiopropionate
(No. 472) and ethyl 3-methylthiopropionate (No. 476).

One-hundred-and-six of the 137 sulfur-containing substances in
this group of flavours have been detected as natural components of
traditional foods (Maarse et al., 1994; see Table 2). Quantitative
data on the natural occurrence of 19 of these substances have been
reported which indicate that the intake of 17 of them is predominantly
from food (i.e. a consumption ratio >1; Stofberg & Kirschman, 1985;
Stofberg & Grundschober, 1987). The exceptions are methyl
3-methylthiopropionate (No. 472) (consumption ratio = 0.0006 in Europe
and 0.1 in the United States) and ethyl 3-methylthiopropionate (No.
476) (consumption ratio = 0.05 in Europe and 1 in the United States)
suggesting that the intake of these two substances is greater from
their use as flavours than from their consumption in food.

1.3 Metabolic considerations

The large group of 137 flavouring agents considered at this
meeting was divided into 12 subgroups on the basis of the position of
the sulfur atom, to facilitate the assessment of their metabolism and
the data on toxicity. The subgroups are:

(i) simple sulfides (thioethers), in which the sulfur is located
between two unoxidized alkyl or aryl side-chains (Nos
452-455, 457-460, and 533);

(ii) acyclic sulfides with oxidized side-chains, in which an
alcohol, aldehyde, ketone, ester, carboxylic acid, or phenol
group is present (Nos 461-463, 465-481, 495-497, 500-503,
and 505);

(iii) cyclic sulfides (Nos 456, 464, 498, 499, 534, 543, 550, and
562);

(iv) simple thiols with unoxidized aliphatic or aromatic
side-chains (Nos 508-531);

(v) thiols with oxidized side chains, in which an alcohol,
aldehyde, ketone, ester, or carboxylic acid group is present
(Nos 544-549, 551-561, and 563);

(vi) dithiols (Nos 532 and 535-542);

(vii) simple disulfides (Nos 564-572 and 575-579);

(viii) disulfides with oxidized side chains (Nos 580 and 581);

(ix) trisulfides and polysulfides (Nos 582-588);

(x) heterocyclic disulfides (Nos 573 and 574);

(xi) thioesters (Nos 482-494, 504, and 506a and b); and

(xii) sulfoxides (No. 507).

All of the sulfur substances considered are of low relative
molecular mass and are sufficiently lipophilic to be absorbed from the
intestine. These flavouring agents would be metabolized through many
different pathways. As metabolism would usually result in increased
polarity and greater likelihood of excretion, they would not be
expected to accumulate in the body. Many substances, such as thiols
and disulfides, would be able to form disulfide bonds with endogenous
thiols. Disulfides formed with cysteine could be excreted in the urine
as the xenobiotic cysteine disulfide, whereas formation of disulfides
with endogenous macromolecules would delay elimination and could
result in effects such as enzyme inhibition.

Table 1. Summary of results of safety evaluations of aliphatic and aromatic sulfides and thiols

Substance JECFA CAS No. Step B3 Step B4. Adequate Step B5 Conclusion
and structure No. Does margin of safety Does intake based on
intake for substance or exceed current
exceed related substance? 1.5 µg/day? intake
threshold
for human
intake?

Subgroup (i): Simple sulfides (thioethers)
Structural class I

Methyl sulfide 452 75-18-3 No Yes. A NOEL of 250 N/R No safety
mg/kg bw per day was concern
reported in a 14-week
study in rats treated
with methyl sulfide at
multiple doses.

Methyl ethyl 453 624-89-5 No Yes. A NOEL of 250 mg/kg bw N/R No safety
sulfide per day was reported in concern
a 14-week study in rats
treated with methyl sulfide
at multiple doses.

Diethyl sulfide 454 352-93-2 No Yes. A NOEL of 250 mg/kg bw N/R No safety
per day was reported in a concern
14-week study in rats treated
with methyl sulfide at multiple
doses.

Table 1. (continued)

Butyl sulfide 455 544-40-1 No Yes. A NOEL of 250 mg/kg bw per N/R No safety
day was reported in a 14-week concern
study in rats treated with
methyl sulfide at multiple doses.

(1-Butenyl-1) 457 32951-19-2 No Yes. A NOEL of 250 mg/kg bw per N/R No safety
methyl sulfide day was reported in a 14-week concern
study in rats treated with methyl
sulfide at multiple doses.

Bis(methylthio)methane 533 1618-26-4 No Yes. A NOEL of 250 mg/kg bw per N/R No safety
day was reported in a 14-week concern
study in rats treated with methyl
sulfide (No. 452) at multiple
doses

Table 1. (continued)

Structural class II

Allyl sulfide 458 592-88-1 No No. Allyl mercaptan is not predicted Yes No safety
to be a metabolite of allyl sufide. concern

Methyl phenyl sulfide 459 100-68-5 No No Yes No safety
concern

Benzyl methyl sulfide 460 766-92-7 No No Yes No safety
concern

Table 1. (continued)

Subgroup (ii): Acyclic sulfides with oxidized side-chains

Structural class I

3-(Methylthio)propanol 461 505-10-2 No Yes. A NOEL of 1.4 mg/kg bw per N/R No safety
day was reported in a 90-day syudy concern
in rats given
2-(methylthiomethyl)-3-phenyl-propenal
(No. 505) only at that dose. Data
for methyl sulfide (No. 452) are
relevant to compounds with a simple
oxidized side-chain.

4-(Methylthio)butanol 462 999999-26-9 No Yes. A NOEL of 1.4 mg/kg bw was N/R No safety
in a reported 90-day syudy concern
in rats given
2-(methylthiomethyl)-3-phenyl-propenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

3-(Methylthio)-1-hexanol 463 51755-66-9 No Yes. A NOEL of 1.4 mg/kg bw was reported N/R No safety
in a 90-day syudy in rats given concern
2-(methylthiomethyl)-3-phenyl-propenal
(No. 505) only at that dose.
Data for methyl sulfide (No. 452) are
relevant to compounds with a simple
oxidized side-chain.

2-Methylthioacetaldehyde 465 23328-62-3 No Yes. A NOEL of 1.4 mg/kg bw was reported N/R No safety
in a 90-day syudy in rats given concern
2-(methylthiomethyl)-3-phenyl-propenal
(No. 505) only at that dose.
Data for methyl sulfide (No. 452) are
relevant to compounds with a simple
oxidized side-chain.

Table 1. (continued)

3-(Methylthio) 466 3268-49-3 No Yes. A NOEL of 1.4 mg/kg bw per day was N/R No safety
propionaldehyde reported in a 90-day study in rats concern
treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

3-(Methylthio)butanal 467 16630-52-7 No Yes. A NOEL of 1.4 mg/kg bw per day was N/R No safety
reported in a 90-day study in rats concern
treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

4-(Methylthio)butanal 468 42919-64-2 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

3-Methylthiohexanal 469 38433-74-8 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

2-(Methylthio) 470 40878-72-6 No No No No safety
methyl-2-butenal concern

2,8-Dithianon-4-ene-4-carbox- 471 59902-01-1 No No No No safety
aldehyde concern

Table 1. (continued)

Methyl 3-methylthiopropionate 472 13532-18-8 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain. The simple side-chain acid
and ester would be predicted to be of
low toxicity.

Table 1. (continued)

Methylthiomethyl butyrate 473 74758-93-3 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Methyl 4-(methylthio)butyrate 474 53053-51-3 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

Ethyl 2-(methylthio)acetate 475 4455-13-4 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Ethyl 3-methylthiopropionate 476 133327-56-5 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

Ethyl 4-(methylthio)butyrate 477 22014-48-8 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

3-(Methylthio)propyl acetate 478 16630-55-0 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data
for methyl sulfide (No. 452) are
relevant to compounds with a simple
oxidized side-chain.

Table 1. (continued)

Methylthiomethyl hexanoate 479 74758-91-1 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Ethyl 3-(methylthio)butyrate 480 Pending No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day syudy in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

3-(Methylthio)hexyl acetate 481 51755-85-2 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

1-Methylthio-2-propanone 495 14109-72-9 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study concern
in rats given
2-(methylthiomethyl)-3-phenyl-propenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

1-(Methylthio)-2-butanone 496 13678-58-5 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

4-(Methylthio)-2-butanone 497 34047-39-7 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

4-(Methylthio)-4-methyl-2- 500 23550-40-5 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
pentanone was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Di(butan-3-one-1-yl) sulfide 502 40790-04-3 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

Structural class II

ortho-(Methylthio)phenol 503 1073-29-6 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

Table 1. (continued)

Structural class III

4-(Methylthio)-2-oxobutanoic 501 51828-97-8 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
acid, sodium salt was reported in a 90-day study in concern
rats treated with
2-(methylthiomethyl)-3-phenylpropenal
(No. 505) only at that dose. Data for
methyl sulfide (No. 452) are relevant
to compounds with a simple oxidized
side-chain.

2-(Methylthiomethyl)-3-phenyl 505 65887-08-3 No Yes. A NOEL of 1.4 mg/kg bw per day N/R No safety
- propenal was reported in a 90-day study in concern
rats treated with this substance only
at that dose. Data for methyl sulfide
(No. 452) are relevant to compounds
with a simple oxidized side-chain.

Table 1. (continued)

Subgroup (iii): Cyclic sulfides

Structural class I

2,5-Dimethyl-2,5-dihydroxy-1,4- 562 55704-78-4 No Yes. A NOEL of 3.1 mg/kg bw per day N/R No safety
dithiane was reported in a 90-day study in rats concern
treated with this substance only at
that dose.

2,5-Dihydroxy-1,4-dithiane 550 40018-26-6 No Yes. A NOEL of 3.1 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
2,5-dimethyl-2,5-dihydroxy-1,4-dithiane
(No. 562) only at that dose.

Table 1. (continued)

Structural class II

2-Methyl-4-propyl-1,3-oxathiane 464 67715-80-4 No Yes. A NOEL of 0.44 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with this substance only at
that dose.

4,5-Dihydro-3-(2H)-thiophenone 498 1003-04-9 No Yes. A NOEL of 9.2 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with this substance only at
that dose.

Table 1. (continued)

2-Methyltetrahydrothiophen-3-one 499 13679-85-1 No Yes. A NOEL of 9.2 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with
4,5-dihydro-3-(2H)-thiophenone (No. 498)
only at that dose.

1,4-Dithiane 456 505-29-3 No Yes. NOELs of 0.44, 7, and 0.2 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-methyl-4-propyl-1,3-oxathiane
(No. 464), 2-methyl-1,3-dithiolane
(No. 534), and tri-thioacetone
(No. 543), respectively, only at those
doses.

Table 1. (continued)

2-Methyl-1,3-dithiolane 534 5616-51-3 No Yes. A NOEL of 7 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with this substance only at
that dose.

Trithioacetone 543 828-26-2 No Yes. A NOEL of 0.2 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with this substance only at
that dose.

Subgroup (iv): Thiols

Structural class I

Methyl mercaptan 508 74-93-1 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

Table 1. (continued)

Propanethiol 509 107-03-9 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

2-Propanethiol 510 75-33-2 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

1-Butanethiol 511 109-79-5 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

Table 1. (continued)

2-Methyl-1-propanethiol 512 513-44-0 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

3-Methylbutanethiol 513 541-31-1 No Yes. A NOEL of 0.56 mg/kg bw per day NR No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

2-Pentanethiol 514 2084-19-7 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

Table 1. (continued)

2-Methyl-1-butanethiol 515 1878-18-8 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

3-Methyl-2-butanethiol 517 2084-18-6 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

1-Hexanethiol 518 111-31-9 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

Table 1. (continued)

32-Ethylhexanethiol 519 7341-17-5 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

Prenythiol 522 5287-45-6 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose; see diallyl
trisulfide (No. 587, subgroup ix), which
is predicted to be metabolized to allyl
disulfide and allyl thiol.

Table 1. (continued)

Thiogeraniol 524 39067-80-6 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose; see
diallyl trisulfide (No. 587, subgroup
ix), which is predicted to be
metabolized to allyl disulfide and
allyl thiol.

Structural class II

Cyclopentanethiol 516 1679-07-8 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with this substance only at
that dose.

Table 1. (continued)

2,3- or 10-Mercaptopinane 520 23832-18-0 No Yes. A NOEL of 0.06 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with this substance only at
that dose. NOELs of 0.56, 0.52, 0.43,
and 3.4 mg/kg bw per day were reported
in 90-day studies in rats treated with
cyclo-pentanethiol (No. 516),
ortho-toluenethiol (No. 528),
2,6-dimethylthiophenol (No. 530), and
2-naphthalenethiol (No. 531),
respectively, only at those doses.

Allyl mercaptan 521 870-23-5 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

Table 1. (continued)

1-para-Menthene-8-thiol 523 71159-90-5 No Yes. A NOEL of 0.56 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with cyclopentanethiol
(No. 516) only at that dose.

Benzenethiol 525 108-98-5 No Yes. NOELs of 0.52, 0.43, and 3.4 N/R No safety
mg/kg bw per day were reported in concern
90-day studies in rats treated with
ortho-toluenethiol (No. 528),
2,6-dimethyl-thiophenol (No. 530), and
2-naphthal-enethiol (No. 531),
respectively, only at those doses.

Table 1. (continued)

Benzyl mercaptan 526 100-53-8 No Yes. NOELs of 0.52, 0.43, and 3.4 N/R No safety
mg/kg bw per day were reported in concern
90-day studies in rats treated with
ortho-toluenethiol (No. 528),
2,6-dimethyl-thiophenol (No. 530), and
2-naphthal-enethiol (No. 531),
respectively, only at those doses.

Phenethyl mercaptan 527 4410-99-5 No Yes. NOELs of 0.52, 0.43, and 3.4 N/R No safety
mg/kg bw per day were reported in concern
90-day studies in rats treated with
ortho-toluenethiol (No. 528),
2,6-dimethyl-thiophenol (No. 530), and
2-naphthal-enethiol (No. 531),
respectively, only at those doses.

Table 1. (continued)

ortho-Toluenethiol 528 137-06-4 No Yes. A NOEL of 0.52 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with this substance only at
that dose.

2,6-Dimethylthiophenol 530 118-72-9 No Yes. A NOEL of 0.43 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
treated with this substance only at
that dose.

2-Naphthalenethiol 531 91-60-1 No Yes. A NOEL of 3.4 mg/kg bw per day N/R No safety
was reported in a 90-day study in concern
rats treated with this substance
only at that dose.

Table 1. (continued)

Structural class III

2-Ethylthiophenol 529 4500-58-7 No Yes. NOELs of 0.52, 0.43, and 3.4 N/R No safety
mg/kg bw per day were reported in concern
90-day studies in rats treated with
ortho-toluenethiol (No. 528),
2,6-dimethyl-thiophenol (No. 530),
and 2-naphthal-enethiol (No. 531),
respectively, only at those doses.

Table 1. (continued)

Subgroup (v): Thiols with oxidized side-chains

Structural class I

2-Mercaptopropionic acid 551 79-42-5 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Table 1. (continued)

Ethyl 2-mercaptopropionate 552 19788-49-9 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Ethyl 3-mercaptopropionate 553 5466-06-8 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Table 1. (continued)

3-Mercaptohexyl acetate 554 136954-20-6 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

3-Mercaptohexyl butyrate 555 136954-21-7 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Table 1. (continued)

3-Mercaptohexyl hexanoate 556 136954-22-8 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

1-Mercapto-2-propanone 557 24653-75-6 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Table 1. (continued)

3-Mercapto-2-butanone 558 40789-98-8 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

2-Keto-4-butanethiol 559 34619-12-0 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Table 1. (continued)

3-Mercapto-2-pentanone 560 67633-97-0 No Yes. A NOEL of 1.9 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
given this substance only at that dose.

3-Mercapto-3-methyl-1-butanol 544 34300-94-2 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Table 1. (continued)

3-Mercaptohexanol 545 51755-83-0 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Table 1. (continued)

2-Mercapto-3-butanol 546 37887-04-0 No Yes. A NOEL of 1.9 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
given this substance only at that dose.

alpha-methyl-beta-hydroxypropyl 547 54957-02-7 No Yes. A NOEL of 2.8 mg/kg bw per day N/R No safety
alpha-methyl-beta-mercaptopropyl was reported in a 90-day study in rats concern
sulfide given this substance only at that dose.

4-Methyoxy-2-methyl-2-butane- 548 94087-83-9 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Table 1. (continued)

3-Methyl-3-mercaptobutyl formate 549 50746-10-6 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses.

Table 1. (continued)

Structural class II

para-Mentha-8-thiol-3-one 561 38462-22-5 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those doses.

Table 1. (continued)

Structural class III

Sodium 3-mercapto-oxo-propionate 563 10255-67-1 No Yes. NOELs of 1,9, 2.8, and 1.9 mg/kg N/R No safety
bw per day were reported in 90-day concern
studies in rats treated with
2-mercapto-3-butanol (No. 546),
alpha-methyl-beta-hydroxypropyl
alpha-methyl-beta-mercaptopropyl sulfide
(No. 547), and 3-mercapto-2-pentanone
(No. 560), respectively, only at those
doses. See subgroup (i), No. 452 for the
sulfur moiety; the oxopropionate moiety
would be predicted to be of low
toxicity.

Table 1. (continued)

Subgroup (vi): Dithiols

Structural class I

1,2-Ethanedithiol 532 540-63-6 No Yes. NOELs of 0.7 mg/kg bw per day N/R No safety
were reported in 90-day studies in rats concern
treated with 2,3-butanedithiol
(No. 539) and 1,8-octanedithiol
(No. 541) only at that dose.

1,3-Propanedithiol 535 109-80-8 No Yes. NOELs of 0.7 mg/kg bw per day N/R No safety
were reported in 90-day studies in rats concern
treated with 2,3-butanedithiol (No. 539)
and 1,8-octanedithiol (No. 541) only at
that dose.

Table 1. (continued)

1,2-Propanedithiol 536 814-67-5 No Yes. NOELs of 0.7 mg/kg bw per day N/R No safety
were reported in 90-day studies in rats concern
treated with 2,3-butanedithiol (No. 539)
and 1,8-octanedithiol (No. 541) only at
that dose.

1,2-Butanedithiol 537 16128-68-0 No Yes. NOELs of 0.7 mg/kg bw per day N/R No safety
were reported in 90-day studies in rats concern
treated with 2,3-butanedithiol (No. 539)
and 1,8-octanedithiol (No. 541) only at
that dose.

1,3-Butanedithiol 538 24330-52-7 No Yes. NOELs of 0.7 mg/kg bw per day N/R No safety
were reported in 90-day studies in rats concern
treated with 2,3-butanedithiol (No. 539)
and 1,8-octanedithiol (No. 541) only at
that dose.

Table 1. (continued)

2,3-Butanedithiol 539 4532-64-3 No Yes. A NOEL of 0.7 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
given this substance only at that dose.

1,6-Hexanedithiol 540 1191-43-1 No Yes. NOELs of 0.7 mg/kg bw per day N/R No safety
were reported in 90-day studies in rats concern
treated with 2,3-butanedithiol (No. 539)
and 1,8-octanedithiol (No. 541) only at
that dose.

1,8-Octanedithiol 541 1191-62-4 No Yes. A NOEL of 0.7 mg/kg bw per day N/R No safety
was reported in a 90-day study in rats concern
given this substance only at that dose.

Table 1. (continued)

1,9-Nonanedithiol 542 3489-28-9 No Yes. NOELs of 0.7 mg/kg bw per day N/R No safety
were reported in 90-day studies in rats