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A Report on Sucralose from the Food Sanitation Council
Last updateF03/12/2009

A Report from the Joint Subcommittee on Toxicity and Food Additives
concerning the Designation of Food Additives
and the Revision of Standards for Use under the Food Sanitation Council

January 6, 1999
Food Chemistry Division

Today, the Joint Subcommittee on Toxicity and Food Additives under the Food Sanitation Council has compiled a report on the result of discussions conducted during the session held on December 18, 1998 on the adequacy of the designation of Sucralose as an approved additive. The session was based on the consultation made by the Minister of Health and Welfare to the Food Sanitation Council on June 15, 1998. The Food Chemistry Division hereby announces an outline of the report and work schedule for the designation of Sucralose.

1. Outline of the report
About the adequacy of the designation of Sucralose
2. Schedule
(1) Presentation to the Conference for Promotion of Food Import and Facilitation (2) Notification given to WTO (3) A final report from the Food Sanitation Council to the Minister of Health and Welfare
(4) Amendment of the Enforcement Regulations under the Food Sanitation Law, and announcement of the designation of Sucralose with newly added regulations



* Translated by The San-Ei Gen Foundation for Food Chemical Research. Please refer to the Japanese version, if you find anything unclear on this translation.

Food Sanitation Council Notice, No.5
January 6, 1999
Mr. Masaaki Terada, Chairman
Food Sanitation Council
Masaru Tobe, Chairman
The Subcommittee on Toxicity

Mikio Yamazaki, Chairman
The Subcommittee on Food Additives

A Report from the Joint Subcommittee on Toxicity and Food Additives
concerning the Designation of Food Additives
under the Food Sanitation Council

Today, the Joint Subcommittee on Toxicity and Food Additives under the Food Sanitation Council has compiled a report on the result of discussions conducted during the session held on December 18, 1998 on the adequacy of the designation of Sucralose as an approved additive. The session was based on the consultation made by the Minister of Health and Welfare with the Food Sanitation Council on June 15, 1998, under Notice No. 109 issued by the Ministry of Health and Welfare. We hereby jointly report the result to the Chairperson of the Food Sanitation Council.


The Joint Subcommittee on Toxicity and Food Additives
under the Food Sanitation Council

1. The Joint Subcommittee on Toxicity and Food Additives concerning the Designation of Food Additives under the Food Sanitation Council
1) Date of session December 18, 1998
2) Members' list Omitted

2. The Working Group on the Designation of Food Additives
1) Dates of sessions1st August 6, 1998
2nd October 6, 1998
3rd November 13, 1998
2) Members' list Omitted


Designation of Sucralose
1. Name: sucralose
2. Structural formula:
3. Use: Sweetening agent 4. Origin or details of development and use conditions
5. Effectiveness
6. Safety 7. Absorption, Distribution, Metabolism and Elimination
8. Determination of acceptable daily intake(ADI)
9. Estimation of daily intake
10. Standards for use of sucralose 11. Specifications

The study results and other information mentioned here were given in the accompanying documents listed in Attachment 1.


Attachment 1

Contents of document
Contents
Reference
Document No
Vol.
1 Summary
San-Ei Gen F.F.I., Inc.
1
1

2 Chronology on origin or development and overseas use condition
2-1 Details of origin or development
San-Ei Gen F.F.I., Inc.
2-1
2
2-2 Overseas use condition
San-Ei Gen F.F.I., Inc.
2-2
2

3 Physicochemical characteristics and specifications
3-1 Name
San-Ei Gen F.F.I., Inc.
3-1
2
3-2 Structural formula or rational formula
San-Ei Gen F.F.I., Inc.
3-2
2
3-3 Molecular formula and molecular weight
San-Ei Gen F.F.I., Inc.
3-3
2
3-4 Assay
San-Ei Gen F.F.I., Inc.
3-4
2
3-5 Methods of manufacturing
San-Ei Gen F.F.I., Inc.
3-5
2
3-6 Description
San-Ei Gen F.F.I., Inc.
3-6
2
3-7 Identification
San-Ei Gen F.F.I., Inc.
3-7
2
3-8 Specific properties
San-Ei Gen F.F.I., Inc.
3-8
2
3-9 Purity tests
San-Ei Gen F.F.I., Inc.
3-9
2
3-10 Water
San-Ei Gen F.F.I., Inc.
3-10
2
3-11 Residues on ignition
San-Ei Gen F.F.I., Inc.
3-11
2
3-12 Method of assay
San-Ei Gen F.F.I., Inc.
3-12
2
3-13 Stability
Tate & Lyle Speciality Sweeteners
3-13
2
3-14 Analytical method for the food additives in food
Tate & Lyle Speciality Sweeteners and
San-Ei Gen F.F.I., Inc.
3-14
2
3-15 Specification
San-Ei Gen F.F.I., Inc.
3-15
2
3-16 Overall judgement table
San-Ei Gen F.F.I., Inc.
3-16
2

4 Effectiveness
4-1 Effectiveness
Tate & Lyle Speciality Sweeteners
4-1
3
4-2 Comparison in the effects with other similar food additives
Tate & Lyle Speciality Sweeteners and
San-Ei Gen F.F.I., Inc.
4-2
4
4-3 Stability in foods
Tate & Lyle Speciality Sweeteners and
San-Ei Gen F.F.I., Inc.
4-3
4

5 Safety evaluation
(1) Toxicity studies
5-1 Investigation of report on the safety of sucralose
San-Ei Gen F.F.I., Inc.
5-1
5
5-2 Safety evaluation for sucralose
5-2-1 Acute toxicity study
5-2-1-1 Acute oral toxicity studies in the rat.
Johnson & Johnson
Research Foundation
(1980)
5-2-1-1
(E002)
6
5-2-1-2 Acute oral toxicity to mice.
Life Science Research
(1977)
5-2-1-2
(E001)
6

5-2-2 Subacute toxicity study
5-2-2-1 8-week toxicity study in rat .
Life Science Research
(1983)
5-2-2-1
(E031)
6
5-2-2-2 Dose range finding study in rat during lactation.
Johnson & Johnson
Research Foundation
(1984)
5-2-2-2
(E060)
6
5-2-2-3 9-weeks toxicity study in rat.
Hazleton Lab. America
(1985)
5-2-2-3
(E098)
6
5-2-2-4 4, 9 and 13-week toxicity study in rat.
Inveresk Res. International
(1988)
5-2-2-4
(E151)
6
5-2-2-5 Dose range finding study in mice (34 days).
Johnson & Johnson
Research Foundation
(1983)
5-2-2-5
(E062)
6

5-2-3 Chronic toxicity study
5-2-3-1 Dietary administration study in rat (1)
Pharmaco-LSR
(1993)
5-2-3-1
(E160)
6
5-2-3-2 Dietary administration study in rat (2)
Pharmaco-LSR
(1994)
5-2-3-2
(E161)
6
5-2-3-3 Oral toxicity study in dogs (12 months)
Hazleton Lab. America
(1985)
5-2-3-3
(E051)
6

5-2-4 Reproduction study
5-2-4-1 Anti-fertility screen in male rats.
Life Science Research
(1978)
5-2-4-1
(E016)
7
5-2-4-2 The effect of sucralose on the glycolytic ability of rat spermatozoa.
University Whiteknights
(1987)
5-2-4-2
(E107)
7
5-2-4-3 Two generation reproductive study in rats.
Life Science Research
(1986)
5-2-4-3
(E056)
7
5-2-4-4 104-Week combined toxicity and oncogenicity study in rats. ; Breeding phase.
Life Science Research
(1987)
5-2-4-4
(E057)
7
5-2-5 Teratogenicity study
5-2-5-1 Effects of oral administration upon pregnancy in the rat.
Life Science Research
(1983)
5-2-5-1
(E030)
7
5-2-5-2 Preliminary study in the pregnant rabbit.
Life Science Research
(1987)
5-2-5-2
(E115)
7
5-2-5-3 Preliminary teratology study in the rabbit.
Life Science Research
(1987)
5-2-5-3
(E129)
7
5-2-5-4 Teratology study in the rabbit.
Life Science Research
(1987)
5-2-5-4
(E134)
7

5-2-6 Carcinogenicity study
5-2-6-1 104-Week oncogenicity study in mice.
Life Science Research
(1987)
5-2-6-1
(E055)
8

5-2-7 Combined chronical toxicity/carcinogenicity study

    5-2-7-1 104-Week combined toxicity and oncogenicity study in rats.
Life Science Research
(1986)
5-2-7-1
(E057)
9,10

5-2-8 Antigenicity study

5-2-8-1 Delayed contact hypersensitivity study in guinea-pigs.
Life Science Research
(1986)
5-2-8-1
(E113)
11
5-2-9 Mutagenicity study
5-2-9-1 Reverse mutation test with Salmonella typhimurium. (1)
Life Science Research
(1981)
5-2-9-1
(E015)
11
5-2-9-2 Reverse mutation test with Salmonella typhimurium. (2)
Litton Bionetics Inc.
(1979)
5-2-9-2
(E011)
11
5-2-9-3 Gene mutation test in mouse lymphoma cells.
E & G Mason
Research Institute
(1981)
5-2-9-3
(E014)
11
5-2-9-4 Micronucleus test in mouse bone marrow erythrocytes. (1)
Life Science Research
(1978)
5-2-9-4
(E010)
11
5-2-9-5 Micronucleus test in mouse bone marrow erythrocytes. (2)
Life Science Research
(1986)
5-2-9-5
(E114)
11
5-2-9-6 Chromosome aberration test in the rat bone marrow.
Litton Bionetics Inc.
(1981)
5-2-9-6
(E013)
11
5-2-9-7 Chromosome aberration test in cultured human peripheral lymphocytes.
Life Science Research
(1981)
5-2-9-7
(E012)
11
5-2-9-8 DNA repair test in Escherichia coli.
Litton Bionetics Inc.
(1979)
5-2-9-8
(E011)
11
5-2-10 General pharmacological study
5-2-10-1 Effects on general conditions
5-2-10-1-1 Acute oral toxicity studies in the rat.
Johnson & Johnson
Research Foundation
(1980)
5-2-10-1-1
(E002)
12
5-2-10-1-2 Acute oral toxicity to mice.
Life Science Research
(1977)
5-2-10-1-2
(E001)
12
5-2-10-1-3 Neurotoxicity study in mice.
Life Science Research
(1981)
5-2-10-1-3
(E008)
12
5-2-10-1-4 4, 9 and 13-week toxicity study in rat.
Inveresk Res. International
(1988)
5-2-10-1-4
(E151)
12
5-2-10-1-5 Dietary administration study in rat (2) (26-week)
Pharmaco-LSR
(1994)
5-2-10-1-5
(E161)
12
5-2-10-1-6 A study to observe the tolerance to orally administered single ascending doses of TGS followed by seven days administration in eight normal subjects.
Medical Science Research
(1984)
5-2-10-1-6
(E047)
12
5-2-10-1-7 A tolerance study in normal subjects of varying doses of TGS administered continuously for a period of thirteen weeks.
Medical Science Research
(1986)
5-2-10-1-7
(E048)
12

5-2-10-2 Effects on the central nervous system
5-2-10-2-1 Neurotoxicity study in mice.
Life Science Research
(1981)
5-2-10-2-1
(E008)
12
5-2-10-2-2 Neurotoxicity study in marmoset monkeys.
Life Science Research
(1981)
5-2-10-2-2
(E009)
12
5-2-10-2-3 A study to observe the tolerance to orally administered single ascending doses of TGS followed by seven days administration in eight normal subjects.
Medical Science Research
(1984)
5-2-10-2-3
(E047)
12

5-2-10-3 Effects on the respiratory and cardiovascular systems
5-2-10-3-1 A study to observe the tolerance to orally administered single ascending doses of TGS followed by seven days administration in eight normal subjects.
Medical Science Research
(1984)
5-2-10-3-1
(E047)
12
5-2-10-3-2 A tolerance study in normal subjects of varying doses of TGS administered continuously for a period of thirteen weeks.
Medical Science Research
(1986)
5-2-10-3-2
(E048)
12
5-2-10-4 Effects on the gastrointestinal system
5-2-10-4-1 9-week toxicity study in rat.
Hazleton Lab. America
(1985)
5-2-10-4-1
(E098)
12
5-2-10-4-2 4, 9 and 13-week toxicity study in rat.
Inveresk Res. International
(1988)
5-2-10-4-2
(E151)
12
5-2-10-4-3 Dietary administration study in rat (2) (26-week)
Pharmaco-LSR
(1994)
5-2-10-4-3
(E161)
12
5-2-10-5 Effects on water and electrolyte metabolism
5-2-10-5-1 8-week toxicity study in rat.
Life Science Research
(1983)
5-2-10-5-1
(E031)
13
5-2-10-5-2 9-week toxicity study in rat.
Hazleton Lab. America
(1985)
5-2-10-5-2
(E098)
13
5-2-10-5-3 104-Week combined toxicity and oncogenicity study in rats.
Life Science Research
(1986)
5-2-10-5-3
(E057)
13

5-2-11 Other toxicity study
5-2-11-1 Neurotoxicity study in mice.
Life Science Research
(1981)
5-2-11-1
(E008)
14
5-2-11-2 Neurotoxicity study in marmoset monkeys.
Life Science Research
(1981)
5-2-11-2
(E009)
14
5-2-11-3 Immunotoxicity study in rats.
TNO Nutrition
and Food Research
(1994)
5-2-11-3
(E162)
14
5-2-11-4 Eight-week palatability study in female rats.
Life Science Research
(1985)
5-2-11-4
(E058)
14
5-2-11-5 14-week palatability study in rats.
Life Science Research
(1988)
5-2-11-5
(E143)
14
5-2-11-6 An investigation of the acceptability of aqueous solutions of sucralose to rats.
Life Science Research
(1987)
5-2-11-6
(E130)
14
5-2-11-7 An investigation of diet spillage among rats fed diet containing sucralose.
Life Science Research
(1991)
5-2-11-7
(E154)
14
5-2-11-8 14-day palatability study in beagle dogs.
Life Science Research
(1980)
5-2-11-8
(E007)
14

5-2-13 Clinical study
5-2-13-1 Glycemic effect of a single high oral dose of the novel sweetener sucralose in patients with diabetes.
Mezitis, N.M.E. et al.
Diabetes Care, 19, 1004-1005, (1996)
5-2-13-1
22
5-2-13-2 A six-month study of the effect of sucralose vs placebo on glucose homeostasis in patients with non-insulin-dependent diabetes mellitus.
Mount Sinai Hospital
(1997)
5-2-13-2
(E157)
22
5-2-13-3 An evaluation of specific clinical chemistry parameters and methods in Study E157 : A six-month study of the effect of sucralose vs placebo on glucose homeostasis in patients with non-insulin-dependent diabetes mellitus.
University of Missouri-Columbia
(1996)
5-2-13-3
(E168)
22
5-2-13-4 A 12 week study of the effect of sucralose on glucose homeostasis and HbA1c in normal healthy volunteers.
Leicester Clinical
Research Center Ltd.
(1996)
5-2-13-4
(E169)
22
5-2-13-5 A three-month study of the effect of sucralose versus placebo on glucose homeostasis in subjects with non-insulin-dependent diabetes mellitus.
University of California
San Diego, et al.
(1997)
5-2-13-5
(E171)
22

5-3 Safety evaluation for the hydrolysis products of sucralose and compounds related to sucralose
5-3-1 Acute toxicity study
5-3-1-1 TGS-HP : Acute oral toxicity in the rat. (1)
Life Science Research
(1982)
5-3-1-1
(E028)
18
5-3-1-2 TGS-HP : Acute oral toxicity in the rat. (2)
Johnson & Johnson
Research Foundation
(1980)
5-3-1-2
(E002)
18
5-3-1-3 TGS-HP : Acute oral toxicity in the mouse.
Life Science Research
(1982)
5-3-1-3
(E029)
18
5-3-1-4 3/C334(6-CDG) : Acute oral toxicity in the rat.
Life science Research
(1977)
5-3-1-4
(E050)
18
5-3-1-5 TCDS : Acute oral toxicity in the mouse.
Life science Research
(1976)
5-3-1-5
(E069)
18

5-3-2 Subacute toxicity study
5-3-2-1 TGS-HP : 13-week toxicity study in rats.
Life Science Research
(1986)
5-3-2-1
(E054)
18
5-3-2-2 TGS-HP : Dose range finding/toxicity study in the dog.
Johnson & Johnson
Research Foundation
(1984)
5-3-2-2
(E061)
18

5-3-3 Chronic toxicity study
5-3-3-1 TGS-HP : Twenty-six week oral toxicity study in dogs.
Litton Bionetics Inc.
(1985)
5-3-3-1
(E068)
18
5-3-4 Reproduction study
5-3-4-1 TGS-HP : Two generation reproductive study in rats.
Life Science Research
(1986)
5-3-4-1
(E052)
18
5-3-4-2 1,6-DCF : Effect on male fertility in the rat.
Ortho Pharmaceutical Co.
(1982)
5-3-4-2
(E090)
18
5-3-4-3 3/C-339, 3/C-340 : Anti-fertility screen in male rats.
Life science Research
(1978)
5-3-4-3
(E016)
18
5-3-4-4 3/C-343~346, 3/C-348 : Anti-fertility screen in male rats.
Life science Research
(1978)
5-3-4-4
(E038)
18
5-3-4-5 6-CF : Anti-fertility evaluation in the male rat.
Life science Research
(1984)
5-3-4-5
(E037)
18
5-3-4-6 4,6'-DGS : Anti-fertility evaluation in the male rat.
Life science Research
(1986)
5-3-4-6
(E100)
18
5-3-4-7 TCDS : The effect on the glycolytic ability of rat spermatozoa.
The University Whiteknights
(1987)
5-3-4-7
(E107)
18
5-3-4-8 6-CDG, 6-CDM : The effects on male fertility and motor function in several species.
Ortho Pharmaceutical Co.
(1981)
5-3-4-8
(E091)
18

5-3-5 Teratogenicity study
5-3-5-1 TGS-HP : Effects of oral administration upon pregnancy in the rat.
Life Science Research
(1983)
5-3-5-1
(E032)
18

5-3-6 Carcinogenicity study
5-3-7 Antigenicity study
5-3-8 Mutagenicity study
5-3-8-1 TGS-HP : Reverse mutation test with Salmonella typhimurium.
Life Science Research
(1981)
5-3-8-1
(E015)
20
5-3-8-2 TGS-HP : Dominant lethal test in mice.
Life Science Research
(1983)
5-3-8-2
(E034)
20
5-3-8-3 1,6-DCF : Reverse mutation test with Salmonella typhimurium. (1)
Life Science Research
(1980)
5-3-8-3
(E020)
20
5-3-8-4 1,6-DCF : Reverse mutation test with Salmonella typhimurium. (2)
EG & G Mason
Research Institute
(1981)
5-3-8-4
(E023)
20
5-3-8-5 1,6-DCF : Gene mutation test in mouse lymphoma cells. (1)
EG & G Mason
Research Institute
(1981)
5-3-8-5
(E022)
20
5-3-8-6 : Gene mutation test in mouse lymphoma cells. (2)
EG & G Mason
Research Institute
(1981)
5-3-8-6
(E024)
20
5-3-8-7 1,6-DCF : Assessment of its mutagenic potential in Drosophila melanogaster, using the sex-linked recessive lethal test.
Life Science Research
(1981)
5-3-8-7
(E021)
20
5-3-8-8 1,6-DCF : Single exposure dose selection study for in vivo micronucleus assay in the mouse.
Hazleton Lab. America
(1988)
5-3-8-8
(E152)
20
5-3-8-9 1,6-DCF : In vivo micronucleus assay in the mouse.
Hazleton Lab. America
(1988)
5-3-8-9
(E149)
20
5-3-8-10 1,6-DCF : Investigation of effects on bone marrow chromosomes of the rat after acute and subacute oral administration.
Life Science Research
(1981)
5-3-8-10
(E019)
20
5-3-8-11 1,6-DCF : In vitro assessment of the clastogenic action on mouse bone marrow erythrocytes in the micronucleus test.
Life Science Research
(1981)
5-3-8-11
(E012)
20
5-3-8-12 1,6-DCF : In vivo sister chromatid exchange assay in the mouse.
Hazleton Lab. America
(1988)
5-3-8-12
(E150)
20
5-3-8-13 1,6-DCF : Study to evaluate the potential of 1,6-dichlorofructose to induce unscheduled DNA synthesis (UDS) in isolated rat hepatocytes in vitro.
Hazleton Europe
(1994)
5-3-8-13
(E165)
20
5-3-8-14 4-CG : Reverse mutation test with Salmonella typhimurium.
Life Science Research
(1980)
5-3-8-14
(E025)
20
5-3-8-15 4-CG : Gene mutation test in mouse lymphoma cells.
EG & G Mason
Research Institute
(1981)
5-3-8-15
(E026)
20
5-3-8-16 4-CG : Mutagenicity evaluation in the rat bone marrow cytogenetic assay.
Litton Bionetics, Inc.
(1981)
5-3-8-16
(E027)
20
5-3-8-17 4-CG : In vitro assessment of the clastogenic action on mouse bone marrow erythrocytes in the micronucleus test.
Life Science Research
(1981)
5-3-8-17
(E012)
20
5-3-8-18 C/334(6-CDG) : The micronucleus test in mouse bone marrow erythrocytes..
Life Science Research
(1978)
5-3-8-18
(E010)
20
5-3-8-19 C/337 : The micronucleus test in mouse bone marrow erythrocytes..
Life Science Research
(1978)
5-3-8-19
(E010)
20
5-3-8-20 3/C340(1-CF) : Reverse mutation test with Salmonella typhimurium.
Life Science Research
(1981)
5-3-8-20
(E074)
20
5-3-8-21 C/339 : The micronucleus test in mouse bone marrow erythrocytes.
Life Science Research
(1978)
5-3-8-21
(E072)
20
5-3-8-22 C/338 : The micronucleus test in mouse bone marrow erythrocytes.
Life Science Research
(1978)
5-3-8-22
(E072)
20
5-3-9 Other toxicity study
5-3-9-1 TGS-HP : Neurotoxicity study in mice.
Life Science Research
(1981)
5-3-9-1
(E008)
20
5-3-9-2 TGS-HP : Neurotoxicity study in marmoset monkeys.
Life Science Research
(1981)
5-3-9-2
(E009)
20
5-3-9-3 TGS-HP : Palatability study in dogs.
Litton Bionetics Inc.
(1984)
5-3-9-3
(E065)
20

(2) Metabolism and pharmacokinetic studies
5-2-12 Metabolism and pharmacokinetic studies (Sucralose)
5-2-12-1 Absorption, tissue distribution and excretion in the rat.
Life Science Research
(1981)
5-2-12-1
(E004)
15
5-2-12-2 Dietary toxicity study in rat (8 weeks).-A study on the metabolism
Life Science Research
(1981)
5-2-12-2
(E031)
15
5-2-12-3 104-Week combined toxicity and oncogenicity study in rats. -Mesurement of metabolic adaptation.
Life Science Research
(1981)
5-2-12-3
(E057)
15
5-2-12-4 A study on the metabolism of sucralose after oral and intravenous administration to the rat.
University of Southampton
(1987)
5-2-12-4
(E137)
15
5-2-12-5 Comparative pharmacokinetics after dietary and oral gavage administration to rats.
Huntingdon Research
Centre Ltd.
(1994)
5-2-12-5
(E163)
15
5-2-12-6 Pharmacokinetic studies after oral administration to pregnant rabbits and rats.
Huntingdon Research
Centre Ltd.
(1994)
5-2-12-6
(E164)
15
5-2-12-7 Studies of the absorption, excretion and metabolism in the mouse.
Huntingdon Research
Centre Ltd.
(1987)
5-2-12-7
(E146)
15
5-2-12-8 Pharmacokinetics in dogs following intravenous administration.
Life Science Research
(1984)
5-2-12-8
(E049)
15
5-2-12-9 Intravenous-oral cross over dog metabolism study.
Huntingdon Research
Centre Ltd.
(1986)
5-2-12-9
(E123)
16
5-2-12-10 Isolation and identification of an unknown radioactive component present in urine after intravenous administration of sucralose.
Huntingdon Research
Centre Ltd.
(1987)
5-2-12-10
(E133)
16
5-2-12-11 Studies of the metabolism in the rabbit.
Huntingdon Research
Centre Ltd.
(1987)
5-2-12-11
(E124)
16
5-2-12-12 Preliminary teratology study in the rabbit.
Life Science Research
(1987)
5-2-12-12
(E129)
16
5-2-12-13 Urinary excretion in human after a single oral dose.
Tate & Lyle
(1981)
5-2-12-13
(E003)
16
5-2-12-14 Absorption and excretion in human.
Life Science Research
(1983)
5-2-12-14
(E033)
16
5-2-12-15 The examination of the radioactive material in the stored urine taken from three human volunteers given an oral dose of [14C]TGS.
Tate & Lyle
(1986)
5-2-12-15
(E033a)
17
5-2-12-16 A randomized double-blind study in normal subjects to investigate the influence of TGS on the absorption of sucrose and the secretion of insulin.
Medical Science
Research UK
(1984)
5-2-12-16
(E046)
17
5-2-12-17 A study to observe the tolerance to orally administered single ascending doses of TGS followed by seven days administration in eight normal subjects.
Medical Science
Research UK
(1984)
5-2-12-17
(E047)
17
5-2-12-18 A tolerance study in normal subjects of varying doses of TGS administered continuously for a period of thirteen weeks.
Medical Science
Research UK
(1986)
5-2-12-18
(E048)
17
5-2-12-19 A study of the metabolism and pharmacokinetics following oral administration to healthy human volunteers.
Univ. Southampton
(1986)
5-2-12-19
(E128)
17
5-2-12-20 A study of the metabolism of 14C-TGS following oral administration to healthy human volunteers.
Univ. Southampton
(1988)
5-2-12-20
(E145)
17
5-2-12-21 Stability of chlorinated disaccharides to hydrolysis by microbial, plant and mammalian glycosidases.
Tate & Lyle Group
Research & Development
(1986)
5-2-12-21
(E104)
17
5-2-12-22 The effect of oral administration on some aspects of the metabolism of D-glucose by tissues of the rat.
University of Reading
(1978)
5-2-12-22
(E005)
17
5-2-12-23 The influence of sucralose on carbohydrate metabolism in the rat.
Med. Sch. St. George's
Hospital, London
5-2-12-23
(E064)
17
5-2-12-24 Enzyme induction studies of TGS in the rat.
Huntingdon Research
Centre Ltd.
(1988)
5-2-12-24
(E144)
17
5-3-10 Metabolism and pharmacokinetic studies (the hydrolysis products of sucralose and compounds related to sucralose)
5-3-10-1 Enzyme induction studies of TGS-HP in the rat.
Huntingdon Research
Centre Ltd.
(1988)
5-3-10-1
(E144)
21
5-3-10-2 1,6-DCF : Distribution in blood, brain, testes and urine at intervals after oral dosing of male rats.
Life Science Research
(1981)
5-3-10-2
(E017)
21
5-3-10-3 1,6-DCF : Metabolism and dechlorination in the rat.
University College, UK
(1987)
5-3-10-3
(E116)
21
5-3-10-4 4-CG and 1,6-DCF : Metabolic disposition in the rat.
Life Science Research
(1980)
5-3-10-4
(E018)
21
5-3-10-5 1,6-DCF : Metabolism in the rat.
University College, UK
(1988)
5-3-10-5
(E147)
21
5-3-10-6 The cellular effects of 1,6-DCF : Preliminary studies.
Univ. Med. And Rent.
New Jersey
(1985)
5-3-10-6
(E085)
21
5-3-10-7 4-CG : Metabolism in the rat.
University College, UK
(1987)
5-3-10-7
(E139)
21
5-3-10-8 In vitro studies on the hepatic metabolism of some chlorodeoxysugars.
University of Surrey
(1980)
5-3-10-8
(E136)
21

(3) The daily intake of the food additive
5-4 The daily intake of sucralose.
San-Ei Gen F.F.I., Inc.
5-4
21

6 Standards for use
6-1 Documentation on the target foods and use.
San-Ei Gen F.F.I., Inc.
6-1
21
6-2 Documentation on the amount of use.
San-Ei Gen F.F.I., Inc.
6-2
21







Attachment 2
Specification for sucralose
Specification
NameSucralose
Chemical nameTrichlorogalactosucrose
(4,1',6'-trichlorogalactosucrose)
Chemical structure
Chemical formulaC12H19Cl3O8
Molecular weight397.64
CAS No.56038-13-2
ContentsSucralose, when dried, contains 98.0-102.0% of sucralose (C12H19Cl3O8)
Description
Sucralose occurs as a white to grayish-white crystalline powder. It is odorless*, has a strong sweet taste and is freely soluble in water, methanol and ethanol, and is slightly soluble in ethyl acetate.
Identification (1) The infrared absorption spectrum of a potassium bromide dispersion sample has a similar absorption bands to the standard spectrum of sucralose with a similar intensity at similar wavelength.

(2) Dissolve 1.0g of sucralose in 10ml of methanol, apply 5l of this solution for thin-layer chromatography to the bottom of the chromatographic plate. Place the plate in mobile phase which contains mixture of sodium chloride (dissolve 1g in a solvesnt to make 20m) and acetonitrile (7:3), and allow the solvent front to ascend approximately 15cm. Remove the plate, allow it to dry, and spray it with the solution which contains 15%(v/v) sulfuric acid in methanol. Heat the plate in an oven at 125°C for 10 min. Chromatographic plate coated with octadesyl silyl silica gel can be used in this methods. The Rf value as a spot of sucralose is 0.4-0.6 under the conditions described above.
Purity
(1) Clarity and color of solution
Clear (1.0g, in 10ml water)
(2) Specific rotation =+84.0~+87.5° (1.0g, in 10 ml water, calculated on the anhydrous basis)
(3) pHpH= 3.0~6.0 (2.0g, in 20 ml water)
(4) Heavy metalsNot more than 10 mg/g (1.0g, method 2, 1.0ml lead standard solution as control solution)
(5) ArsenicNot more than 4.0 mg/g as As2O3. (0.50g, method 2, apparatus B)
(6) Other chlorinated
disaccharide
Not more than 0.5%
Dissolve 1.0 g of sucralose in 10 ml of methanol (sample solution). Take 0.5ml of this sample solution and add methanol to make 100ml (standard solution). Apply 5l of sample or control solution to the bottom of the chromatographic plate for thin-layer chromatography as described on Identification(2). The spot of sample solution is only detected on same position to that of standard solution. If other spot in sample solution is detected, the detected spot in sample solution is not more intense in color than that in standard solution.
(7) Chlorinated
monosaccharide
Not more than 0.16% as calculated on fructose.
Dissolve 2.5 g of sucralose and add methanol to make 10ml exactly (sample solution). Take exactly 10.0g of D-mannitol and add water to make 100ml, exactly (standard [A] solution). Take exactly both 10.0g of D-mannitol and 40mg of fructose and add water to make 100ml, exactly (standard [B] solution). Apply 1l of sample, standard [A] or [B] solution to silicagel thin-layer plate of 0.25mm in thickness for thin-layer chromatography and dry. Repeat another 4 times this process. Spray the plate with the solution which contains p-anisidine phtalate. Heat the plate in an over at 98-102°C for 10min. The spot in sample solution is not more intense in color than that in standard [B] solution. The spot in standard [A] solution results from a overheating of the plate, and the test should be repeated again in use of another plate.
(8) Triphenylphosphine oxideNot more than 150mg/g
Dissoluve 100 mg of sucralose or triphenylphosphine oxide in mixture of acetonitrile and water (67:33) and make exact 10 ml solution, separately. Take exactly 1ml of triphenylphosphine oxide solution and add mixture of acetonitrile and water (67:33) to make 100 ml solution, exactly (standard solution). Take 25ml of sample solution or standard solution for liquid chromatography under the condition described below.

System
Detector : UV-detector ( 220 nm)
Column packing material : 5 mm octadecyl silyl silica gel
Column : A stainless steel tube of 4.6 mm (internal diameter) ´15 cm (length)
Column temperature : 40°C
Mobile phase : a mixture of acetonitrile and water (67 : 33)
Flow rate : 1.5 ml/min.

Record the mean peak areas for the standard and test solution as As and At, respectively. Calculate the concentration of triphenylphosphine oxide in the sample from the following formula.

(9) MethanolNot more than 0.1%
Dissolve exactly 2.0 g of sucralose, add water to make 10 ml exactly and mix (sample solution). Take exactly 2 ml of methanol, add water to make 100 ml exactly and mix. Take exactly 1ml of this solution, add water to make 100 ml exactly and mix (standard solution). Take 1ml of sample solution or standard solution for liquid chromatography under the condition described below.

System
Detector : Hydrogen frame ionization detector
Column packing material : 150~180 mm of porous polymer beads for gas chromatography
Column : glass column of 2~4 mm (internal diameter) ´ about 2 m (length)
Column temperature : constant temperature at about 150°C
Inlet temperature : 200°C
Detector temperature : 250°C
Carrier gas and flow rate : Use nitrogen or helium. Adjust flow rate or temperature to detect a peak of methanol in about 4 min.

Record the mean peak areas for the standard and test solution as SA and AS, respectively. Calculate the concentration of methanol in the sample from the following formula.

where CS is the concentration of methanol in the standard in percent.
Residue in IgnitionNot more than 0.7%.
WaterNot more than 2.0% (1g, Direct titration)
Method of assayDissolve 1g of sucralose add water to make 100ml, exactly. Take exactly 10ml of this solution, add 10ml of sodium hydroxide (dissolve 1g in a solvesnt to make 10ml), equip with a reflux condenser, boil gently for 30min, cool and neutralize it by diluted-nitric acid. Titrate with 0.1 mol/l of silver as electric indicator and silver-silver chloride as reference electrode. Perform a blank test in the same manner, make any necessary correction, and calculate on the dried basis.

0.1mol/l Silver nitrate 1ml = 13.255mg C12H19Cl3O8
*The term "odorless" means odorless or practically odorless on the Japanese Standards for Food Additives.



Attachment 3
Comparison draft specification of sucralose
with specifications established by other international organizations

Definition
Specification (draft)
JECFA
FCC

Description
Description
White to grayish-white, crystalline powder.White to off-white, crystalline powder.White to off-white, crystalline powder.
Odorless
Odorless*
Practically odorless
Practically odorless
Sweet taste
Sweet taste
Sweet taste
Sweet taste
Solubility
It is freely soluble in water, in methanol and ethanol and is slightly soluble in ethyl acetate.It is freely soluble in water, in methanol and in alcohol and slightly soluble in ethyl acetate.It is freely soluble in water, in methanol and in alcohol and slightly soluble in ethyl acetate.
Identification
Infrared absorption
The infrared absorption spectrum of a potassium bromide dispersion sample has a similar absorption bands to the standard spectrum with a similar intensity at similar wavelength.The infrared absorption spectrum of a potassium bromide dispersion of the sample exhibits relative maxima at similar wavenumbers as those shown in the reference spectrum.The infrared absorption spectrum of a potassium bromide dispersion of the sample exhibits relative maxima at similar wavelengths as those shown in Sucralose Standard for analytical use.
Thin-layer chromatography
The Rf value is from 0.4 to 0.6.The main spot has the same Rf value as that of the main spot of Standard Solution A.The main spot has the same Rf value as that of the main spot of Standard Solution A.



Purity




Clarity
Clear
(1.0g,in 10ml water)
-
-
Specific rotation
+84.0~+87.5°
(1.0g, in 10ml water, calculated on the anhydrous basis)
+84.0~+87.5°
(10%w/v,calculated on the anhydrous basis.)
+84.0~+87.5°
(1g,water,100ml,calculated on the anhydrous basis.)
pH
3.0~6.0
(2.0g, in 20ml water)
-
-
Heavy metals
Not more than 10mg/g
(1.0g,Method 2, 1.0ml lead standard solution as control solution)
Not more than 10mg/kg as Pb.
Not more than 10mg/kg as Pb.
Arsenic
Not more than 4.0g/g as As2O3.
(0.50g,method 2,apparatus B)
Not more than 3mg/kg as As.
Not more than 3mg/kg as As.
Other chlorinated disaccharides
Not more than 0.5%
The main spot has the same Rf value as the main spot in Solution A. No other spot is more intense than the spot in Solution B.
The main spot has the same Rf value as the main spot in Solution A. No other spot is more intense than the spot in Solution B.
Chlorinated monosaccharide
Not more than 0.16% as calculated on fructose
Not more colored than the spot from Reference solution B.
Not more colored than the spot from Reference solution B.
Triphenylphosphine oxide
Not more than 150 mg/g
Not more than 150mg/kg
-
Methanol
Not more than 0.1%
Not more than 0.1%
Not more than 0.1%.
Residue in Ignition
Not more than 0.7%.
Not more than 0.7%.
Not more than 0.7%.
Water
Not more than 2.0%.
Not more than 2.0%.
Not more than 2.0%.
Content
98~102.0%
98~102%
98.0~102.0%
*The term "odorless" means odorless or practically odorless on the Japanese Standards for Food Additives.

**