Procedure for Preparing Application Documents for Approval of Food Additives in Japan

Transcription

1 Procedure for Preparing Application Documents for Approval of Food Additives in Japan 1

2 Outline Documents to Be Submitted for Application How to Prepare Application Documents Overview Documents I. Information on the food additive to be assessed II. Findings regarding effectiveness III. Findings regarding safety IV. References 2

3 Documents to Be Submitted for Application Guidelines for the Designation of Food Additives and Revision of Standards for Use of Food Additives (MHLW Notice No. 29, 22 March 1996) Purpose: The guidelines are designed to outline the procedures required to apply for the designation of food additives, pursuant to Article 10 of the Food Sanitation Act, and for the establishment of use standards for food additives, pursuant to Article 11. The guidelines provide details of the documents to be submitted for application, such as information on safety data and recommended methods for safety studies. Documents Application form Japanese only Accompanying documents Japanese only Overview Documents Japanese or English Reference documents 3

4 How to Prepare Application Documents The Procedure for Preparing Application Documents for Designation of Food Additives and Revision of Use Standards for Food Additives (MHLW Notice, 9 September 2014) Purpose Deepen applicants understanding of the designation procedure for food additives Help applicants efficiently prepare application documents Outline This guide explains how to write the application documents, based on the guidelines published in MHLW Notice of 22 March It contains: explanations points to which attention should be paid how to collect relevant information examples of description for each item. An English version is available at 4

5 Overview Documents Ⅰ.Information on the food additive to be assessed 1. Name and uses 2. Origin or details of development 3. Use status in foreign countries 4. Assessments by national and international organizations 5. Physicochemical properties 6. Use standards (draft) 7. Other Ⅲ.Findings regarding safety 1. Toxicokinetics studies (ADME) 2. Toxicological studies 3. Findings in humans 4. Estimation of daily intake Ⅳ.References Ⅱ.Findings regarding effectiveness 1. Effectiveness as food additive and comparison with other additives with the same use 2. Stability in food 3. Effects on nutritional components in food 5

6 Overview Documents Ⅰ.Information on the food additive to be assessed 1. Name and uses 2. Origin or details of development 3. Use status in foreign countries 4. Assessments by national and international organizations 5. Physicochemical properties 6. Use standards (draft) 7. Other Ⅲ.Findings regarding safety 1. Toxicokinetics studies (ADME) 2. Toxicological studies 3. Findings in humans 4. Estimation of daily intake Ⅳ.References Ⅱ.Findings regarding effectiveness 1. Effectiveness as food additive and comparison with other additives with the same use 2. Stability in food 3. Effects on nutritional components in food 6

7 I. Information on the food additive to be assessed (1) I. Information on the food additive to be assessed 1. Name and uses (1) Name General name (Japanese and English names) Chemical name (conforming to IUPAC Name) (2) Registry number CAS registry number INS (International Numbering System) number, etc. (3) Uses Use status in Japan and other countries (e.g., EU, USA) Intended uses/purposes specified by Codex Alimentarius Commission (Codex) 7

8 I. Information on the food additive to be assessed (2) 2. Origin or details of development An outline leading up to the request for designation, such as when and where (country) the target substance was developed where (countries) it became used as a food additive. If the substance naturally occurs in food products, provide information on a history of human consumption as food. 8

9 I. Information on the food additive to be assessed (3) 3. Use status in other countries Codex use standards Foreign countries authorization status and use standards <Points to note> Indicate use standards specified by the Codex, and authorization status and use standards in the EU, the USA, Australia and New Zealand. When the maximum use concentrations are established for more than one food product, indicate the concentrations for all corresponding food products (not only those for the target foods, but also those for other foods). Attach the evidence of the authorizations and use standards, such as copies of regulatory documents. 9

10 I. Information on the food additive to be assessed (4) 4. Assessments by national and international organizations An overview of the results of safety evaluations by international organizations such as JECFA and relevant national authorities <Points to note> Describe the grounds for setting ADI and an overview of the assessments. Attach copies of the assessment reports. 10

11 Example of description [Assessments by national and international organizations] (Polyvinylpyrrolidone) Evaluation by JECFA At the 10th Assembly (1966): A conditional ADI of 0 to 1 mg/kg body wt./day was established for polyvinylpyrrolidone. At the 17th Assembly (1973): The ADI was rescinded over concerns of potential internal accumulation of the substance through intake by reticuloendothelial system (RES) cells of the mesenteric lymph nodes or others. At the 25th Assembly (1981): The provisional ADI (0 to 1 mg/kg body wt./day) was restored based on review of accumulated research data. At the 27th Assembly (1983): The provisional ADI was modified to 0 to 25 mg/kg body wt./day from 0 to 1 mg/kg body wt./day based on reexamination of toxicity data on polyvinylpyrrolidone, which showed no harmful effects in a long-term toxicity study. At the 30th Assembly (1986): An ADI of 0 to 50 mg/kg body wt./day was established for polyvinylpyrrolidone, based on data showing that the current concentration of hydrazine in polyvinylpyrrolidone is not greater than 1 mg/kg. 11

12 I. Information on the food additive to be assessed (5) 5. Physicochemical properties The structural formula, manufacturing method, specifications*, stability, and analytical methods of the food additive (to be assessed) in food products * Specifications include: 1) Draft specifications 2) A comparison table for the draft specifications and existing specifications (including ones established by international organizations and relevant national authorities, and pharmaceutical specifications) 3) Grounds for proposing the draft specifications 4) Verification data on testing methods and the test results. 12

13 I. Information on the food additive to be assessed (6) (1) Structural formula Structural or rational formula Refer to the Japan s Specifications and Standards for Food Additives (JSFA) document for an organic compound. Molecular formula and molecular weight Describe the molecular formula and molecular weight for an organic compound, the compositional formula and formula weight for an inorganic compound, in accordance with the general rules of JSFA. For a mixture, describe the molecular formulas and molecular weights of all the ingredients contained. (2) Manufacturing method Briefly describe the manufacturing process, for example, in a flow chart. Indicate the removal process of hazardous factors. 13

14 I. Information on the food additive to be assessed (7) (3) Stability Describe the stability of the food additive, including its decomposition products. (4) Analytical methods of the food additive in food products Establish methods to qualitatively and quantitatively identify the food additive in the target foods. If there is no need to establish use standards, or if the food additive does not remain in food, the setting of the assay can be omitted. <Points to note> Indicate analytical methods in cases where the use standards will be established. Consider quantitative methods to separate the target additive from other food additives used for the same purpose. 14

15 I. Information on the food additive to be assessed (8) (5) Specifications 1) Draft specifications The name, content (purity), chemical and physical properties (identification, specific properties), limits of impurities, and purity tests of the additive <Points to note> Preferably list these items in a tabular form. Where appropriate, refer to the JECFA Combined Compendium of Food Additive Specifications, the US Food Chemical Codex (FCC), the EU legislation, and the Japanese Pharmacopoeia. Attach copies of those reference documents. If no specifications exist for the target food additive, propose new draft specifications. As a general rule, use testing methods indicated under General Tests in JSFA. 15

16 I. Information on the food additive to be assessed (9) 2) A comparison table for the draft specifications and existing specifications A table comparing the draft specifications with the existing specifications, including JECFA specifications, foreign countries specifications and pharmaceutical specifications. 16

17 I. Information on the food additive to be assessed (10) 3) Grounds for proposing the draft specifications The grounds (reason for setting each item of the draft specifications, the source, reaction principle, etc.) and an overview of the review of testing methods in the order of the item numbers in the draft specifications. <Points to note> For any items established in international or foreign countries specifications but not included in the draft specifications, describe the reasons. When using newly developed testing methods or methods modified from any standard testing methods, describe those methods in detail and present the reasons for not using the testing methods specified in JSFA. 17

18 I. Information on the food additive to be assessed (11) 4) Verification data on testing methods and the test results Verification data of the testing methods, and data showing the conformity of the target food additive to the values proposed in the draft specifications with respect to the content (purity), chemical and physical properties (identification, specific properties), limits of impurities, etc. <Points to note> Provide verification data of testing methods (e.g., recovery tests) to show that the proposed methods are appropriate. Provide analytical results with an appropriate number of lots (e.g., 3 lots per product, 3 measurements per lot) to show that the target food additive conforms to the values proposed in the draft specifications. 18

19 Item Example of description [Draft specifications] (Monoammonium L-Glutamate) 1 Japanese Name Draft Specifications L- グルタミン酸アンモニウム 2 English Name Monoammonium L-Glutamate 1 8 Definition -- 9 Content 10 Description 17 Assay (Method of Assay) 18 Storage Standards -- Contains not less than 99.0% of monoammonium L-glutamate monohydrate (C 5 H 12 N 2 O 4 H 2 O) on the dried basis. Monoammonium L-Glutamate occurs as colorless to white crystals or white crystalline powder. Weigh accurately about 0.15 g of Monoammonium L- Glutamate, add 3 ml of formic acid to dissolve, and then add 50 ml of acetic acid. Titrate the resulting solution with 0.1 mol/l perchloric acid. Confirm the end point Ref. Spec , 2 Reference specifications 1: JECFA Combined Compendium of Food Additive Specifications (Ref. X) 2: Japan s Specifications and Standards for Food Additives, 8th Edition (Ref. X) 19

20 Content Description Identification tests Test for Example of description [Comparison Table] (Monoammonium L-Glutamate) Draft Specifications JECFA FCC EU Not less than 99.0% (dried Not less than 99.0% (dried 98.5% 101.5% (dried 99.0% 101.0% (anhydrous basis) basis) basis) basis) Colorless to white crystals White, free flowing or white crystalline powder crystalline powder Positive (TLC: ninhydrin coloration) White, practically odorless crystals or crystalline powder Positive (TLC: ninhydrin coloration) -- White, almost odorless crystals or crystalline powder Positive (TLC) Test for Positive Positive -- Positive Solubility Not established Freely soluble in water Infrared Spectrum Not established -- Matches reference spectra -- (Specific properties) Specific Rotation [α] 20 D (dried basis) ph (10 w/v%, hydrochloric acid (1 6)) ph (1.0 g, water 20 ml) (10 w/v%, 2N HCl) ph (1 in 20) (10 w/v%, (10% 2N HCl) soln., 2N HCl) (Identification) ph (1:20) (Description) ph (5% solution) (Identification) Purity tests Lead (Pb) Not more than Not more than Not more than Not more than 2 µg/g 1 mg/kg 5 mg/kg 2 mg/kg Arsenic (As) Not more than 3 µg/g acid Negative (TLC) Negative (TLC) -- Not more than 0.2% Loss on Drying Not more than 0.5% Not more than 0.5% Not more than 0.5% Not more than 0.5% (50 C, 4 h) (50 C, 4 h) (50 C, 4 h) (50 C, 4 h) Residue on Ignition Not more than 0.1% Not more than 0.1% Not more than 0.1% Not more than 0.1% (800 C, 15 min) (800 C, 15 min) (800 C, 15 min) Assay (Method of Assay) Non-aqueous titration, Non-aqueous titration, Non-aqueous titration, No procedure listed sample mass 0.15 g, 0.1 sample mass 200 mg, 0.1N sample mass 250 mg, 0.1N mol/l perchloric acid perchloric acid perchloric acid 20

21 I. Information on the food additive to be assessed (12) 6. Draft of use standards Consider whether to set use standards, based on a comprehensive review of the safety, effectiveness and estimated intake of the target food additive as well as the Codex and foreign countries standards. <Points to note> Refer to existing use standards of other food additives in Japan. Indicate draft use standards in a table form, where appropriate. In case of revision of existing use standards, indicate all parts for the revision by underlines and striking out. 21

22 I. Information on the food additive to be assessed (13) (1) Draft use standards If it is considered necessary to set the maximum amounts of the use of the additive or the maximum amounts that can remain in foods, indicate draft use standards. (2) Grounds for proposing the draft use standards Provide the grounds for proposing the draft use standards, based on use status in foreign countries and materials related to effectiveness and safety. Attach the materials cited as the grounds for proposing the draft use standards, as reference documents. <Points to note> Consider whether the use of the target additive is unlikely to pose a safety concern, taking into account safety data 22 and intake estimates.

23 Overview Documents Ⅰ.Information on the food additive to be assessed 1. Name and uses 2. Origin or details of development 3. Use status in foreign countries 4. Assessments by national and international organizations 5. Physicochemical properties 6. Use standards (draft) 7. Other Ⅲ.Findings regarding safety 1. Toxicokinetics studies (ADME) 2. Toxicological studies 3. Findings in humans 4. Estimation of daily intake Ⅳ.References Ⅱ.Findings regarding effectiveness 1. Effectiveness as food additive and comparison with other additives with the same use 2. Stability in food 3. Effects on nutritional components in food 23

24 II. Findings regarding effectiveness (1) II. Findings regarding effectiveness Evidence from appropriately designed tests to demonstrate that the food additive has the intended effect and to clarify the purpose of its use Examples Antioxidants: Tests to clarify correlations between antioxidant effects on the target foods and the added amounts, as well as time-course after addition. Preservatives: Tests to clarify preserving effects on the target foods. Comparisons with effects of other food additives already approved for the same use Tests on the stability of the food additive in foods. If the food additive is not stable in foods, indicate substances to be produced by breakdown and those quantities. Effects of the food additive on main nutrients in foods 24

25 II. Findings regarding effectiveness (2) <Points to note> Effectiveness data should cover all target foods. If the applicant presents effectiveness data on only some of the target foods, justification should be provided. Attach the effectiveness data. Indicate difference (advantageous features) from other approved food additives with the same use. Explain the intended uses with functional mechanisms and relevant data. 25

26 Example of description [Effectiveness] (Polysorbate) (1) Characteristics as an Emulsifier Emulsifiers are substances that have a hydrophilic group and lipophilic group in each molecule. Arrayed between water and oil or between water and air, they facilitate emulsification and stabilize mixtures. Emulsifiers may be the O/W type with oil droplets in water, or the W/O type with water droplets in oil. As O/W emulsifiers, polysorbates are strongly hydrophilic and have an HLB *1, the index of the balance between hydrophilic and lipophilic groups, ranging from 10 to 17. Many conventional emulsifiers have a low or medium HLB with high lipophilicity. Sucrose fatty acid esters and glycerin fatty acid esters can be used to prepare emulsifiers with a wide HLB range by respectively varying their degree of esterification or glycerin polymerization, and the type of fatty acid. Nonetheless, it is thought to be difficult to obtain an HLB as high as a polysorbate. HLBs for polysorbates and other emulsifiers are compiled in the following table. (Ref. X) *1 HLB (Hydrophlic Lipophilic Balance): The Value shows the degree of affinity to oil and water and takes 0 to 20. Lipophilic property becomes higher as it approaches 0 and hydrophlic property becomes higher as it approaches 20. Name HLB Polysorbates a) Fatty acid monoglyceride 3-4 Sucrose fatty acid esters 3-15 Sorbian fatty acid ester 2-8 propylene glycol fatty acid ester 3-4 Vegetable lecithin - a) Polysorbate 20: 16.7; Polysorbate 60: 14.9; Polysorbate 65: 10.5; Polysorbate 80:

27 Example of description [Effectiveness] (Polysorbate) (continued) (2) Emulsifying Power Test for O/W Systems For a blend of 50 g soy oil and 450 g tap water with no emulsifier as control segment, test segments were prepared by adding 5 g each of the emulsifiers provided in the table, such as polysorbate 60 or glycerin fatty acid ester, to either soy oil or tap water. Soy oil, water, and emulsifier (test segment) were then emulsified with a TK Homo Mixer at 60 C, 10,000 rpm for 5 minutes. The emulsion was transferred to an emulsion test tube and left to stand at room temperature. The amount of separation to the oil layer was measured over time. The test segment employing polysorbate 60 did not result in observation of any oil flotation after 24 hours; however, glycerin fatty acid ester and lecithin caused gelation and uneven emulsification, while sorbitan fatty acid ester and propylene glycol fatty acid ester resulted in 100% oil flotation after 24 hours. Oil droplets were present after 24 hours for sucrose fatty acid ester, demonstrating insufficient emulsifying power. (Ref. X) Emulsifier The amount of separation to the oil layer Addition 0.5h 1h 2h 24h method HLB None 100% 100% 100% 100% - - Polysorbate 60 0% 0% 0% 0% Add to soy oil 14.9 Glycerin fatty acid ester Gelatinization Gelatinization Gelatinization Gelatinization Add to soy oil 3.8 Sucrose fatty acid esters 0% 0% 0% 0% a) Add to water 11 Sorbian fatty acid ester 100% 100% 100% 100% Add to soy oil 4.7 propylene glycol fatty acid ester 10% 40% 60% 100% Add to soy oil 3.4 Lecithin Gelatinization Gelatinization Gelatinization Gelatinization Add to soy oil - a) Oil droplets on its surface 27

28 Overview Documents Ⅰ.Information on the food additive to be assessed 1. Name and uses 2. Origin or details of development 3. Use status in foreign countries 4. Assessments by national and international organizations 5. Physicochemical properties 6. Use standards (draft) 7. Other Ⅲ.Findings regarding safety 1. Toxicokinetics studies (ADME) 2. Toxicological studies 3. Findings in humans 4. Estimation of daily intake Ⅳ.References Ⅱ.Findings regarding effectiveness 1. Effectiveness as food additive and comparison with other additives with the same use 2. Stability in food 3. Effects on nutritional components in food 28

29 III. Findings regarding safety (1) III. Findings regarding safety 1. Toxicokinetics studies (ADME) Purpose: to obtain information on toxicokinetics (absorption, distribution, metabolism and excretion) of a test substance following administration to experimental animals in order to extrapolate toxicokinetics and development of possible adverse effects in humans. Include considerations that will contribute to the evaluation of toxicity studies where possible. 29

30 III. Findings regarding safety (2) <Points to note> When making a reference to existing assessment reports by JECFA or others, indicate the source of the study. Indicate the species, strains, gender and number of test animals as well as the method of administration, vehicle, dose and method of labeling. Present the study results in a table form, where possible. When residue levels are determined by a test using radioisotope, preferably indicate them in residual radiation level (%TRR or %TAR) or residual concentration (mg/kg or ug/kg). Provide considerations, including those on toxicokinetics and the development of possible adverse effects in humans, where possible. 30

31 III. Findings regarding safety (3) (1) Absorption Blood concentration-time profile Indicate the extent and rate of absorption of the test substance, such as the maximum concentration in blood (Cmax) after dosing, the time to reach the maximum concentration (Tmax), and the area under the blood concentration-time curve (AUC) in test animals. Compare these parameters with those obtained by intravenous administrations or other standard administration methods, where possible. Absorption rate Indicate the levels of urinary, fecal, biliary and respiratory excretion after administration of the test substance as well as the absorption rate in the body calculated on the basis of the total excretion level. 31

32 III. Findings regarding safety (4) (2) Distribution Indicate the organ and tissue distribution including the changes and accumulation over time after single and repeated dose administration of the test substance to test animals. Indicate the measurements at several time points in order to accurately reflect toxicokinetics. Preferably, provide considerations on the form of the test substance in organs and tissues characterized by high concentrations or accumulation of the test substance following repeated dose administration, as well as organs and tissues associated with adverse effects. 32

33 III. Findings regarding safety (5) (3) Metabolism Indicate quantitative values for the test substance (unchanged compound) and its metabolites in biological samples, such as blood, urine, bile and feces, after single and repeated dose administration to test animals in order to provide information on the metabolic pathway and the extent and rate of metabolism. Describe in vitro test results of samples of the organs involved in metabolism, where available. (4) Excretion Indicate the levels of urinary, fecal, respiratory, biliary, lactic or other excretion over time after single and repeated dose administration to test animals in order to provide information on the excretion pathway of the test substance and its principal metabolites as well as the extent and rate of their excretion. 33

34 Example of description [Toxicokinetics studies] (1) Absorption 1 Absorption in rats a. Blood concentration profile According to the report by XX [name of author] (XX [year of report]), a GLPcompliant study was conducted to analyze blood concentration profiles after the XX administration [method of administration] of XX [test substance] (XX, XX, XX mg/kg bodyweight/day) for XX [time per period] in XX-old XX [animal species] (X males and females each per group [group establishment]). As shown in Table 1, the results showed that the blood concentrations of XX [test substance] in the XX dose group(s) peaked (XX to XX mg/l) at X hours post-dose, and was XX at X hours post-dose and XX at X hours post-dose, with a T1/2 of X hours and an AUC of X µg hr/g (Ref. X). Gender Dose (mg/kg body weight) Tmax (hr) Cmax (µg/g) T 1/2 (hr) AUC (µg hr/g) Table 1: Toxicokinetics parameters in blood 34

35 III. Findings regarding safety (6) 2. Toxicological studies Purpose: to obtain information on the effects of the administration of a test substance on experimental animals in order to deduce how adverse effects can develop in humans and the dose levels of the substance that can cause adverse effects. 1) Acute toxicity studies 2) Subchronic toxicity studies 3) Chronic toxicity studies and carcinogenicity studies 4) Reproductive and developmental toxicity studies 5) Genotoxicity studies (mutagenicity tests) 6) Other studies such as allergenicity 35

36 III. Findings regarding safety (7) <Points to note> When making a reference to existing assessment reports by JECFA or others, indicate the source of the study. In principle, describe toxicity studies involving oral administration of a test substance. Present the study results in a table form, where possible. Indicate the bacterial strains, types of cells, the animal species and strains, gender, number of test animals, the method of administration, vehicle, and dose levels. Review food additive degradation products and contaminants, where necessary. Indicate the doses in the unit of mg/kg body weight per day, where possible. Indicate the conformity of the studies with the GLP, where possible. 36

37 Example of description [Toxicity studies] <In case of using tables> (2) Repeated-dose toxicity studies According to the report by XX [name of author] (XX [year of report]), a GLPcompliant study was conducted on the XX administration [method of administration] of XX [test substance] (XX, XX, XX mg/kg bodyweight/day) for XX [period] in XX-old XX [animal species] (X males and females each per group [group establishment]) setting administered group as Table 6 (Ref. X). Table X: Dosage level Dosage level (% or ppm) A, B, C Equivalent to mg/kg body weight/day A, B, C Table X: Toxic findings in XX [study title] toxicity study (XX [animal species]) Dose Males Females C mg/kg/day Single cell necrosis of hepatocytes Increases in absolute and relative weight of liver B mg/kg/day Increases in absolute and relative weight of liver Centrilobular hepatocyte hypertrophy Centrilobular hepatocyte hypertrophy 37

38 Example of description [Toxicity studies] <In case of not using tables> (2) Repeated-dose toxicity studies According to the report by XX [name of author] (XX [year of report]), a GLPcompliant study was conducted on the XX administration [method of administration] of XX [test substance] (XX, XX, XX mg/kg bodyweight/day) for XX [period] in XX-old XX [animal species] (X males and females each per group [group establishment]). The results showed no treatment-related effects on XX [observation parameters such as general condition, body weight, food consumption, and water consumption, and test parameters such as hematology, blood biochemistry, urinalysis, ophthalmology or other functional tests, necropsy, or histopathology]. XX [findings] in XX [observation parameters such as general condition, body weight, food consumption, and water consumption, and test parameters such as hematology, blood biochemistry, urinalysis, ophthalmology or other functional tests, necropsy, or histopathology] were observed in XX [males and females] in the XX [dose] group. These findings were (or were not) considered to indicate toxicity based on XX [reasons]. The NOAEL (LOAEL) was, thus, determined to be XX [dose] in this study. (Ref. X) 38

39 Example of description [Toxicity studies] (4) Genotoxicity studies (mutagenicity test) Table X: Summary of in vitro genotoxicity studies Type of test Test subject Test substance Treatment concentration and dose Results Reference Reverse mutation assay Chromosomal aberration assay S. typhimurium (TA XX, TA XX strain) S. typhimurium (TA XX, TA XX strain) Chinese hamster ovary cells(cho cells) Human peripheral blood lymphocytes X to X mg/plate (+/-S9) Negative XX, Year X to X mg/plate (+/-S9) Positive XX, Year X to X mg/ml (-S9) X to X mg/ml (+S9) X to X mg/ml (-S9) X to X mg/ml (+S9) Negative Negative Positive XX, Year XX, Year Table XX: Summary of in vivo genotoxicity studies Type of test Test subject Test substance Treatment concentration and dose Results Reference Micronucleus assay Reporter gene transgenic animal mutagenicity assay XX mice; 5 males and females each (bone marrow cells) XX mice; 5 males and females each (hepatocytes) gpt delta mice; 5 males and females each (liver, kidneys) X, X, and X mg/kg body weight (single oral dose) X, X, and X mg/kg body weight (single oral dose) X, X, and X mg/kg body weight (Xweek oral dosing) Negative Positive Negative XX, Year XX, Year XX, Year 39

40 III. Findings regarding safety (8) 3. Findings in humans Describe the available information on human data. <Points to note> When making a reference to existing assessment reports by JECFA or others, indicate the source of the study. Indicate gender, age, number of individuals, health status, administration methods and dose levels. 40

41 Example of description [Findings in humans] (1) Intervention studies According to the report by XX [name of author] (XX [year of report]), a randomized clinical study was conducted in XX Year in XX [location], in which XX- to XX-year old (average age XX) XX [study population] were randomized by a double-blind method to a placebo group (XX subjects) or an XX [test substance] (X mg/kg body weight/day) ingestion group for oral ingestion XX times a day [dosing method (such as capsules at breakfast)] for XX [period]. The results revealed no test substance treatment-related effects on XX [observation parameters such as general condition, hematology, blood biochemistry, urinalysis] (revealed that XX was affected). (Ref. X) (2) Cohort studies According to the report by XX [name of author] (XX [year of report]) cited in the report of XX [assessment document source], an XX-year cohort study was conducted in X [gender] XX subjects (XX to XX years of age) in XX [location]. XX patients contracted XX [disease]. The relative risk for XX [disease] was XX (95% CI = XX to XX) in the X mg/kg body weight/day and higher dose groups when compared to groups with XX [test substance] consumption < X mg/kg bodyweight/day, revealing that XX [test substance] consumption X mg/kg body weight/day was strongly correlated to increased risk for XX [disease]. (Ref. X) 41

42 III. Findings regarding safety (9) 4. Estimation of daily intake In general, there are three methods to estimate the daily intake of a food additive. (1) Method of multiplying the daily intakes of the individual food products that can contain the food additive by the corresponding use levels of the additive (2) Market basket study (3) Method based on production statistics survey 42

43 III. Findings regarding safety (10) <Points to note> When proposing to set maximum use concentrations of the additive in foods, estimate its daily intake by using the method (1) above. Where there will be an expansion in the scope of target foods, estimate not only the current intake of the additive, but also the increase expected in its daily intake. Use a body weight of 55.1 kg, instead of 50 kg, to estimate the daily intake. (This is in accordance with the decision by the Food Safety Commission of Japan on 31 March 2014.) 43

44 Example of description [Estimation of daily intake] Estimated daily intake of sugar and advantame (Food consumption data are from 2008 national health and nutrition survey results.) Food Product Intake of food product Estimated sucrose intake Advantame addition Estimated advantame intake (g) (g) (ppm) (mg) (mg/kg body wt./day) Bread (excl. confectionary bread) Confectionary bread Sugars, sweeteners Leaf pickles Takuan, other pickles Jams Fruit juice, fruit drinks Fish, shellfish (preserved) Fish, shellfish (paste products) Fish ham, fish sausage Ham, sausage Fermented milk, lactic acid bacteria beverage Other dairy products Japanese confections Cakes, pastries Biscuits, cookies Hard candy Other candy Coffee, cocoa Other preference drinks Sauces Mayonnaise Other seasonings Total

45 Overview Documents Ⅰ.Information on the food additive to be assessed 1. Name and uses 2. Origin or details of development 3. Use status in foreign countries 4. Assessments by national and international organizations 5. Physicochemical properties 6. Use standards (draft) 7. Other Ⅲ.Findings regarding safety 1. Toxicokinetics studies (ADME) 2. Toxicological studies 3. Findings in humans 4. Estimation of daily intake Ⅳ.References Ⅱ.Findings regarding effectiveness 1. Effectiveness as food additive and comparison with other additives with the same use 2. Stability in food 3. Effects on nutritional components in food 45

46 IV. References IV. References A list of reference materials that are referred to in the overview documents. <Points to note> The list of reference materials should be in the order of citation. Reference materials written in languages other than English and Japanese should be accompanied by Japanese or English translations. Example 1. Kobayashi H: Airway biofilm disease: clinical manifestations and therapeutic possibilities using macrolides. J Infect Chemother 1995; 1: Gelfand J A and Vannier E. Babesia species. In Mandell G L, Bennett J E, and Dolin R(ed.), Mandell, Douglas, and Bennettʼs principles and practice of infectious diseases, 6th ed., vol. 2. Churchill Livingstone, Philadelphia, Pa. 2005; p