Summary of Health Canada’s Safety Assessment of Green Tea Extract for Use as a Supplemental Ingredient

September 20, 2023

Version 2

Abstract

Health Canada's Food Directorate assessed Green Tea Extract (GTE) for safety, based on publicly available information. The Food Directorate concluded that there was sufficient information to establish conditions under which standardized GTE could be consumed safely as a supplemental ingredient in supplemented foods. Consequently, Health Canada will permit the use of green tea extract (EGCG/catechins)^{Footnote 1} as a supplemental ingredient in supplemented foods under certain conditions. The conditions are outlined in the Notification of Modification.

Introduction

Between 2004 and 2012, after the Natural Health Products Regulations were put in place, Health Canada approved a number of products that had characteristics of both foods and natural health products (NHPs) as NHPs. This inadvertently created confusion among consumers and in 2012, following extensive consultations, Health Canada began regulating products that look like foods and are consumed as foods, as foods, noting that this would allow Canadians to make more informed choices due to consistent nutrition information and labelling requirements.

During the transition between regulatory frameworks, certain herbal and non-herbal ingredients in these products were identified as not having a history of safe food use or were being used in these products at a level that was inconsistent with food use. As an interim measure, Health Canada used Temporary Marketing Authorizations (TMAs) to permit the sale of products, on a case-by-case basis and under specific conditions, while regulations were being developed for these types of products (i.e., supplemented foods containing supplemental ingredients). Supplemental ingredients have historically been marketed as providing specific physiological or generally beneficial health effects. However, they can pose health risks if overconsumed by the general population, or if consumed by certain vulnerable populations.

Some of these ingredients, including Green Tea Extract (GTE) were listed in Appendix 2 of Health Canada's Category Specific Guidance for Temporary Marketing Authorization: Supplemented Food, for further assessment to determine conditions (e.g., use levels, specifications, and/or labelling statements), if any, under which they would be safe for use as supplemental ingredients.

The scientific information/studies that serve as the basis of the safety assessments were obtained from a search of publicly available primary literature, web searches on specific topics, and citations noted in other articles. This document summarizes the safety considerations that informed Health Canada to allow the use of green tea extract (EGCG/catechins) as a supplemental ingredient.

Approach

The acceptability of a food ingredient typically considers its safety for the general population, over a lifetime of exposure with no limits on consumption; however, the safety assessment approach for supplemental ingredients gave further consideration to the potential use of cautionary labels to mitigate risks, when unlimited consumption may not be safe. Based on the Food Directorate's safety assessment approach, only limited cautionary labelling is considered appropriate for foods containing supplemental ingredients (such as GTE). This labelling is designed to mitigate potential risk(s) identified for sensitive subpopulations, and to help ensure that the intake of the supplemental ingredient, through the diet, remains within acceptable (i.e., safe) levels. Ingredients that require more extensive cautionary labelling (e.g., contraindications) to protect the consumer are not considered appropriate for food use. More information about labelling of Supplemented Foods is available in the Guidance Document: Supplemented Foods Regulations.

Safety Assessment

The safety assessment included a review of the available information on GTE for the purposes of evaluating toxicological, nutritional and allergenicity endpoints. Based on this information, and in consideration of the background dietary exposures, a recommended maximum daily intake (RMDI) was derived for the use of GTE as a supplemental ingredient.

Characterization/Standardization of the Supplemental Ingredient

GTE composition varies based on the starting material, as well as processing conditions (e.g., solvent, temperature). This safety assessment applies to catechin-enriched green tea extracts derived from the leaves of Camellia sinensis, and which are not appreciable sources of caffeine. The assessment applies to extracts with an epigallocatechin gallate (EGCG; the primary catechin constituent of GTE) content ranging between 40% (minimum) and 50% (maximum), a total catechin content ranging between 70% (minimum) and 80% (maximum), and a caffeine content of not more than 5%. Acceptable preparations include dry extracts, fluid extracts, tinctures, decoctions and infusions obtained via water and/or food grade organic solvent extraction techniques. This safety assessment does not apply to modified forms of GTE or those with special carrier systems that could alter its bioavailability, distribution, metabolism or excretion when ingested.
Dietary Exposure

Infusions^{Footnote 2} of Camellia sinensis leaf have a history of food use as a tea (in Asia) for centuries. Green tea extracts containing higher concentrations of catechins (e.g., minimum 95%) have a history of use as flavourings in food (Burdock, 2010).

The background dietary exposure to GTE, and its primary catechin constituent EGCG, could not be fully characterized due to a lack of information regarding use as an ingredient (e.g., flavouring) in foods. However, a conservative background dietary exposure for adults, based on data from the 2015 Canadian Community Health Survey (Health Canada, 2018), was 3 cups of green tea per day or approximately 300 mg EGCG per day. A more typical background dietary exposure was 1 cup of green tea per day or approximately 100 mg of EGCG per day (Health Canada, 2018).

Requirements for complying with the Supplemented Food Regulations

As with any food, the onus is on the food manufacturer or distributor to ensure that a food offered for sale in Canada complies with all regulatory provisions, including but not limited to requirements under the Food and Drugs Act (FDA) and the Safe Food for Canadians Act (SFCA), and the Regulations associated with these Acts. This includes, for example, ensuring compliance with food labelling requirements, provisions for the use of food additives, and the general prohibitions in section 4 of the FDA, which prohibits selling a food that contains a poisonous or harmful substance. More information on other requirements for Supplemented Foods is available in the Guidance Document: Supplemented Foods Regulations. These requirements are independent from the safety review of GTE itself, as described in this document.

Toxicological Safety

Absorption, Distribution, Metabolism and Excretion Studies

In general, GTE catechins are not well-absorbed after consumption. For example, less than 0.2% of the EGCG consumed was found in the blood following its administration (Chen et al., 1997; Kim et al., 2000; Zhang et al., 2004). EGCG and other catechins have short half-lives in the body, and therefore do not accumulate with multiple doses (Lee et al., 2002; Chow et al., 2003). While other studies have noted higher absorption of EGCG, it is noted that this is under specific conditions of being administered alone (i.e., not as a mixture of different catechins), while fasting, or when administered as a bolus dose (Chen et al., 1997; Zhu et al., 2000; Feng, 2006; Isbrucker et al., 2006a; James et al., 2015).

Toxicology Studies

Acute, subchronic, chronic, genotoxicity, reproductive, and developmental endpoints were considered to determine the potential toxicity of GTE. Results are summarized below (N.B. studies cited below are not exhaustive, but rather represent the studies that are critical to the conclusions of the safety assessment of GTE).

Laboratory animal (e.g., mouse, rat, dog) toxicity studies, with exposure to various GTE and EGCG formulations for durations ranging from 13 weeks to 24 months, were reviewed. The critical toxicity study was a combined chronic/carcinogenicity study conducted by Yoshida et al. (2011). In this study, a well-characterized GTE formulation (i.e., 76.4% total catechins and 43.6% EGCG) was administered to rats, in the diet, at doses equivalent to up to 1922.9 mg/kg bw per day (males) and 2525.7 mg/kg bw per day (females) for a 1-year period (chronic study) and a 2-year period (carcinogenicity study). No appreciable, treatment-related toxicity was observed in the chronic study, when considering clinical signs and mortality, body weight, serum biochemistry and urinalysis, and macroscopic and histological examination of the organs. The only exception was slight hypertrophy reported in the hepatocytes of high-dose males, as well as increased liver weight. However, no corresponding indications of hepatotoxicity were observed (e.g., serum biochemistry and histopathological examination). Therefore, while the changes were considered treatment-related, these were not considered as evidence for adverse effects. In the carcinogenicity study, no treatment-related tumours were observed for any organ or tissue (including the liver). The no-observed-adverse-effect level (NOAEL) for this study is considered to be the highest dose tested (i.e., 1922.9 mg/kg bw per day for males; the more sensitive sex).

In some studies, body weight gain (but not food intake) was shown to be inhibited in mice and rats administered EGCG in the diet (NTP, 2016; Morita, 2009; Takami et al., 2008; Yoshida et al., 2011). This effect was attributed to decreased caloric intake, sometimes reported to be related to the brittle nature of food pellets at higher doses.

Any adverse effects observed across the available and relevant toxicological studies in animals were typically associated with the method of administration of the test material, the purity of the test material, and whether or not the animals were pre-fed or fasted. For example, local gastrointestinal (GI) damage, including asymptomatic gastric erosion, diarrhea, vomiting, ulceration, hemorrhage, and epithelial necrosis, was observed in some animal studies, and the severity of these GI effects was dose-dependent (Isbrucker et al., 2006a; Johnson et al., 1999; McCormick et al., 1999; Takami et al., 2008). However, these GI effects, and their severity, were more evident in studies where EGCG was administered via oral gavage and/or using fasted animals. GI effects were minor, or absent, in studies where EGCG was administered via the diet, drinking water, or under pre-fed conditions.

Animal studies that administered highly-concentrated green tea catechins or EGCG alone (i.e., not as part of a mixture of catechins), as a bolus dose (oral gavage or capsules) under fasted conditions, resulted in severe toxicity observed in various organs (e.g., liver, kidney, thymus, spleen, and pancreas) at doses as low as 150 mg EGCG/kg bw per day (Chan et al., 2010; Isbrucker et al., 2006a; Johnson et al., 1999; McCormick et al., 1999). The most notable health effect related to green tea catechins (more specifically EGCG) in these studies, and under these conditions, is liver toxicity.

The severity of hepatotoxicity progressed in a dose-dependent manner, ranging from centrilobular hypertrophy (without pathological lesions) and mild elevation of liver enzymes, to severe hepatocellular necrosis and bile duct hyperplasia. In rodent studies testing EGCG, the doses associated with hepatotoxicity from dietary exposure (NOAEL = 500 mg EGCG/kg bw per day) were 10-fold (i.e., one order of magnitude) higher than the doses associated with hepatotoxicity via gavage (NOAEL = 45 mg EGCG/kg bw per day) (Isbrucker et al., 2006a; McCormick et al., 1999). EGCG studies in dogs observed that fasted animals receiving a bolus dose (via capsule) were more prone, by about one order of magnitude, to severe liver damage than pre-fed animals receiving a comparable amount of EGCG in divided doses (NOAEL of 40 mg EGCG/kg bw per day versus 460 mg EGCG/kg bw per day in the fasted versus pre-fed dogs) (Isbrucker et al., 2006a; Johnson et al., 1999).

GTE (and individual catechins) are not genotoxic, based on mutagenicity and clastogenicity in vitro and in vivo assays. While high concentrations of catechins can result in positive responses in in vitro genotoxicity assays, results are negative in vivo. The positive in vitro results are suspected to relate to the production of hydrogen peroxide, which is not a concern for in vivo environments due to the presence of catalase (which metabolizes this substance to water and oxygen) (Henning et al., 2008; Sang et al., 2011).

No effects were observed in two teratogenicity studies (Isbrucker et al., 2006b; Morita et al., 2008), testing EGCG and a mixture of green tea catechins, respectively. In a two-generation rat study of EGCG (Isbrucker et al., 2006b), reduced pup weight and growth rate for the first generation (F1) and second generation (F2) rats, and slightly delayed sexual maturation of F1 rats, at doses of 300 mg EGCG/kg bw per day and higher were reported. The reduced growth rate is considered to be the cause of the slight delay in sexual maturation. Due to this reduced growth rate of the offspring starting at the mid-dose (300 mg EGCG/kg bw per day), a NOAEL for reproductive and developmental toxicity was determined to be 100 mg EGCG/kg bw per day. The potential sensitivity to effects of GTE during development, as observed in the animal study, as well as the paucity of appropriate clinical data to sufficiently refute this finding (see Clinical Studies, below), supports cautionary labelling for supplemental use of GTE for certain sensitive subpopulations (i.e., children and adolescents under 18 years of age, pregnant/breastfeeding women).

Clinical Studies

The effects observed in clinical studies were similar to those observed in the animal studies, and occurred under similar conditions.

Clinical trials support the general pattern of GI effects following consumption of high doses of GTE and EGCG, as described above. Most of the GI disturbance in human studies occurred following exposure to solid dosage forms of GTE (e.g., capsules), and the severity of these GI effects increased dramatically under fasted conditions.

A number of randomized clinical trials identified liver-related outcomes. The test articles used in these studies included green tea, GTE or purified EGCG. Some of these studies involved healthy patients, while a greater number involved patients with various disease conditions. The length of these clinical trials ranged from 3 months to 12 months, and many had small sample sizes. The incidence and severity of hepatotoxicity increased when GTE or EGCG was administered under fasted conditions or as a bolus dose. Exposure to green tea, GTE or purified EGCG as part of the diet, drinking water, or under pre-fed conditions reduced these effects.

The human studies demonstrated that hepatotoxicity events linked to green tea preparations are relatively rare. The events reported in the clinical trials were generally related to an increase of liver enzymes (alanine aminotransferase and/or aspartate aminotransferase and/or alkaline phosphatase), resulting in mild hepatic toxicity (grade 1 or 2 in most cases)^{Footnote 3}. These effects were reported mainly in studies where GTE or EGCG was consumed in solid dosage form (e.g., as capsules), and consumed under fasting conditions.

None of the clinical trials reported increased liver enzymes or adverse liver effects at doses below 600 mg EGCG per day. Doses ranging from 600 to 800 mg EGCG per day (in capsule form) resulted in statistically significantly elevated liver enzyme activity compared to the placebo group (but still within the normal range), while doses greater than 800 mg EGCG per day were associated with liver enzyme activity above the normal range, and in some cases resulted in liver damage (Dostal et al., 2015; Dekant et al., 2017).

Evidence from a limited number of case reports of abnormal liver function tests related to consumption of conventional infusions of green tea for extended periods (e.g., 5 years) suggests that genetic factors are likely important in modulating susceptibility in humans. A comprehensive review of the hepatotoxicity of GTE conducted by the United States Pharmacopeia (USP)'s Green Tea Extract Hepatotoxicity Expert Panel (Oketch-Rabah et al., 2020) stated that it is reasonable to expect that a patient's genetic predisposition plays a significant role as to whether or not an individual develops liver injury following the intake of GTE, which is the case for other drugs that cause idiosyncratic liver injuries. The expert panel also assessed the available data for a potential link between the presence of hepatotoxic contaminants (e.g., pesticide residues, solvent residues, heavy metals) that may be present in GTE and the hepatotoxic effects observed in clinical trials. No potential links to hepatotoxic contaminants were identified based on the observed pattern of hepatotoxicity associated with GTE.

One clinical study (Matsuyama et al., 2008) involving school-aged obese children (aged 6-16 years) administered a catechin-rich beverage for 24 weeks. The EGCG content in this product was equivalent to a cup of green tea (102 mg EGCG), and the total catechin content was higher than a cup of green tea (576 mg total catechins). This study was conducted to evaluate the effects of a catechin-rich beverage on body fat and cardiovascular disease risk factors in obese children, as well as to investigate the safety of daily ingestion of a green tea catechin-rich drink in children. After 24 weeks of treatment, there were no statistically significant changes seen in the levels of aspartate aminotransferase or alanine aminotransferases (enzyme indicators of liver damage). However, the amount of EGCG administered was not high enough to support the safety of children consuming supplemental GTE (i.e., in addition to background dietary consumption). Additionally, the study was conducted over a short-term timeframe, and thus is not sufficient to show effects of consumption during the entire developmental period.

None of the available clinical studies addressed the safety of supplemental GTE in pregnant/breastfeeding women. The potential developmental sensitivity to EGCG in the aforementioned animal study, as well as the paucity of clinical data to sufficiently refute this finding, supports cautionary labelling for supplemental use of GTE for this sensitive sub-population (i.e., pregnant/breastfeeding women).

Recommended Maximum Daily Intake (RMDI) Derivation

Based on the human studies of healthy populations, a NOAEL for GTE equivalent to 600 mg EGCG per day, was identified. This NOAEL is considered conservative because it includes trials involving the administration of GTE in capsule form (i.e., bolus dose), which is associated with greater incidence and severity of hepatotoxicity.

Based on the critical animal toxicity study, a NOAEL for GTE of 1922.9 mg GTE/kg bw per day (equivalent to 838.4 mg EGCG/kg bw per day based on a 43.6% EGCG content of the test material) was identified (Yoshida et al., 2011). The NOAEL (838.4 mg EGCG/kg bw per day) was divided by a standard uncertainty factor of 100 to account for inter- and intra-species differences, and multiplied by a standard adult body weight of 70 kg, to result in 600 mg EGCG per day (rounded value), consistent with the NOAEL identified in clinical studies.

As stated above, background dietary exposure to GTE could not be fully characterized. Therefore, the conservative background dietary exposure estimate (i.e., 300 mg EGCG per day) was subtracted from the aforementioned NOAEL value, resulting in a recommended maximum daily intake (RMDI) of 300 mg EGCG per day (equivalent to 600 mg total catechins per day) for GTE use as a supplemental ingredient in food. The potential for background dietary exposure of GTE, in addition to the risk of liver injury, supports cautionary labelling for the supplemental use of GTE to prevent overconsumption.

To reduce the risk of liver injury associated with high single-intakes, and in consideration of the aforementioned RMDI, it was further recommended to restrict the maximum serving amount to be equivalent to a single cup of green tea (i.e., 100 mg EGCG per serving).

This RMDI and maximum serving amount for the use of GTE as a supplemental ingredient in foods are considered to be conservative and protective of consumers, including for potential liver effects. It is further noted that the supplemental use of GTE (i.e., added to foods and not taken as a bolus dose [i.e., capsule] or under fasting conditions), is such that its use as a supplemental ingredient would not be expected to be associated with adverse liver effects.

Allergenicity

Green tea and GTE are consumed extensively worldwide, and based on a review of the published literature, allergies to GTE are rare.

Nutritional Safety

Green tea catechins can bind to dietary proteins, and could affect protein bioavailability and digestion (EFSA, 2018). Therefore, they may pose nutritional safety concerns if consumed in large quantities (and repetitively) with foods high in protein. As per the aforementioned recommendations, catechin intake from a single-serving of supplemental GTE would be equivalent to consuming one cup of green tea per serving, and under the conditions identified in the Characterization/Standardization of the Supplemental Ingredient section, is not expected to be a concern. Therefore, the use of GTE is not expected to have a significant impact on dietary protein utilization.

There is evidence that polyphenols^{Footnote 4} can bind iron, consequently inhibiting iron absorption (Disler et al., 1975; Zijp et al., 2000); however, the effect is much smaller when polyphenols and iron are not consumed together (Zijp et al., 2000). The presence of ascorbic acid has been shown to reverse the inhibitory effects of polyphenols on iron absorption (Ma et al., 2011; Siegenberg et al., 1991). Due to the possibility of decreased iron absorption, it is advisable for population groups most susceptible to developing iron deficiency (i.e., infants, children, pregnant women) to avoid supplemental consumption of polyphenol-rich beverages and foods. Cautionary labelling is supported as a mitigation measure in these sensitive subpopulations.

Conclusion & Decision

Health Canada's Food Directorate determined there to be sufficient information to establish conditions under which standardized GTE would be safe for use as a supplemental ingredient in supplemented foods. Consequently, Health Canada will permit the use of green tea extract (EGCG/catechins) as a supplemental ingredient in supplemented foods under certain conditions. These conditions are outlined in the Notification of Modification .

Supplemental ingredient submissions for GTE

To propose future, additional changes to the conditions of use for green tea extract (EGCG/catechins) as a supplemental ingredient, stakeholders can submit a pre-market request to the Food Directorate as described in the Guidance Document: Supplemented Foods Regulations. Manufacturers and distributors are encouraged to request a pre-submission consultation with the Food Directorate to seek additional guidance so that a complete submission can be filed at the outset, potentially reducing the number of requests to the applicant for clarification or additional information, or preventing the submission from being rejected for incompleteness. Pre-submission consultations on supplemental ingredients may be arranged by contacting the Submission Management and Information Unit (smiu-ugdi@hc-sc.gc.ca).

The information set out below is recommended to be included in the submission, if relevant to the nature of the request.

For requests to include GTE formulations outside of the current green tea extract (EGCG/catechins) characterization, the submission must characterize in detail the GTE that is requested for supplemental use. It must also clearly demonstrate that the safety information in the submission applies to the requested GTE. For example, the submission must explain why the results of toxicity testing of a particular GTE formulation apply to the GTE to be used as a supplemental ingredient.

In general, any submitted safety information should be of good quality (e.g., GLP/GCP and OECD compliant), and contain full study reports, not summaries. The reports should provide clear, detailed characterization of the GTE test material, and a full description of the study design, including methods, the type and number of animals treated, the doses administered, and the toxicological endpoints measured. Studies should also provide a detailed documentation of the test results. Similarly, the submission of clinical studies should provide fulsome details of the study design, providing toxicologically focused endpoints that contribute information to the assessment of the safety of the ingredient.

Future requests to modify green tea extract (EGCG/catechins) conditions, such as the maximum serving amount, RMDI or labelling, may require addressing data gaps that were identified in the current toxicological and nutritional assessments, such as the following:

Toxicological data gaps/uncertainties

1. Liver injury
2. Reproductive and developmental toxicity

Nutritional data gaps/uncertainties:

3. Information that would provide adequate evidence that GTE would not affect digestion or absorption of other nutrients, especially in the intestines, and/or information that it would not pose nutritional safety concerns if foods supplemented with GTE were to be consumed frequently over a long period of time in different food matrices.

Health Canada may ask for additional data or other information related to the safety of GTE for use as a supplemental ingredient after reviewing the above information.

References

Burdock, G.A. 2010. Fenaroli's Handbook of Flavor Ingredients. 6th Edition. Green Tea Extract. CRC Press. Boca Raton, FL. p. 1872.

Chan, P.C., Ramot, Y., Malarkey, D.E., Blackshear, P., Kissling, G.E., Travlos, G., Nyska, A. 2010. Fourteen- week toxicity study of green tea extract in rats and mice. Toxicologic Pathology, 38: 1070-1084.

Chen, L., Lee, M. Li, H. and Yang, C.S. 1997. Absorption, distribution, and elimination of tea polyphenols in rats. Drug Metabolism and Disposition, 25(9): 1045-1050.

Chow, H. H., Cai, Y., Hakim, I. A., Crowell, J. A., Shahi, F., Brooks, C. A., Dorr, R.T., Hara, Y., and Alberts, D.S. 2003. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clinical Cancer Research, 9(9): 3312-3319.

Dekant, W., Fujii, K., Shibata, E., Morita, O., Shimotoyodome, A. 2017. Short Review: Safety assessment of green tea based beverages and dried green tea extracts as nutritional supplements. Toxicology Letters, 277: 104-108.

Disler, P. B., Lynch, S.R., Charlton, R.W., Torrance, J.D., Bothwell, T.H., Walker, R.B., Mayet, F. 1975. The effect of tea on iron absorption. Gut, 16: 193-200.
Dostal, A. M., Samavat, H., Bedell, S., Torkelson, C., Wang, R., Swenson, K., et al. 2015. The safety of green tea extract supplementation in postmenopausal women at risk for breast cancer: results of the Minnesota Green Tea Trial. Food and Chemical Toxicology, 83: 26-35.

European Food and safety Authority (EFSA). 2018. Panel on Food Additives and Nutrient Sources Added to Food (ANS): Scientific opinion on the safety of green tea catechins. EFSA Journal, 16(4): 5239.

Feng, W.Y. 2006. Metabolism of green tea catechins: An overview. Current Drug Metabolism, 7: 755-809.

Health Canada. 2018. Food consumption Table derived from Statistics Canada's 2015 Canadian Community Health Survey, Nutrition, Share File. Ottawa. Available from:
https://www.canada.ca/en/health-canada/services/food-nutrition/food-nutrition-surveillance/health-nutrition-surveys/canadian-community-health-survey-cchs/2015-canadian-community-health-survey-nutrition-food-nutrition-surveillance.html

Henning, S.M., Niu, Y., Lee, N.H., Thames, G.D., Minutti, R.R., Wang, H., Go, V.L.W. and Heber, D. 2004. Bioavailability and antioxidant activity of tea flavanols after consumption of green tea, black tea, or a green tea extract supplement. The American Journal of Clinical Nutrition, 80: 1558-1564.

Isbrucker, R.A., Edwards, J.A., Wolz, E., Davidovich, A. and Bausch, J. 2006a. Safety studies on epigallocatechin gallate (EGCG) preparations. Part 2: Dermal, acute, and short-term toxicity studies. Food and Chemical Toxicology, 44: 636-650.

Isbrucker, R.A., Edwards, J.A., Wolz, E., Davidovich, A. and Bausch, J. 2006b. Safety studies on epigallocatechin gallate (EGCG) preparations. Part 3: Teratogenicity and reproductive toxicity studies in rats. Food and Chemical Toxicology, 44: 651-661.

James, K. D., Forester, S. C., Lambert, J. D. 2015. Dietary pretreatment with green tea polyphenol, (-)-epigallocatechin-3-gallate reduces the bioavailability and hepatotoxicity of subsequent oral bolus doses of (-)-epigallocatechin-3-gallate. Food and Chemical Toxicology, 76: 103-108.

Johnson, W.D., et al. 1999. Subchronic oral toxicity of green tea polyphenols in rats and dogs. In: The Toxicologist: SOT 1999 Annual Meeting Abstracts, 57-58.

Kim, S., Lee, M.J., Hong, J., Li, C., Smith, T.J., Yang, G.Y., Seril, D.N. and Yang, C.S. 2000. Plasma and tissue levels of tea catechins in rats and mice during chronic consumption of green tea polyphenols. Nutrition and Cancer, 37(1): 41-48.

Lee, M.J., Maliakal, P., Chen, L., Meng, X., Bondoc, F.Y., Prabhu, S., Lambert, G., Mohr, S., Yang, C.S. 2002. Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans: formation of different metabolites and individual variability. Cancer Epidemiology, Biomarkers and Prevention, 11:1025-1032.

Ma, Q., Kim, E., Lindsay, E.A., Han, O. 2011. Bioactive dietary polyphenols inhibit heme iron absorption in a dose-dependent manner in human intestinal Caco-2 cells. Journal of Food Science, 76: H143-50.
Matsuyama, T., Tanaka, Y., Kamimaki, I, Nagao, T., Tokimitsu, I. 2008. Catechin safely improved higher levels of fatness, blood pressure, and cholesterol in children. Obesity, 16: 1338-1348.
McCormick, D.L. et al (Abstract only). 1999. Subchronic oral toxicity of epigallocatechin gallate (EGCG) in rats and dogs. In: The Toxicologist: SOT 1999 Annual Meeting Abstracts. Vol. 57.

Morita, O., Knapp, J. F., Tamaki, Y., Stump, D.G., Moore, J.S., Nemec, M.D. 2008. Effects of green tea catechin on embryo/fetal development in rats. Food and Chemical Toxicology, 47: 1296-1303.

Morita, O., Kirkpatrick, J. B., Tamaki, Y., Chengelis, C. P., Beck, M. J., Bruner, R. H. 2009. Safety assessment of heat-sterilized green tea catechin preparation: A 6-month repeat-dose study in rats. Food and Chemical Toxicology, 47: 1760-1770.

National Toxicology Program (NTP). April 2016. NTP Technical report on the toxicology studies of green tea extract in F344/NTac rats and B6C3F1/N mice and toxicology and carcinogenesis studies of green tea extract in Wistar HAN [Crl:WI(Han)] rats and B6C3F1/N mice (gavage studies). NTP TR 585. Available from: https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr585_508.pdf

Oketch-Rabah, H.A., Roe, A.L., Rider, C.V., Bonkovsky, H.L., Giancaspro, G.I., Navarro, et al. 2020. United States Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts. Toxicology Reports, 7: 386-402.

Sang, S., Lambert, J.D., Ho, C-T., Yang, C.S. 2011. Review: The chemistry and biotransformation of tea constituents. Pharmacological Research, 64: 87-99.

Siegenberg, D., Baynes, R.D., Bothwell, T.H., Macfarlane, B.J., Lamparelli, R.D., Car, N.G., MacPhail, P., Schmidt, U., Tal, A., Mayet, F. 1991. Ascorbic acid prevents the dose-dependent inhibitory effects of polyphenols and phytates on nonheme-iron absorption. The American Journal of Clinical Nutrition, 53: 537-541.

Takami, S., Imai, T., Hasumura, M., Cho, Y-M., Onose, J., Hirose, M. 2008. Evaluation of toxicity of green tea catechins with 90-day dietary administration to F344 rats. Food and Chemical Toxicology, 46: 2224-2229.

Yoshida, M., Takahashi, M., Inoue, K., Nakae, D. and Nishikawa, A. 2011. Lack of chronic toxicity and carcinogenicity of dietary administered catechin mixture of Wistar Hannover GALA rats. The Journal of Toxicological Sciences, 36(3): 297-311

Zhang, L., Zheng, Y., Chow, M.S.S. and Zuo, Z. 2004. Investigation of intestinal absorption and disposition of green tea catechins by Caco-2 monolayer model. International Journal of Pharmaceutics, 287: 1-12.

Zhu, M., Chen, Y. and Li, R.C. 2000. Oral absorption and bioavailability of tea catechins. Planta Medica, 66: 444-447.

Zijp, I.M., Korver, O., Tijburg, L.B. 2000. Effect of tea and other dietary factors on iron absorption. Critical Reviews in Food Science and Nutrition Sep; 40(5): 371-98.