Monograph: Indole-3-Carbinol

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This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications (PLAs) and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredient.

Notes

Text in parentheses is additional optional information which can be included on the PLA and product label at the applicant's discretion.
The solidus (/) indicates that the terms and/or the statements are synonymous. Either term or statement may be selected by the applicant.

Date

February 24, 2023

Proper name(s), Common name(s), Source information

Table 1. Proper name(s), Common name(s), Source information
Proper name(s)	Common name(s)	Source information			Preparation(s)
Proper name(s)	Common name(s)	Source ingredient(s)	Source material(s)	Part(s)	Preparation(s)
3-Hydroxymethylindole	Indole-3-carbinol	N/A	Brassica oleracea var. botrytis Brassica oleracea var. capitata Brassica oleracea var. gemmifera Brassica oleracea var. italica	Whole plant	Isolate
3-Hydroxymethylindole	Indole-3-carbinol	Indole-3-carbinol	N/A	N/A	Synthetic

References: Proper name: NIH 2019; Common name: NIH 2019; Source information: Jongen 1996, Komiyama et al. 1995, Kwon et al. 1994, Bradfield and Bjeldanes 1991.

Route of Administration

Oral

Dosage Form(s)

This monograph excludes foods or food-like dosage forms as indicated in the Compendium of Monographs Guidance Document.

Acceptable dosage forms for oral use are indicated in the dosage form drop-down list of the web-based Product Licence Application form for Compendial applications.

Use(s) or Purpose(s)

Source of/Provides (an) antioxidant(s) (Fowke et al. 2006; Reed et al. 2005; Herraiz et al. 2004).
Source of/Provides (an) antioxidant(s) that help(s) fight/protect (cell) against/reduce (the oxidative effects of/the oxidative damage caused by/cell damage caused by) free radicals (Fowke et al. 2006; Reed et al. 2005; Herraiz et al. 2004).
Helps to support/promote healthy estrogen metabolism/balance (Reed et al. 2005; Bell et al. 2000; Wong et al. 1997; Bradlow et al. 1994).

Note: If Indole-3-carbinol is combined with another medicinal ingredient with antioxidant properties at Class II and III, there is an option to use the antioxidant statements in plural. The singular should be used when the product only contains one medicinal ingredient associated with this claim.

Dose

Subpopulation(s)

Adults 18 years and older

Quantity(ies)

Antioxidant

Not to exceed 400 milligrams of Indole-3-carbinol, per day (Laidlaw et al. 2010; Naik et al. 2006; Reed et al. 2005; McAlindon et al. 2001; Bell et al. 2000; Wong et al. 1997; Bradlow et al. 1994).

Healthy Estrogen Metabolism

200 - 400 milligrams of Indole-3-carbinol, per day (Laidlaw et al. 2010; Naik et al. 2006; Reed et al. 2005; McAlindon et al. 2001; Bell et al. 2000; Wong et al. 1997; Bradlow et al. 1994).

Direction(s) for use

No statement required.

Duration(s) of use

No statement required.

Risk Information

Caution(s) and warning(s)

Products making a healthy estrogen balance/metabolism claim

Consult a health care practitioner/health care provider/health care professional/doctor/physician prior to use to exclude the diagnosis of a serious cause of hormonal imbalance (UpToDate 2019).

Products providing 20 mg or more of Indole-3-carbinol, per day

Consult a health care practitioner/health care provider/health care professional/doctor/physician prior to use if you are taking medications or natural health products (Linus Pauling Institute 2017; Brinker 2010; Reed et al. 2005; Bradlow et al. 1994).
Consult a health care practitioner/health care provider/health care professional/doctor/physician prior to use if you are attempting to conceive (Bennetts et al. 2008; Michnovicz et al. 1997).
Stop use and consult a health care practitioner/health care provider/health care professional/doctor/physician if you develop liver-related symptoms (e.g. yellowing of the eyes and/or skin, dark urine, abdominal pain, jaundice) or symptoms of low estrogen (Reed et al. 2005; Dalessandri et al. 2004; Bell et al. 2000; Michnovicz et al. 1997; Wong et al. 1997; Bradlow et al. 1994).

Products providing 20 mg or more of Indole-3-carbinol, per day

All subpopulations or Female subpopulation only

Consult a health care practitioner/health care provider/health care professional/doctor/physician prior to use if you have a liver disorder or symptoms of low estrogen such as joint pain, mood changes, changes in libido, hot flashes, night sweats, vaginal dryness or irregular menstruations (Reed et al. 2005; Dalessandri et al. 2004; Bell et al. 2000; Michnovicz et al. 1997; Wong et al. 1997; Bradlow et al. 1994).

Male subpopulation only

Consult a health care practitioner/health care provider/health care professional/doctor/physician prior to use if you have a liver disorder or symptoms of low estrogen such as joint pain, mood changes or changes in libido (Reed et al. 2005; Dalessandri et al. 2004; Bell et al. 2000; Michnovicz et al. 1997; Wong et al. 1997; Bradlow et al. 1994).

Contraindication(s)

All products

Do not use this product if you are pregnant or breastfeeding (Reed et al. 2006, Michnovicz et al. 1997).

Known adverse reaction(s)

No statement required.

Non Medicinal Ingredients

Must be chosen from the current Natural and Non-prescription Health Products Directorate Natural Health Products Ingredients Database (NHPID) and must meet the limitations outlined in the database.

Storage Condition(s)

Keep in a cool, dry place, protected from light (Zeligs 2001).

Specifications

The finished product specifications must be established in accordance with the requirements described in the Natural and Non-prescription Health Products Directorate (NNHPD) Quality of Natural Health Products Guide.
The medicinal ingredient must comply with the requirements outlined in the NHPID.

References Cited

Bell MC, Crowley-Nowick P, Bradlow HL, Sepkovic DW, Schmidt-Grimminger D, Howell P, Mayeaux EJ, Tucker A, Turbat-Herrea EA, Mathis JM. Placebo-Controlled Trial of Indole-3-Carbinol in the Treatment of CIN. Gynecological Oncology 2000;78:123-9.

Bennetts LE, De Iuliis GN, Nixon B, Kime M, Zelski K, McVicar CM, Lewis SE, Aitken RJ. Impact of estrogenic compounds on DNA integrity in human spermatozoa: evidence for cross-linking and redox cycling activities. Mutation Research 2008;641(1-2):1-11.

Bradfield CA, Bjeldanes LF. Modification of carcinogen metabolism by indolylic autolysis products of Brassica oleraceae. Advances in Experimental Medicine and Biology 1991;289:153-163.

Bradlow HL, Michnovicz JJ, Halper M, Miller DG, Wong GY, Osborne MP. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiology, Biomarkers and Prevention 1994;3(7):591-5.

Brinker F. Updates and Additions for Herbal Contraindications and Drug Interactions plus Herbal Adjuncts with Medicines, 4th edition. Sandy (OR): Eclectic Medical Publications. [Internet]. [Accessed 2019 July 4]. Available from: https://www.eclecticherb.com/herb-contraindications-drug-interactions

Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: effect of 3,3'- diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutrition and Cancer 2004;50:161-7.

Fowke JH, Morrow JD, Motley S, Bostick RM, Ness RM. Brassica vegetable consumption reduces urinary F2-isoprostane levels independent of micronutrient intake. Carcinogenesis 2006;27(10):2096-2102.

Herraiz T, Galisteo J. Endogenous and dietary indoles: a class of antioxidants and radical scavengers in the ABTS assay. Free Radical Research 2004;38(3):323-331.

Jongen, WMF. Glucosinates in Brassica: Occurrence and significance as cancer-modulating agents. Proceedings of the Nutrition Society 1996;55(1B):433-446.

Kwon, C.S., Grose, K.R., Riby, J., Chen, Y.H. & Bjeldanes, L.F. In vivo production and enzyme inducing activity of indolo[3,2-b]carbazole. Journal of Agricultural and Food Chemistry 1994;42(11):2536-2540.

Laidlaw M, Cockerline CA, Sepkovic DW. Effects of a breast-health herbal formula supplement on estrogen metabolism in pre- and post-menopausal women not taking hormonal contraceptives or supplements: a randomized controlled trial. Breast Cancer 2010;4:85-95.

Linus Pauling Institute, Oregon State University. 2017. [Internet]. [Accessed 2019 July 4]. Available from: https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/indole-3-carbinol

McAlindon TE, Gulin J, Chen T, Klug T, Lahita R, Nuite M. Indole-3-carbinol in women with SLEL: effect on estrogen metabolism and disease activity. Lupus 2001;10(11):779-83.

Michnovicz JJ, Adlercreutz H, Bradlow JL.1997. Changes in Levels of Urinary Estrogen Metabolites After Oral Indole-3-Carbinol Treatment in Humans. Journal of the National Cancer Institute 1997; Vol. 89, Mo. 10.

Naik R, Nixon S, Lopes A, Godfrey K, Hatem MH, Monaghan JM. A randomized phase II trials of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia. International Journal of Gynecological Cancer 2006;16(2):786-90.

NIH 2019: National Institutes of Health. National Institute of Health. [Internet]. [Accessed 2019 July 4]. Available from: https://chem.nlm.nih.gov/chemidplus/rn/700-06-1

Reed GA, Arneson DW, Putnam WC, Smith HJ, Gray JC, Sullivan DK, Mayo MS, Crowell JA, Hurwitz A. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3'-diindolylmethane. Cancer Epidemiology, Biomarkers and Prevention 2006;15(12):2477-81.

Reed GA, Peterson KS, Smith HJ, Gray JC, Sullivan DK, Mayo MS, Crowell JA, Hurwitz A. A phase I study of indole-3-carbinol in women: tolerability and effects. Cancer Epidemiology, Biomarkers and Prevention 2005;14(8):1953-60.

UpToDate 2019. Diagnostic evaluation of polycystic ovary syndrome in adolescents. [Internet] [Accessed 2019 July 4]. Available from: https://www.uptodate.com/contents/diagnostic-evaluation-of-polycystic-ovary-syndrome-in-adolescents?search=Diagnostic%20evaluation%20of%20polycystic%20ovary%20syndrome%20in%20adolescents&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne M. Dose-ranging study of indole-3-carbinol for breast cancer prevention. Journal of Cellular Biochemistry Supplement 1997;28-29:111-6.

Zeligs, MA. 2001. The Cruciferous Choice: Diindolylmethane or I3C? Phytonutrient Supplements for Cancer Prevention and Health Promotion. [Accessed 2019 July 4]. Available from: http://www.dimfaq.com/site/cruchoice.htm

References Reviewed

Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle 2005;4:1201-1215.

Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochemical Pharmacology 2006;71:1397-1421.

Bradlow HL. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In vivo 2008;22:441-6.

Cavalieri E, Rogan E. Catechol quinones of estrogens in the initiation of breast, prostate, and other human cancers: keynote lecture Estrogens and Cancer. Bradlow HL and Carruba G (eds.). Annals of the New York Academy of Sciences 2006;1089:286-301. Cited In: Bradlow (2008).

Chang YC, Riby J, Chang GH, Peng BC, Firestone G, Bjeldanes LF. Cytostatic and antiestrogenic effectsof 2-(indole-3-ylmethyl)-3,3'-diindolylmethane, a major in vivo product of dietary indole-3-carbinol. Biochemical Pharmacology 1999;58:825-834. [Abstract only]

ChEBI 2012: Chemical Entities of Biological Interest. [Internet]. [Accessed: 2012 March 12].

Dashwood RH. 1998. Indole-3-carbinol: anticarcinogen or tumor promoter in brassica vegetables? Chemico-Biological Interactions 110(1-2):1-5. [Abstract only]

HC 2011: Health Canada. MedEffect Canada: Adverse Reaction and Medical Device Problem Reporting. [Internet]. Ottawa (ON): Health Canada. [Accessed 2012 April 14].

Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous Vegetables and Human Cancer Risk: Epidemiologic Evidence and Mechanistic Basis. Pharmacological Research 2007; 55(3):224-236.

iHerb Natural Products. 2012. [Internet]. [Accessed: 2012 March 12].

Kim YS, Milner JA. Targets for indole-3-carbinol in cancer prevention. Journal of Nutritional Biochemistry 2005;16:65-73.

Komiyama M, Higuchi K, Noguchi H. Selective synthesis using cyclodextrins as catalysts. Preparation of 3-(hydroxymethyl)indole from indole and formaldehyde. Supramolecular Chemistry 1995;4(4):265-269.

Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. International Journal of Obesity and Related Metabolic Disorders 1998;22:227-9. [Abstract only]

Minich DM, Bland JS. A Review of the Clinical Efficacy and Safety of Cruciferous Vegetable Phytochemicals Nutrition Reviews 2007;65(6):259-267. [Abstract only]

NMCD 2012: Natural Medicines Comprehensive Database. 2012. [Internet]. Stockton (CA): Therapeutic Research Faculty. [Accessed 2012 March 12].

NCBI 2012: National Center for Biotechnology Information. [Internet]. [Accessed: 2012 March 12].

NTP 2012: National Toxicology Program. Background Information Indole-3-carbinol (I3C). [Internet]. [Accessed: 2012 March 12].

Rogan EG. The natural chemopreventive compound indole-3-carbinol: state of the science. In Vivo 2006;20:221-228.

Rosen CA, Bryson PC. Indole-3-carbinol for recurrent respiratory papillomatosis: long-term results. Journal of Voice 2004;18:248-53.

Rosen CA, Woodson GE, Thompson JW, Hengesteg AP, Bradlow HL. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngology - Head and Neck Surgery 1998;118(6):810-5.

Sarkar FH, Li Y. Indole-3-carbinol and prostate cancer. Journal of Nutrition 2004;134:3493S-3498S.

Verhoeven DT, Verhagen H, Goldbohm RA, van den Brandt PA, van Poppe. G. A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chemico-Biological Interactions 1997;103(2):79-129. [Abstract only]

WebMD 2012. Women's Health: Normal Testosterone and Estrogen Levels in Women. [Internet] [Accessed 2012 March 12].

Yuan Gao-feng, Bo Sun, Jing Yuan, and Qiao-mei Wang. Effects of different cooking methods on health-promoting compounds of broccoli. Journal of Zhejiang University Science B 2009; 10(8):580-588. [Abstract only]