Bioflavonoids

Part 5 of Schedule 4 of the Therapeutic Goods Regulations provides a list of miscellaneous substances which may be included in listable drug products as active ingredients. This list includes the entry Bioflavonoids (except quercetin).

Bioflavonoids have been defined by reference to a joint monograph developed in 1990 by the TGA in consultation with the Nutritional Foods Association of Australia (NFAA) and the Proprietary Medicines Association of Australia (PMAA) and published in Guidelines for applicants: Listing drug products in the Australian Register of Therapeutic Goods for supply in Australia. This monograph describes a bioflavonoid as "a natural extract derived solely from citrus fruit, rich in gamma benzopyrones glycosides or phenolic glycosides known as bioflavonoids, the major ones being hesperidin, eriocitrin and diosmitin".

At the time of development of the monograph, the majority of bioflavonoids used by industry were derived from citrus and the monograph provided a specification for the citrus derived bioflavonoids. Quercetin was specifically excluded because of a suspected causal association with brain tumours in rats.

The bioflavonoid monograph has no legal standing and sponsors have recently interpreted the entry in Part 5 of Schedule 4 of the Regulations to also include bioflavonoids from other sources. However, the TGA has not, in general, evaluated the safety of bioflavonoids derived from other than citrus. There has therefore been a need to confirm the safety of the bioflavonoid ingredients where sufficient information has not been supplied with the application (eg that the bioflavonoids do not include quercetin, which is specifically excluded by the Regulations).

This issue has been discussed by the Joint TGA Industry Herbal Task Force. Industry has indicated recently that the bioflavonoid monograph in the Guidelines may be both dated and potentially exclusive of other sources of bioflavonoids such as grapeseed and bilberry. A paper setting out the industry's view has been prepared by the NFAA and presented to the TGA. All other sponsors of bioflavonoid containing products are also invited to contribute to the review. It is proposed that following consideration by the Complementary Medicines Section, the matter will be presented to the Complementary Medicines Evaluation Committee for advice.

In the interim, sponsors of listing applications which include bioflavonoids as active ingredients should indicate in their application that the bioflavonoids do not contain quercetin, in compliance with the entry in the Regulations.

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CMEC news

Application for the evaluation of a new complementary medicine substance

A draft form titled 'Application for an Evaluation of a New Complementary Medicine Substance' is available from the Complementary Medicines Section.

When finalised this form will need to be completed by or for each applicant who wishes the Complementary Medicines Section of the Therapeutic Goods Administration to assess whether a new complementary medicine substance could be permitted in listable or non-prescription registrable products. Until the form is finalised, applicants are asked to use the draft format.

CMEC approves new listable substances

Seventeen new Listable substances have been approved by the TGA this year. The Complementary Medicines Evaluation Committee (CMEC) recommended that a number of low risk substances be permitted as active ingredients in Listable therapeutic goods and the following have been included in Schedule 4 of the Regulations:

1. enzyme-hydrolysed rice, other than for the use in oral rehydration products
2. high amylose maize starch
3. royal jelly, provided the label carries the required warning statement
4. shark cartilage
5. zinc ascorbate, and
6. Pinus pinaster stem bark extract (concentrate).

In addition, certain substances approved for use in foods are permitted for use in Listed therapeutic goods at the level permitted in the Food Standards Code for that ingredient. These include:

1. creatine, creatine monohydrate and creatine phosphate - up to 3 g total creatine per daily dose from all sources used in the product
2. chromium picolinate, high chromium yeast and chromium nicotinate - so as to provide no more than a total of 50 µg chromium per daily dose from all sources used in the product
3. cupric citrate - so as to provide no more than 750 µg copper per daily dose
4. high molybdenum yeast - so as to provide no more than 62.5 µg molybdenum per daily dose
5. mixed tocopherols and pyridoxal-5-phosphate - no limit, and
6. calcium phosphate monobasic.

These amendments were gazetted on 16 July 1998.

Kava not to be scheduled

The National Poisons and Scheduling Committee (NDPSC) in their May meeting agreed that kava, Piper methysticum, should not be included in Schedule 4 of the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP). An entry in Schedule 4 would have meant kava as a therapeutic good would only be available on prescription. NDPSC had sought advice from the Complementary Medicines Evaluation Committee (CMEC) and other interested parties on a proposal to control kava for therapeutic use by an entry in Schedule 4 of the SUSDP. The CMEC recommended to NDPSC not to include kava in Schedule 4 of the SUSDP. Kava as a therapeutic good can be adequately regulated for health and safety as a Listed product. CMEC reviewed the safety of kava in therapeutic form at its March and April meetings and indicated that it was unlikely to be abused. The CMEC recommended to maintain kava in products Listed in the Australian Register of Therapeutic Goods, but with restrictions on the maximum amount of active ingredients per dose and a maximum recommended daily dose. The CMEC agreed in principle to the following label warnings for kava:

1. "Those who are pregnant or nursing are not recommended to use kava", and
2. "Not for prolonged use. If symptoms persist, seek advice from a health care practitioner".

Other new substances under review

Other new substances under review The TGA is currently assessing a number of new substances sought by the industry for inclusion in products. Ingredients being assessed include hydroxy citric acid (Garcinia species derived), L-carnitine, choline, inositol, betaine HCl, and coenzyme Q10. The amino acids being assessed are tryptophan, arginine, D- or DLphenylalanine, methionine, carnitine, and glutamine. These amino acids are currently not permitted in Listed goods.

Since many therapeutic goods and isolated food ingredients can be consumed at levels far in excess of those normally contained in foods, there is a greater possibility of misuse and adverse effects from consumption of products of this type. Furthermore, while the effects on human health from consuming these individual components as part of a food may have been determined, the effects of consuming mixtures of these substances in therapeutically active amounts when isolated from foods, has yet to be established. The TGA is seeking public comment on health and safety aspects relating to the consumption of the above, alone or in combination, in therapeutic goods.

The CMEC has looked at warning labels, limitations for indications and development of standards which will permit a number of ingredients to be used in listed products. CMEC has also provided advice on several other issues to assist the TGA resolve problems which have been identified in relation to certain listable ingredients subject to the Customs (Prohibited Imports) Regulations.

The CMEC will also provide advice on the substances selenium and chitosan under the current Section 7 declaration proposals.

Safety of herbal ingredients - identifying low risk herbal ingredients

Comment is invited on the regulation of products containing herbal ingredients, where the preparation of herbal ingredients varies from traditional methods on which a history of low risk use has been established. A discussion paper titled Proposal for Public Comment: Identifying Low Risk Herbal Ingredients is available from the Complementary Medicines Section. This paper identifies the key safety issues which TGA needs to address and proposes a regulatory solution.

The Complementary Medicines Evaluation Committee (CMEC) has discussed the issues and has recommended that this paper be made available for broad public consultation.

If you wish any information contained in a submission to remain confidential to the TGA, you should clearly identify the sensitive information and provide justification for treating it in confidence. Please note that the information you provide may be disclosed under the provisions of the FOI legislation.

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Establishment of acceptable daily intakes for agricultural chemicals and veterinary drugs

Background

Over the past several decades, pesticides and other agricultural chemicals and veterinary drugs have become an important factor in food production. The availability of these chemicals has enabled significant increases in agricultural productivity to be achieved. The use of agricultural and veterinary chemicals may result directly or indirectly, in the presence of small amounts of the chemical or its breakdown products in food commodities. The amount of the chemical remaining in the produce is called "residue".

The consumption of residues of agricultural and veterinary chemicals is not desirable, however where their presence in food is anticipated, it is essential that a mechanism exists to assess the likelihood of risks to the public and to reduce those risks to a minimum. The current approach for limiting human exposure to chemicals in food is to ensure that the chemical is applied at the minimum amount required to achieve effective pest or disease control thereby leaving the lowest practicable residue which is toxicologically acceptable. This is a two step process and is achieved by means of establishing Acceptable Daily Intakes (ADIs) and Maximum Residue Limits (MRLs).

An ADI is a health limit and defined as the daily intake of a chemical which, during an entire lifetime, appears to be without appreciable risk to the health of the consumer on the basis of all the known facts at the time. An MRL is a legal limit and is defined as the maximum concentration of a chemical residue that is legally permitted in or on a food or food commodity when that chemical is applied.

Process

Prior to the registration of an agricultural or veterinary chemical product, applicants must provide registration authorities with information in support of the use of the product, including detailed toxicological studies. The toxicological studies are assessed within the Chemicals and Non-Prescription Drug Branch with a view to determining the potential hazards associated with exposure to the chemical and also, where the chemical is used on food producing crops or animals, to establishing an ADI.

The range of toxicological studies required to be undertaken is detailed in the"Ag Manual" and the "Vet Manual" which are published by the National Registration Authority. Designs for the conduct of toxicological studies have become standardised to a large extent and international guidelines have been developed to achieve consistency in experimental techniques.

Assessment of individual toxicity studies includes the determination of a no-observable-effect level (NOEL), which is the highest administered dose which does not cause any detectable (usually adverse) effect in the study. The overall NOEL for a chemical, determined in the most sensitive species, is then used to estimate the ADI.

The ADI for humans is calculated by dividing the overall NOEL from the animal studies by a safety factor. The magnitude of the safety factor is selected to account for uncertainties in extrapolation of animal data to humans, variation between humans, the completeness of the toxicological data base and the nature of the potential adverse effects.

The most common safety factor is 100 which takes into account that humans may be 10 times more sensitive to the chemical than experimental animals and that a proportion of the population may be 10 times more sensitive than the average person. Where there is satisfactory information in humans, there is no necessity to extrapolate from animal data and a safety factor of 10 is considered adequate to account for inter-individual variation. On the other hand when the toxicity data base is incomplete or when the nature of the potential hazards indicate the need for additional caution, a further safety factor of 10 to 20 may be incorporated. In these situations, the overall NOEL is divided by a safety factor of 1000 to 2000 in determining the ADI.

The toxicological studies on which the overall NOEL is based are invariably carried out by oral dosing of animals and usually by incorporation of the chemical in the diet. The subsequent establishment of an ADI is thus directed to human exposure by the oral route. Due to possible differences in absorption and other kinetic and metabolic parameters, the comparison of intakes by other routes with the ADI should be interpreted with caution.

The ADI is therefore used to set an upper limit for daily intake of a particular chemical residue from all food sources. MRLs in food commodities are generally based on actual residues obtained in experimental field trials where the chemical is applied and the treated crop/animal is managed according to sound agricultural or veterinary practice. The theoretical daily intake of a chemical may be calculated using the MRL in various food commodities and mean daily food consumption figures for the relevant food groups. The resulting intake should be at or below the ADI for the particular chemical. If the likely intake of the chemical is above the ADI, registration of the product would not be granted unless it was possible to modify the use pattern to achieve lower residues. In practice, chemical residues are commonly below the MRL and actual intakes represent only a fraction of the ADI.

Monitoring

Registration of a new agricultural or veterinary chemical product includes the approval of a particular use pattern which is listed on the approved label. Adherence to this pattern of use should lead to residues in food no greater than the MRL. Certain raw food commodities are subject to random testing for chemical residues through the National Residue Survey conducted by the Department of Primary Industries and Energy. The results of the NRS continue to show a high level of compliance with Australian MRLs. Additionally, the Market Basket Survey measures chemical residues in processed foods. The latter is undertaken by the Australia New Zealand Food Authority and consistently demonstrates that the intake of chemical residues in food are well within safe limits.

Documents

ADI list: Acceptable daily intakes for agricultural and veterinary chemicals. TGA (1997). Australian Government Publishing Service, Canberra. Available from GIS.

MRL Standard: Maximum residue limits in food and animal feedstuffs. NRA (1996). Australian Government Publishing Service, Canberra. Available from GIS.

Progress on international treaty negotiations

Persistent Organic Pollutants

Negotiation of an international convention to control the manufacture, storage and release into the environment of certain toxic persistent organic pollutants (POPs) commenced in June 1998 under the auspices of the United Nations Environment Program. The Australian delegation consisted of representatives from a number of Departments: Foreign Affairs and Trade led the delegation, while a representative from TGA participated to ensure health concerns and technical issues relating to these chemicals were addressed.

The POPs Convention will initially cover twelve chemicals - DDT, aldrin, dieldrin, endrin, chlordane, heptachlor, hexachlorobenzene, mirex, toxaphene, polychlorinated biphenyls, dioxins and furans - identified for international action because of their toxicity, environmental persistence and their capacity for long-range dispersion across national boundaries. It is intended that Convention negotiations will be concluded by 2000.

Australia has already banned or restricted the production and use of most of the twelve listed POPs. However, like many countries, Australia does produce some POPs - dioxins and furans - as by-products of industrial processes and also has some naturally occurring emissions. The objective of Australian involvement in these negotiations will be to ensure that Australia's health, trade and environment interests as they relate to these chemicals are protected, and that our particular national circumstances are taken into account in the development of any international regulatory framework and addition of new chemicals to the controlled list.

The first session of the Intergovernmental Negotiating Committee (INC) convened to draft a POPs convention was hosted by the Canadian Government. Two common themes in opening statements made by governments at the Montreal meeting were support for the activities undertaken by UNEP prior to commencement of the negotiations and for the negotiating mandate set down by the UNEP Governing Council. Delegates at the Montreal meeting agreed to establish a criteria expert group and another contact group to examine implementation aspects of a future instrument, including technical and financial assistance issues.

Prior Informed Consent

Representatives from Australia and 94 other countries reached agreement in March 1998 on a Convention for Prior Informed Consent (PIC) for trade in hazardous chemicals. The Convention will formalise and strengthen an existing, voluntary system administered by the Food and Agriculture Organisation and the United Nations Environment Program, ensuring that a country is able to make informed decisions as to whether or not it wishes to import a chemical that has been banned or severely restricted by another country because of its health and/or environmental risks, and under what conditions. While Australia and many other developed countries have established comprehensive procedures to ensure chemical safety within their borders, many developing countries still lack the capacity to assess chemical risks and enforce regulations, resulting in significant risks to human health and the environment in these countries. The PIC Convention will be open for signature in Rotterdam in September.