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Scheduling delegate's final decisions, June 2016
Scheduling of medicines and poisons
3.1 Symphytum spp. (Comfrey)
Part A - Final decisions on matters referred to an expert advisory committee
3. Scheduling proposals referred to the March 2016 joint meeting of the Advisory Committee on Chemicals Scheduling and Advisory Committee on Medicines Scheduling (ACCS-ACMS#12)
3.1 Symphytum spp. (Comfrey)
Referred Delegate's scheduling proposal
To amend the existing schedule entries for SYMPHYTUM spp. (Comfrey) to resolve ambiguity between restricted uses in Schedule 10/Appendix C and Schedule 5 entries for dermal use and use in cosmetics. It is proposed that the existing Schedule 10/Appendix C entry be amended as follows:
- SYMPHYTUM spp. (Comfrey) in preparations for internal use.
Applicant's application and scheduling proposal
Delegate-initiated application. The reasons for the request were:
- Scheduling clarification - there is ambiguity between existing entries in Schedule 5 and Schedule 10/Appendix C. It is unclear whether the existing entries reflect the intent of the Committee when existing entries were established.
The historical records associated with the development of the Schedule 5 and 10 entries for SYMPHYTUM spp. (Comfrey) refer to the various uses of comfrey and the potential for oral exposure through food and the use of traditional medicines (predominately homeopathic) as well as dermal exposure through the application of creams and ointments. The main concern appears to have been the potential hepatotoxicity of pyrrolizidine alkaloids found in SYMPHYTUM species (Comfrey). It has been noted that the limited extent of dermal absorption and systemic availability of these alkaloids when applied dermally reduces the risks of toxicity such that it is consistent with the criteria for a Schedule 5 entry. While other exposure routes and therapeutic uses have significant toxicity concerns and warrant higher restrictions via listing in Schedule 10 (then Appendix C). The resultant revised wording of the Schedule 5 and 10 entries at the May 1998 NDPSC meeting did not provide this level of clarity as to which products are covered by the two entries.
Current scheduling status
SYMPHYTUM spp. (Comfrey) is currently listed in Schedules 5 and 10/Appendix C and in Appendix F.
Schedule 10/Appendix C
SYMPHYTUM spp. (Comfrey) for therapeutic or cosmetic use except when included in Schedule 5.
SYMPHYTUM spp. (Comfrey) for dermal use.
SYMPHYTUM spp. (Comfrey) when included in Schedule 5.
Safety directions: 31, 32
SYMPHYTUM spp. (Comfrey) has been considered by previous scheduling committees on a number of occasions.
It was first considered in May 1978 to be low risk except where consumption of large quantities was involved and was not scheduled.
In November 1983, the committee noted that while human poisonings had not been recorded, comfrey contained a carcinogenic alkaloid shown to produce a cumulative toxic effect. The committee agreed to include comfrey prepared and packed for internal use in humans as a new Schedule 1 entry for comfrey of:
- COMFREY (Symphytum) being preparations and admixtures for internal use of comminuted leaves or dried and powdered root or any part of the dried plant.
In May 1992, the committee considered submissions in relation to the proposed exemption for topical applications of comfrey due to the low level of pyrrolizidine alkaloids (PAs) in the plants and the low level of dermal absorption. A 1988 review by the Commonwealth Health Department noted that "creams that contain Symphytum officinale extract are not considered to be a significant source of the intake of comfrey in view of the low dermal absorption of the pyrrolizidine alkaloids".
The committee considered that while theoretically an element of risk of liver damage and cancer due to low levels of exposure to PAs in man could not be denied, the likelihood following exposure to small amounts of PAs of the kind present in comfrey was extremely low, even in the case of exposure involving un-braided skin. The committee could not justify the prohibition of the use of the plant in approved external use formulations. The committee examined the list of ointment bases provided by the Traditional Medicines Evaluation Committee and considered that they would not increase the dermal absorption of comfrey to a level which would have toxicological concerns. The substance was included in Schedule 5 with two new Appendix F warnings as follows:
SYMPHYTUM spp. (Comfrey) for therapeutic use except when included in Schedule 5.
SYMPHYTUM spp. (Comfrey) in ointments and creams for dermal use.
Appendix F, Part 3
Symphytum spp. (Comfrey) when included in Schedule 5.
Safety Directions: 31. Do not use on broken skin. 32. Do not use under occlusive dressing.
In May 1998, the committee considered a submission to allow the sale of comfrey when in dermal preparations such as sprays. It noted the Schedule 5 entry included creams and ointments for dermal use and all other therapeutic preparations were covered by the Appendix C entry.
The 1998 committee noted that at the previous consideration percutaneous absorption of comfrey, with hepatotoxic PAs was a major issue in the consideration of an exemption for comfrey in dermal preparations. It also noted that to achieve therapeutic effects, some absorption would be required and if vehicles such as DMSO were used, enhanced absorption would be expected. The current scheduling did not preclude the use of specific vehicles and that the issue of inappropriate formulations could be an issue to be considered by the TGA at the time of registration. The committee agreed that the restriction for 'creams and ointments' should be deleted from the Schedule 5 entry. The Appendix F warning statements were considered appropriate.
The committee agreed that there was potential for confusion in the interpretation of the entries for use in cosmetics, as the Appendix C entry specifically mentioned therapeutic use, but the Schedule 5 entry did not. The committee agreed that the toxicity associated with topical comfrey in either therapeutic or cosmetic use was the same. The committee agreed the Appendix C entry should clarify that it was its intention that comfrey for cosmetic use should be controlled in the same way as therapeutic preparations.
No change was made to the Appendix F warnings. The current schedule 5 and 10 (then Appendix C) entries were set in May 1998
Pre-meeting public submissions
Three submissions were received. Two submissions supported the proposal, and one opposed the proposal.
- The first submission noted that there are a number of dermal non-prescription products (creams and ointments) entered in the ARTG contain Symphytum officinale, advocating that the current Schedule 5 entry for dermal preparations is appropriate, but that it may be appropriate to amend the Schedule 10 entry to ensure no ambiguity with the Schedule 5 entry.
- The second submission supported clarifying the Schedule entries. They proposed the amendment to Schedule 5 be as follows: SYMPHYTUM spp. (Comfrey) for dermal use except when included in Schedule 10.
- The third submission did not support the proposal on the grounds that natural "herb" or "organic" materials should not be banned.
Summary of ACCS-ACMS advice to the delegates
The committee agreed that the existing schedule entries were ambiguous and recommended that the Schedule 10 entry for Symphytum be amended as follows:
Schedule 10/Appendix C - Amend Entry
SYMPHYTUM spp. (Comfrey) in preparations for human or animal use except when in Schedule 5
Schedule 5 - Amend Entry
SYMPHYTUM spp. (Comfrey) in preparations for dermal therapeutic or dermal cosmetic use
The committee advised an implementation date of 1 October 2016 would be appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendations comprised the following:
- To rectify ambiguity in current entries.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- ACCS and ACMS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors23;
- Other relevant information.
Delegate's interim decision
The delegates note, and accept, the advice from the joint meeting of the ACCS and ACMS, and agree to amend the current entries for symphytum spp (comfrey) in schedules 5 and 10. The delegates note that previous considerations by the NDPSC, in regard to the scheduling of products containing symphytum spp, had been mainly concerned with limiting human exposures via routes that could result in significant systemic exposures (except via food, which is not regulated by poison scheduling). The intent of the current schedule entries is to use the Schedule 5 entry to allow only certain types of dermal exposures (in therapeutic and cosmetic products applied topically). The proposed amendments aim to clarify that only topically applied therapeutic products and dermally applied cosmetics would be allowed under the Schedule 5 entry. The existing Warning Statement in Appendix F reinforces this message.
The proposed implementation date is 1 October 2016. The proposed edits to existing entries in Schedules 5 and 10 do not constitute an intent to change the current scheduling arrangements; merely to clarify the entries. Accordingly, an early implementation date is appropriate.
The delegates considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance.
Schedule 10 - Amend Entry
SYMPHYTUM spp. (Comfrey) in preparations for human or animal use except when in Schedule 5.
Schedule 5 - Amend Entry
SYMPHYTUM spp. (Comfrey) in preparations for dermal therapeutic or dermal cosmetic use.
Public submissions on the interim decision
One submission was received. The submission commented that the current schedule entry for comfrey is not in line with international practice and requested that cosmetic uses of comfrey be excluded from scheduling. They note comfrey was initially scheduled for oral use due to hepatotoxicity concerns for pyrrolizidine alkaloids (PAs) found in comfrey, but since PAs have low dermal absorption, dermally applied medicines were eventually down scheduled to Schedule 5. They noted that the reason for not excluding dermal application of comfrey from scheduling completely was due to concerns that solvents such as dimethylsulfoxide (DMSO) may allow more PAs through the skin barrier.
The submission further noted DMSO is included in the Poisons Standard, and therefore any cosmetic use with that solvent would already bear a "POISON" label. Comfrey is allowed in cosmetics in the EU and is used as a skin conditioning agent, abrasive, soothing agent and antidandruff ingredient. DMSO is banned in cosmetics in the EU. Amendment to the proposed schedule entry was proposed to reflect these concerns.
Delegate's final decision
The delegates note the submission made in relation to the interim decision that asks for cosmetic use to be excluded from the Schedule 5 entry. The submission suggests a need to align with international regulation of cosmetics but produces no evidence that the topical application of therapeutic and cosmetic products results in different risk profiles. The advice from the joint meeting of the ACCS and ACMS was that dermal application in either therapeutic or cosmetic products should carry a CAUTION label, despite the lower risk of systemic absorption of pyrrolizidine alkaloids. The delegates have therefore decided to confirm the interim decision. The delegates have confirmed that the reasons for the final decision are in keeping with those for the interim decision.
The implementation date is 1 October 2016.