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Scheduling delegate's final decisions: ACCS, November 2015

Scheduling medicines and poisons

19 November 2015

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2.3 Clitoria ternatea extract

Part A - Final decisions on matters referred to an expert advisory committee

2. Scheduling proposals referred to the August 2015 ACCS meeting

2.3 Clitoria ternatea extract

Scheduling proposal

The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):

  • In June 2015 the delegate received a request to consider new entry for Clitoria ternatea extract in Schedule 5, based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to approve a new biological active constituent.
Scheduling application

The reasons for the request were:

  • Clitoria ternatea extract is a new plant-based ethanolic extract comprised of a number of chemicals and plant based compounds including flavonoid glycosides, essential amino acids, pigments, cyclic peptides, lipids, mineral salts and carbohydrates. It is intended for use in an agricultural product.
  • The skin sensitisation study (by local lymph node assay) did not provide robust evidence of a skin sensitisation potential.
  • No acute inhalational toxicity testing was undertaken, however based on the physical properties of the extract and the low toxicity findings in other studies; the OCS does not consider Clitoria ternatea extract to have inhalational safety concerns at this time.
  • No eye irritation studies were undertaken. However, based on the residual ethanol within the extract and the potential mechanical irritation of the extract; Clitoria ternatea extract is considered to have a moderate eye irritation potential.
  • The systemic findings in short-term studies were not considered to warrant scheduling.
  • Clitoria ternatea extract was not an in vivo or in vitro genotoxicant.
  • The carcinogenicity or immunotoxicity potential of Clitoria ternatea extract cannot be determined at this time.
Delegate's reasons for referring this to the committee

While the OCS evaluation report is clear on the basis for its recommendation to list Clitoria ternatea extract in Schedule 5, the sponsor has requested listing in Appendix B (i.e. not scheduled). The SUSMP is quite explicit that a sponsor application to create an Appendix B entry will not be accepted. In order to resolve the differences between the sponsor and the OCS as to the most appropriate scheduling action, the delegate seeks advice from the ACCS.

The delegate asked the committee the following questions:

  • The OCS report indicates that the toxicological endpoint demonstrating consistency with SPF criteria for listing in Schedule 5, is the presumed eye irritancy associated with instilling a powdered substance containing traces of ethanol in the eye. Other toxicological endpoints suggest that scheduling is not necessary. Does the ACCS support the OCS recommendation for listing in Schedule 5?
  • Does the ACCS agree that the lack of an acute inhalation toxicity study is not critical, given the OCS assessment of the matter and the sponsor contention that the potential for the product to generate an aerosol makes it unlikely that it would pose an inhalational hazard and the physico-chemical properties of the extract did not enable the appropriate environment for inhalational studies in the rat.
Substance summary
Toxicokinetics/ADME

Clitoria ternatea extract consists of a range of plant based compounds including flavonoid glycosides, essential amino acids, pigments, cyclic peptides, lipids, mineral salts and carbohydrates common to legumes; all of which are likely to have different absorption, distribution, metabolism and excretion properties. No single or group of ingredients within the extract was identified as a cause of local or systemic toxicity.

Acute toxicity

The acute toxicity end-points for this chemical are listed in the below table.

Toxicity Species Clitoria ternatea extract SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat LD50 >2000 mg/kg bw
Acute dermal toxicity LD50 (mg/kg bw) Rat LD50 >2000 mg/kg bw
Acute inhalational toxicity LC50 (mg/m3/4h) N/A Not considered to pose a hazard at this time
Skin irritation Rabbits Non-irritating Appendix B
Eye irritation N/A Presumed slight-moderate Schedule 5
Skin sensitisation LLNA Mice Non-sensitiser
Repeat-dose toxicity

No toxicological effects or microscopic examination abnormalities were noted in repeat dose oral and dermal studies.

Reproduction and developmental toxicity

No information was provided. However, OCS notes that no toxicity related effects were noted on reproductive organs in repeat-dose studies.

Neurotoxicity

No information was provided. However, OCS notes that no neurotoxic effects were noted in acute or repeat dose studies.

Genotoxicity

Clitoria ternatea extract tested negative in in vivo and in vitro genotoxicity studies.

Observation in humans

No information was provided.

Public exposure

No information was provided.

No domestic (general public) exposure is expected for Clitoria ternatea extract at the time of this application. The intended use of Clitoria ternatea extract is as an insecticide on crops. The OCS notes that the Clitoria ternatea plant is already used in Australia in homeopathic remedies and teas and as fodder for cattle.

International regulations

No information was provided.

Scheduling status

Clitoria ternatea extract is not specifically scheduled. There is little or no precedent for including a plant extract in the Schedules, although there are several powdered or granulated microbiological extracts with comparable toxicity profile (eye irritancy) that have resulted in them being listed in either Schedule 5 or Appendix B. There is one insecticidal plant extract (Azadirachta indica extract), that is currently listed in Schedules 5, 6 and 10. However, its toxicological profile is distinctly different, with potential reproductive toxicity as the critical toxicological endpoint driving the scheduling.

Scheduling history

Clitoria ternatea extract is not currently specifically scheduled, scheduling history is not available.

Public pre-meeting submissions

One public submission was received. The submission stated that there was confusion over why the substance is being proposed for scheduling. The confusion stemmed from the substance not being regulated in other areas, such as its approval for use in food in Australia and that there are no restrictions in place for its use in cosmetics in the US or EU.

The public submissions are available at Public submissions on scheduling matters.

Summary of ACCS advice to the delegate

The committee recommended Clitoria ternatea extract be listed in Appendix B.

Appendix B, Part 1 - Reasons for entry
Substance Standard Statement
Clitoria ternatea extract B - use pattern restricts hazard and area of use
Appendix B, Part 2 - areas of use
Substance Standard Statement
Clitoria ternatea extract 1.2 - Insecticide

The committee recommended an implementation date of 1 February 2016.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.

The reasons for the recommendations comprised the following:

  • Low toxicity for the proposed use pattern
Delegate's interim decision
Appendix B - New Entry

Clitoria ternatea EXTRACT

Subject to: (a) low toxicity; 1.2: insecticide.

The delegate considered the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989: c) the toxicity of the substance.

The proposed implementation date is 1 February 2016.

The reasons for the interim decision comprised the following:

The toxicological profile of Clitoria ternatea extract is well characterised in the OCS evaluation report. The low acute and chronic toxicity profile suggests that scheduling is not necessary. While the acute toxicity tests are consistent with SPF criterial for listing in Schedule 5, the fact that the highest doses tested were at the lower end of the range does not preclude the likelihood that toxic doses are higher than the range specified in SPF Schedule 5 criteria. Accordingly, the delegate accepts ACCS advice that Clitoria ternatea extract is sufficiently nontoxic to be listed in Appendix B.

Delegates' considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors5;
  • Other relevant information.
Public submissions on the interim decision

One submission was received. The submission supported the delegate's interim decision.

Edited versions of these submissions are available at Public submissions on scheduling matters.

Delegate's final decision

The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.


Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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