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Scheduling delegate's final decisions: ACCS, December 2014

Scheduling medicines and poisons

16 December 2014

Book pagination

Final decisions on matters referred to an expert advisory committee: 1.9-1.12

1.9 Fosthiazate

Scheduling decision

  • To create a new Schedule 7 entry:

FOSTHIAZATE

  • Implementation date, 1 February 2015

Scheduling proposal

The ACCS considered the following proposal referred by the chemicals scheduling delegate (the delegate) for advice:

  • To include fosthiazate in either Schedule 6 or 7.

The committee considered and discussed the resolutions with an implementation date of 1 February/1 June/1 October 2015.

On 6 May 2014, the Office of Chemicals Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to register a new active ingredient, requested that the delegate consider including fosthiazate in Schedule 7 with no exemptions or cut-offs.

The reasons for this request were:

  • Fosthiazate has a moderate oral toxicity in rats [LD50 73 and 57 mg/kg bw (male and female respectively), with deaths];
  • It has low to moderate dermal toxicity in rats [LD50 2396 and 861 mg/kg bw (male and female respectively), with deaths];
  • The inhalational toxicity is moderate [LC50 832 and 558 mg/m3 (rats male and female respectively), with deaths];
  • It showed moderate eye irritancy potential in rabbits;
  • It is a skin sensitiser in guinea pigs;
  • Neurological effects (including tremor in rats treated dermally and orally, and uncoordinated movements and salivation in dogs treated orally) were observed at high dose levels in standard repeat-dose studies. Moreover, fosthiazate exhibited cholinesterase inhibition at low doses; and
  • In a two-generation rat study clear evidence of offspring susceptibility was observed [reduced viability and weight gain in offspring at 30 ppm, and termination of the top dose group of 100 ppm (7.2/9.3 mg/kg bw/d) in males and females, respectively], after the first generation. In a rabbit developmental study a treatment-related decrease in the foetal body weight and increased frequency of small foetuses were noted at dose levels where no maternal toxicity was observed.

The delegate's reason for referring this scheduling proposal to the ACCS was that the OCS evaluation report noted that fosthiazate is a potential neurotoxicant and this warrants listing the substance in Schedule 7. The Scheduling Policy Framework for Medicines and Poisons (SPF) suggests that such submissions need consideration by the ACCS.

The delegate asked the ACCS the following question:

  • The acute and repeat-dose toxicity profiles of fosthiazate are consistent with the Scheduling Policy Framework for Medicines and Poisons (SPF, 2010) factors for listing in Schedule 6. The basis for the Schedule 7 recommendation appears to be the very low NOAELs for cholinesterase inhibition (plasma, erythrocyte and brain) and LD50s only slightly above the cut-off between Schedule 6 and Schedule 7, particularly in females. Does the ACCS support listing in Schedule 7?
  • Note that a scheduling cut-off is not yet proposed because no product containing fosthiazate has been submitted for registration. At the time of referral by the delegate, no comment had been received from the sponsor on the OCS scheduling recommendation.

Substance summary

Structure of fosthiazate

Figure 1. Structure of fosthiazate

Fosthiazate is a relatively new group non-fumigant, organophosphorus (OP) nematicide. It also has systemic activity against various species of insects and mites on the foliar parts of the plants. Fosthiazate has been on the market in Japan since 1993 and is currently registered for use on potatoes for controlling cyst nematodes in the U.K2.

Organophosphorus pesticides are used extensively to control agricultural, household and structural pests. These pesticides constitute a diverse group of chemical structures exhibiting a wide range of physicochemical properties, with their primary toxicological action arising from inhibition of the enzyme acetylcholinesterase (AChE)2. Pope (1999)3 considered whether OP pesticides all exert toxicity through a common mechanism and evaluated the comparative toxicity of the 38 OP AChE inhibitors registered for use as pesticides in the United States. It is concluded that all OP anticholinesterases potentially have a common mechanism of toxicity, that is, phosphorylation of AChE causing accumulation of acetylcholine, overstimulation of cholinergic receptors, and consequent clinical signs of cholinergic toxicity. Additional macromolecular targets for some OP pesticides, however, may alter the cascade of events following AChE phosphorylation and thereby modify that common mechanism. Furthermore, other macromolecular targets of some OP pesticides appear capable of altering noncholinergic neurochemical processes. These additional actions may contribute to qualitative and quantitative differences in toxicity sometimes noted in the presence of similar levels of AChE inhibition induced by different OP pesticides. Further investigation of these additional sites of action may allow subclassification and influence the decision to perform combined risk assessments on this class of pesticides based on common mechanism of toxicity.

Acute toxicity

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

Toxicity Species Fosthiazate SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 73 and 57 (M/F), with deaths Moderate to high toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat 2396 and 861 (M/F), with deaths Low to moderate to high toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rat 832 and 558 (M/F), with deaths Moderate to high toxicity
Skin irritation Rabbit Non irritant
Eye irritation Rabbit Moderate irritant
Skin sensitisation (Magnussen & Kligman method) Guinea pig Sensitiser
Repeat-dose toxicity

Short-term and sub-chronic studies in rats, mice and dogs reported cholinesterase inhibition in plasma, erythrocytes and the brain as the main effect at low doses with no observed effect levels (NOEL) of 0.05-0.1 mg/kg bw/d by the oral route across species. Target organs identified at higher doses than those which caused cholinesterase inhibition were the liver and adrenals, with a range of organ weight and histopathological changes observed.

A short-term repeat dose dermal study in rats elicited similar responses to those seen in the oral studies, with cholinesterase inhibition (plasma, erythrocyte) at low doses (2.5 mg/kg bw/d in females) and inhibition in all three regions (plasma, brain and erythrocyte) at ≥25 mg/kg bw/d in both sexes. Histopathological and weight changes were observed in the adrenals at higher doses.

Long term studies in rats, mice and dogs were consistent with the shorter duration repeat dose studies.

Genotoxicity

Fosthiazate was negative in in vitro and in vivo in genotoxicity studies.

Carcinogenicity

There was no evidence of carcinogenic potential in rats or mice in long-term studies.

Reproduction and developmental toxicity

In a two-generation rat study, there was an increase in irregular oestrous cycles, slightly reduced conception rate and fertility index, and a tendency towards prolonged gestation lengths in females. However overall, most of these identified effects were within historical control ranges, and no evidence of reproductive toxicity was observed (noting that sperm parameters and sexual maturation data were not collected). Offspring viability post-partum and weight gain in the first offspring generation were affected by treatment at the mid (30 ppm) and highest dose tested (100 ppm), with subsequent termination of the reproductive study for the highest dose level only in the second generation. No evidence of treatment-related macroscopic, histopathological or developmental changes was observed in F1 or F2 offspring.

Fosthiazate was not a developmental toxicant in rats; however, in rabbits there was an increase in small foetus frequency and a slight reduction in body weights in foetuses at 2 mg/kg bw/d, which was the dose established as the maternal NOEL (being the highest dose tested in the study). However, fosthiazate is not a teratogen, as no treatment-related visceral or skeletal malformations or variations were seen at all doses tested in developmental toxicity studies. Therefore, on the weight of evidence from evaluated data, it is unlikely that fosthiazate is a developmental toxicant.

Observation in humans

No information was provided.

Public exposure

The evaluation report indicated that as no product has been proposed for registration, exposure estimation was not required at this time.

International regulations

No information was provided. The Secretariat obtained the following information.

In the EU, fosthiazate was included in the Annex I of the Directive in September 2003 (Commission directive 2003/84/EC) with the following: "Specific provisions: Only uses as nematicide may be authorised". The EU has been reviewing this regulation, but the Secretariat has been unable to access the latest EU regulation for the substance.

In the US, the US Environmental Protection Authority notes that 'available data provide adequate information to support the conditional registration of fosthiazate technical and end-use products for use on tomatoes'.

In Taiwan, 75% emulsifiable concentrate (EC) fosthiazate is banned (effective 1 January 2014)4.

Scheduling status

Fosthiazate is not specifically scheduled.

Several organophosphates are included in Schedule 6, including acephate and vamidothion, and Schedule 7, including amiton and terbufos. Tolclofos-methyl is listed in Schedule 5.

Scheduling history

Fosthiazate has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

No public submissions were received.

Summary of the ACCS advice to the delegate

The ACCS recommended that a new Schedule 7 entry be created for fosthiazate with an implementation date of 1 February 2015.

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 reason for the recommendation is:

  • Chronic toxicity profile is consistent with Schedule 7 factors.

Delegate's interim decision

The delegate accepts the advice tendered by the ACCS and agrees to include a new entry for fosthiazate in Schedule 7. The toxicity profile of fosthiazate is consistent with that of other neurotoxicant organophosphonates and potentially with the SPF criteria for listing in Schedule 6. However, effects on offspring and some uncertainties about the chronic toxicity profile (quite low NOEL for inhibition of brain cholinesterase in repeated exposure studies), as well as reports of some lethality via eye exposure, all support a more conservative listing in Schedule 7.

The implementation date for this decision is 1 February 2015.

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

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors;
  • Other relevant information.

Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate has confirmed 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.

Schedule entry

Schedule 7 - New entry

FOSTHIAZATE.

1.10 Diethylene glycol monomethyl ether or ethanol, 2(2-methoxyethoxy)

Scheduling decision

  • To create a new Schedule 6 entry:

DIETHYLENE GLYCOL MONOMETHYL ETHER

  • To create a new Appendix C entry:

DIETHYLENE GLYCOL MONOMETHYL ETHER for cosmetic use

  • Implementation date, 1 June 2015

Scheduling proposal

The ACCS considered the following proposal referred by the delegate for advice:

  • Proposal to develop a separate listing for diethylene glycol monomethyl ether in Schedule 6 to complement the current generic listing of diethylene glycol monoalkyl ethers and to consider restrictions on use in cosmetic preparations.

The committee considered and discussed the resolutions with an implementation date of 1 February/1 June/1 October 2015.

On 29 August 2013, NICNAS, under its IMAP programme, recommended that the delegate consider creating a Schedule 6 entry for preparations containing diethylene glycol monomethyl ether for domestic use and a Schedule 7 entry for preparations containing diethylene glycol monomethyl ether for cosmetic use.

The basis for this recommendation was that developmental toxicity is the main concern and as cosmetic use potentially involves direct dermal application, a Schedule 7 entry for cosmetic products is applicable.

The delegate's reason for referring this scheduling proposal to the ACCS was that diethylene glycol monomethyl ether (DEGME) may be currently covered by the generic Schedule 6 entry for ethylene glycol monoalkyl ethers and their acetates. There is a 10% cut-off to exempt these from scheduling.

A related chemical (hexyloxyethanol) was referred to the July 2013 ACCS meeting, which recommended listing in Schedule 6 as a separate entry from the generic entry for ethylene glycol monoalkyl ethers.

The NICNAS IMAP report on DEGME included recommendations for strengthening hazard statements and concentration restrictions on use in products such as cosmetics, household cleaners, paints and floor sealants. The advice of the ACCS was needed to implement any scheduling amendments.

The delegate asked the ACCS the following questions:

  • The NICNAS IMAP assessment particularly notes potential developmental toxicity with relatively high oral no observed adverse effect levels (NOAELs), although somewhat lower dermal NOAELs. The report also notes risk assessments suggesting a relatively low margin of exposure (MoE) for some uses of DEGME (particularly in cosmetics). Does the ACCS consider that Schedule 6 listing (with 10% cut-off to exempt from scheduling) remains appropriate for DEGME?
  • Is there a need to include an entry in Appendix C to prohibit the use of DEGME in cosmetic (or other domestic products?) at concentrations above those listed in the NICNAS IMAP report?
  • Are the current First Aid statements, Warning Statements and Safety Directions in Appendices E & F for scheduled products containing DEGME appropriate?
  • Does the current entry for ethylene glycol monoalkyl ethers in Appendix I (Uniform Paint Standard) adequately address uses of DEGME?
  • What information would be needed to assess the regulatory impacts of any proposed changes to the scheduling of DEGME (e.g. in AgVet products)?

Substance summary

Please refer to the NICNAS IMAP human health Tier II assessment report for ethanol, 2-(2-methoxyethoxy)- available at: Human health tier II assessment for ethanol, 2-(2-methoxyethoxy)-.

Scheduling status

Ethanol, 2-(2-methoxyethoxy)- is not specifically scheduled. Ethylene glycol monoalkyl ethers and their acetates are listed in Schedule 6 and Appendices E, F and I.

Scheduling history

In November 1984, the Poisons Schedule (Standing) Committee (PSC) considered scheduling of ethylene glycol monoalkyl ethers and their acetates. The PSC noted that ethylene glycol monomethyl- and monoethyl ethers were the most toxic of the series which demonstrated significant testicular effects, reproductive toxicity, haematological effects and were toxic at inhalation levels at the TLV. The PSC also noted that other alkyl ethers of demonstrated haematological effects which increased with chain lengths. The PSC therefore decided to include preparations containing 5% or less ethylene glycol monoalkyl ethers and their acetates in Schedule 6.

In February 1985, the PSC reconsidered the November 1984 decision and decided to raise the Schedule 6 ethylene glycol monoalkyl ethers and their acetates exemption cut-off from 5% to 10%.

Pre-meeting public submissions

One submission was received. The submission indicated that the substance is not used in cosmetic products in Australia and it has no objection to aligning with EU regulations.

Summary of ACCS advice to the delegate

The ACCS recommended that preparations for cosmetic use containing diethylene glycol monomethyl ether be included in Appendix C.

The committee also recommended that a new Schedule 6 entry be created for diethylene glycol monomethyl ether and that the delegate seeks further information on non-cosmetic uses, possible exemptions and labelling.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of the substance; (b) the purposes for which the substance is to be used and its extent of use; and (c) the toxicity of the substance.

The reasons for the recommendation comprised the following:

  • The reproductive toxicity of the substance.
  • The substance is readily absorbed through the skin.

Delegate's interim decision

The delegate noted that diethylene glycol monomethyl ether (DEGME) is a diethylene glycol ether, and that it would not be covered by the generic Schedule 6 entry for ethylene glycol monoalkyl ethers and their acetates. The toxicological profile of DEGME includes potential developmental and reproductive toxicity and is therefore comparable to related substances covered by Schedule 6 entries. The delegate therefore proposes to accept ACCS advice that a separate listing for DEGME in Schedule 6 is warranted. The delegate also notes the low MOE estimates associated with its direct application to the skin in cosmetic products, and accepts ACCS advice that a separate listing be created in Appendix C for this use.

The delegate notes that the ACCS was unable to recommend an exemption cut-off for the proposed Schedule 6 entry. In accepting this scheduling proposal, the delegate invites further public comment on any perceived regulatory impacts of a Schedule 6 entry with no cut-off.

The delegate 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; and (c) the toxicity of a substance.

The delegate has decided on an implementation date of 1 June 2015 for this scheduling decision. This is to enable further consultation on the implications of not proposing an exemption cut-off for the Schedule 6 entry.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submission received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors;
  • Other relevant information.

Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate has confirmed 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.

While there were no public submissions relating to the lack of an exemption cut-off following publication of the interim decision, the proposed implementation date of 1 June 2015 allows for further consideration of this matter before the scheduling decision comes into operation.

Schedule entry

Schedule 6 - New entry

DIETHYLENE GLYCOL MONOMETHYL ETHER.

Appendix C - New entry

DIETHYLENE GLYCOL MONOMETHYL ETHER for cosmetic use.

1.11 Linear alkylbenzene sulfonates (C10-C16)

Scheduling decision

  • The delegate has decided not to include this substance in the Poisons Standard.

Scheduling proposal

The ACCS considered the following proposal referred by the delegate for advice:

  • To develop a generic entry for linear alkylbenzene sulfonates (C10-C16), with appropriate low concentration exemption cut-offs. This may also require an amendment to the current Schedule 5 and Appendices E and F entries for sodium dodecylbenzene sulfonate to reflect this generic entry. A further proposal is to include liquid laundry detergents in capsule preparations containing linear alkylbenzene sulfonates (C10-C16) in Schedule 6.

The committee considered and discussed the resolutions with an implementation date of 1 February/1 June/1 October 2015.

On 23 April 2014, NICNAS, under its IMAP programme, requested that the delegate consider a proposal to amend the current Schedule 5 sodium dodecylbenzene sulfonate (SDS) entry to include all other substances in the linear alkylbenzene sulfonate (LAS) group. NICNAS also requested that the delegate consider including liquid laundry detergent capsule preparations containing LAS in Schedule 6 with appropriate low concentration cut-off to exempt from scheduling.

The reasons for this request are:

  • the critical health effects for risk characterisation include systemic acute effects (acute toxicity by the oral route of exposure) and local effects (eye damage and skin irritation);
  • the substances in this group may also compromise the integrity of the skin and increase dermal absorption of other chemicals present in LAS containing product formulations;
  • acute oral toxicity via damage to the mucous membranes has been reported in children exposed to high concentrations of chemicals in liquid laundry detergent capsules containing MEA dodecylbenzene sulfonate;
  • where high concentrations may be used in domestic and cosmetic products, the potential risk of accidental contact with the eye is a concern. Incidental oral exposure resulting in oral toxicity is considered less likely given the types of products in which the chemicals are used, with the exception of liquid laundry detergent capsules;
  • accidental exposure of the chemicals to children, by ingestion and eye and skin contact, has occurred from liquid laundry detergent capsules, which rapidly dissolve in contact with moisture. In some cases referral to a hospital was required (Australian Competition and Consumer Commission (ACCC)). The likelihood of exposure in these cases is much greater than that expected from bulk packaged laundry detergents. The packaging format and fixed volume also enables rapid exposure to a concentrated dose of the chemicals. The ACCC has stated that the liquid laundry detergent capsules in their current form are highly attractive to children given the transparent packaging and bright colours. As there is some concern for children's safety, the ACCC and the relevant industry participants are working together to improve the safety and packaging of these products, should these chemicals be used in liquid laundry detergent capsules in their current form (Accord); and
  • additionally, the chemicals in this group are frequently formulated with related chemicals with similar toxicity including alcohol ethoxylates, laureth sulfates and lauryl sulfates. The risk of cumulative toxicological effect is also a concern. This should be taken into account when considering the appropriate regulatory framework for these chemicals.

The delegate's reason for referring this scheduling proposal to the ACCS was that 18 surfactant compounds have been referred for consideration under the generic title LAS. The scheduling history of this group of compounds is complex. They were last considered by the National Drugs and Poisons Schedule Committee (NDPSC) in 1998. At that time, the NDPSC made a decision to include sodium dodecylbenzene sulfonate in Schedule 5, with a 30% cut-off to exempt from scheduling. It is clear that the NDPSC considered a generic listing for LAS, but refrained from doing so because of incomplete knowledge of the toxicological profiles of the full range of such surfactants and concerns about the regulatory impact on existing uses associated with either a Schedule 5 or Schedule 6 listing. There is an indication that a possible 20% exemption cut-off was considered to lessen the potential regulatory impact.

The delegate asked the ACCS the following questions:

  • In the light of toxicological issues raised in the NICNAS IMAP report (acute toxicity, severe skin/eye irritancy), does the ACCS support the development of a generic entry for LAS in either Schedule 5 or Schedule 6? Should such a generic entry specify the chain length (C10 - 16)?
  • Would a generic entry capture all of the salts identified in the NICNAS IMAP report, including those salts with ethanolamine? Is there any potential overlap with the current Schedule 5 entry for ethanolamine (that excludes its salts and derivatives)?
  • Is there sufficient evidence to support a cut-off to exempt from scheduling at either 30% (the current cut-off for sodium dodecylbenzene sulfonate) or 20% (the cut-off considered by the NDPSC in 1998), or an even lower figure? Note that the above possible cut-offs are well above the likely threshold for eye irritancy (perhaps as low as 0.01 - 1%).
  • Is there a need to create a separate listing in Schedule 6 for LAS in liquid laundry preparations, when packaged in soluble capsules, in order to address the specific child poisoning concerns raised in the NICNAS IMAP report?
  • Is there a need to amend the current Schedule 5 entry for sodium dodecylbenzene sulfonate to align with any proposed generic LAS entry?
  • Are the current First Aid, Warning Statements and Safety Directions for sodium dodecylbenzene sulfonate in Appendices E & F also suitable for a generic LAS entry?
  • The 1998 NDPSC noted that there is potentially a wide range of LAS in use in Australian detergent products, as well as potential surfactant uses in existing AgVet products. Can the ACCS offer any advice on the regulatory impact of a recommendation to develop a generic schedule entry for LAS?

Substance summary

Please refer to the NICNAS IMAP human health Tier II assessment report for linear alkylbenzene sulfonates (C10-C16). This report is publicly available on the NICNAS website: Human health tier II assessment for linear alkylbenzene sulfonates (C10-C16).

Scheduling status

Linear alkylbenzene sulfonate is not listed in the Schedules. Sodium dodecylbenzene sulfonate has been specifically listed in Schedule 5 and Appendices E and F.

SCHEDULE 5

SODIUM DODECYLBENZENE SULFONATE except in preparations containing 30 per cent or less of sodium dodecylbenzene sulfonate.

APPENDIX E
Poisons Standard statements
Sodium dodecylbenzene sulfonate

A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once).

G3 - If swallowed, do NOT induce vomiting.

E2 - If in eyes, hold eyelids apart and flush the eye continuously with running water. Continue flushing until advised to stop by a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor, or for at least 15 minutes.

S1 - If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water.

APPENDIX F
Poisons Warning statements Safety direction
Sodium dodecylbenzene sulfonate 79 Will irritate eyes. 1 Avoid contact with eyes.

Scheduling history

SDS was first considered at the May 1997 National Drugs and Poisons Schedule Meeting (NDPSC). The NDPSC considered potassium peroxomonosulfate and SDS and decided to include potassium peroxomonosulfate in Schedule 6 and indicated that, based on its toxicological profile, SDS should be included in Schedule 6. NDPSC, however, expressed concern that SDS may already be in widespread use and wished to give industries that may be affected an opportunity to comment on the scheduling. Therefore, the NDPSC decided to foreshadow the inclusion of SDS in Schedule 6.

In May 1998, the NDPSC considered the May 1997 foreshadowed decision and discussed whether it was appropriate to establish a group entry for LAS under Schedule 6, based on a lowest oral LD50 value for LAS of 404 mg/kg in rats, severe dermal irritancy of 15% aqueous solutions of SDS and LAS in rabbits, and severe ocular irritancy of SDS in rabbits. The NDPSC noted that the evaluator indicated that the Cosmetics Ingredient Review Expert Panel had concluded that SDS, triethanolamine dodecylbenzene sulfonate and sodium decylbenzene sulfonate "are safe as cosmetic ingredients in the current practices of use". The NDPSC also noted that although the International Programme on Chemical Safety review highlighted a need for further studies, there were no adverse conclusions as to consumer safety. For these reasons, it was suggested that it may be possible to limit the scope of scheduling of these substances to their use in agricultural/veterinary products. Following discussion, the NDPSC agreed to classify SDS as a Schedule 5 substance instead of a Schedule 6 substance. Overall, the NDPSC supported a Schedule 5 classification for SDS, with exemption from scheduling being permitted for products containing 20% or less of SDS provided these products were labelled to warn of potential eye irritancy. The NDPSC also decided to include SDS in Appendices E and F.

In August 1998, the NDPSC, based on the public submissions presented in the requests for reconsideration, and particularly the advice that products containing up to 30% SDS are being marketed, agreed with the proposal that the cut-off from Schedule 5 to exempt should be raised to 30%. The NDPSC agreed also that, in view of the long history of use of domestic products containing SDS with little evidence of harm, warning statements should not be required on unscheduled products.

Pre-meeting public submissions

Two submissions were received. Both submissions requested that the current schedule listing of the substance is appropriate, i.e. no change required.

Summary of ACCS advice to the delegate

The ACCS recommended that LAS compounds have been used in the domestic laundry market for a very long time and the product safety and exposure is well characterised. The committee does not consider that additional scheduling controls are required.

However, safety concerns have arisen as a consequence of the relatively new presentation of liquid laundry capsules. The committee is aware of the steps already taken by the ACCC and industry to develop an industry Guideline for Labelling and Packaging of these products and recommended a review in 12 months to determine its impact and to reconsider whether scheduling of these substances is recommended.

Delegate's interim decision

The delegate notes the scheduling history of this group of substances and that the current advice from the ACCS is consistent with previous deliberations of the NDPSC. While the delegate agrees that the toxicological profile of this group of substances is consistent with SPF criteria for listing in Schedules 5 and 6, the long history of use in domestic washing and detergent products without apparent need for scheduling controls is a pertinent factor in the delegate's interim decision NOT to create a specific entry covering all the substances in this group, nor to amend current listings in Schedules 5 and 6 for related substances. The delegate notes the potentially significant regulatory impact of broadening schedule entries for this group of substances and determines that such actions are not warranted on the basis of demonstrated or perceived risk, as opposed to the potential hazard based on their intrinsic toxicity. The delegate notes safety concerns associated with new detergent product types and the attempts to resolve these issues through consumer safety laws and application of an industry code. The delegate awaits the outcome of these initiatives before any further reconsideration of scheduling of this group of substances.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

Delegate's 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 factors;
  • Other relevant information.

Public submissions on the interim decision

One submission was received, which supported the delegate's interim decision to await the outcomes of the industry self-regulation initiative on laundry capsules containing linear alkylbenzene sulfonates. The submission noted that this is in line with Best Practice Regulation Guidelines, which promotes consideration of non-regulatory approaches to resolve issues before considering whether regulation is required.

Delegate's final decision

The delegate notes the submissions 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.

1.12 Metofluthrin

Scheduling decision

  • To create a new Schedule 5 entry:

METOFLUTHRIN in impregnated fabric mosquito repellent preparations for use in a vaporizer containing 15 mg or less of metofluthrin per disk.

  • To amend the current Schedule 6 entry:

METOFLUTHRIN except when included in Schedule 5

  • Implementation date, 1 February 2015

Scheduling proposal

The ACCS considered the following proposal referred by the delegate for advice:

  • To amend the current Schedule 6 metofluthrin entry to exclude mosquito repellent preparations containing 312 g/kg or less of metofluthrin from scheduling.

The committee considered and discussed the resolutions with an implementation date of 1 February/1 June/1 October 2015.

On 4 April 2014, the APVMA, based on an application to amend the current metofuthrin entry, requested that the delegate consider a proposal to amend the current Schedule 6 listing of metofluthrin to exempt mosquito repellent preparations containing 312 g/kg or less of metofluthrin from scheduling.

The delegate's reason for referring this scheduling proposal to the ACCS was that the SPF suggests that re-scheduling applications need consideration by the ACCS. The specific product under consideration is a battery-driven device that releases metofluthrin from an impregnated fabric pad into the atmosphere around the product user.

The delegate asked the ACCS the following questions:

  • The original OCS evaluation report and advice from the February 2011 ACCS meeting noted in particular the inhalation toxicity profile in support of the recommendation to list metofluthin in Schedule 6, with no exemption. In the absence of any new submitted data on the specific insect repellent product, the OCS's view is that the toxicity/hazard profile of the product is considered to be comparable to that of the active. Does the ACCS consider that a sufficient case has been made by the applicant to consider re-scheduling the specific insect repellent product? If so, does the ACCS support its exemption from Schedule 6, or listing in Schedule 5?
  • The ACCS may wish to take into consideration the sponsor's arguments and an expert report sought by the APVMA relating to the issue of the MOE estimates for adults and children, as they relate to the proposed label warning statements and safety directions (particularly those relating to avoidance of inhalation), but the ACCS is reminded that such label statements are no longer within the jurisdiction of the scheduling delegate.

Substance summary

Metofluthrin is a pyrethroid ester. It evaporates readily and therefore requires no external heat5. Majority of pyrethroids are derived by modifying the chrysanthemic acid moiety of pyrethrin I and esterifying the alcohols. Synthetic pyrethroids have been developed to improve the specificity and activity of pyrethrins, while maintaining the high knockdown and low terrestrial vertebrate toxicity. Pyrethrins, pyrethroids, DDT and DDT analogues belong to a group of chemicals that are neurotoxic and share a similar mode of action that is distinctive from other classes of insecticides.

Pyrethroids have been classified toxicologically into two subclasses based on the induction of either whole body tremors (T-syndrome) or a coarse whole body tremor progressing to sinuous writhing (choreoathetosis) with salivation (CS-syndrome) following near-lethal dose levels in both rats and mice, and closely follows the chemical structure of the two types of pyrethroids. Type I pyrethroids are characterized by the T-syndrome which consists of aggressive sparring, sensitivity to external stimuli, fine tremors progressing to whole body tremors and prostration. Type I pyrethroids also elevate core body temperature, which is attributed to the excessive muscular activity associated with tremors. Type II pyrethroids are characterized by the CS-syndrome which is comprised initially of pawing and burrowing behaviour followed by profuse salivation, choreoathetosis and increased startle.

Increasing the dose levels of pyrethrins and pyrethroids results in a proportional increase in motor activity, which is the classic dose-response effect with respect to neurotoxic substances. Pyrethrins and pyrethroids act very quickly to produce symptoms of lost coordination and paralysis, which are known as 'the knockdown effect', and which are often accompanied by spasms and tremors that induce intense repetitive activation in sense organs and in myelinated nerve fibers. The spasms can be violent and can cause the loss of extremities, such as legs and wings in insects6.

Structure of metofluthrin

Figure 2. Structure of metofluthrin

Acute toxicity

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

Toxicity Species Metofluthrin SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rats >2000 Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rats >2000 Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rats >1080 and ≤1960 mg/m3 (one death at 1080 mg/m3, all animals died at 1960 mg/m3) Moderate to high toxicity
Skin irritation Rabbits slight
Eye irritation Rabbits Not an eye irritant
Skin sensitisation (guinea pig maximisation test) Guinea pig Negative

Repeat-dose toxicity

In a four-week repeat-dose inhalation toxicity study, 10 rats/sex/dose were exposed (nose-only) to the mist aerosol of metofluthrin at doses of 0, 9.84, 50.6, 98.7 or 196 mg/m3 for 4 hours/day for 28 days (OCS indicated that the duration of exposure recommended by OECD 412 is for 6 hours/day). Seven males and three females died at 196 mg/m3. Gross necropsy was performed on all animals that died, the cause of death, however, could not be absolutely determined. Clinical signs seen immediately following exposure at 196 mg/m3 were tremor, hypersensitivity, ataxic gait, tiptoe gait, clonic convulsion, hypothermia and lateral position which were observed in males until day 26 and in females until day 24 of exposure. There was an increased incidence of tail tremor and tremor at 196 mg/m3 (days 1-4) in both sexes. There was a significant but transient reduction in food and water consumption in males at 196 mg/m3 on day 3 of exposure. These changes may be related to neurologic signs as they were only noted at the beginning of exposure. There were no treatment-related changes in bodyweight, urinalysis, ophthalmology, haematology or blood biochemistry. The no observed effect level (NOEL) was 98.7 mg/m3 based on increased mortality, clinical signs and atrophy of the pancreas and submandibular gland in males and females at 196 mg/m3.

In a one-month oral toxicity study 12 rats/sex/dose were administered with metofluthrin in the diet at concentrations of 0, 300, 1000 or 3000 ppm. An additional 6 rats/sex/group were administered metofluthrin in the diet at concentrations of 0 or 3000 ppm for one month, followed by a two-week recovery period. One female was found dead on day 4 of treatment at 3000 ppm. Prior to death, tremor was observed in this animal and gross pathology showed dark changes and enlargement of the liver. Tremor was observed during days 2-5 in males and females at 3000 ppm, but disappeared by day 11 in males and day 7 in females. These changes may be related to the appearance of neurologic symptoms in the early phase of treatment. There was a significant increase in the absolute liver weight in males and females at 3000 ppm, and relative liver weight at 1000 and 3000 ppm. Liver effects observed during gross pathology and histopathology included dark changes in the liver of females at 1000 ppm and in both sexes at 3000 ppm, hepatocellular hypertrophy in both sexes at 1000 and 3000 ppm, a decrease of slight or mild diffuse hepatocyte vacuolation in both sexes at 3000 ppm, and an increased amount of smooth endoplasmic reticulum in two males at 3000 ppm. These changes were not observed at the end of the recovery period. The NOEL was 300 ppm (equivalent to 28.6 mg/kg bw/d) in males, based on reduced bodyweight, bodyweight gain, increased cholesterol and phospholipid levels, and histopathological changes to the liver in males at 1000 ppm.

Mutagenicity

Metofluthrin was not mutagenic in a bacterial reverse mutation assay with and without metabolic activation.

Genotoxicity

It was not genotoxic in an in vitro chromosomal aberration assay in Chinese hamster lung cells with and without S9. Additionally, no evidence of a genotoxic potential was seen in an in vivo micronucleus test in the mouse.

Neurotoxicity

In an acute neurotoxicity study, a single dose was administered via gavage to groups of 10 male and 10 female rats, at doses of 0, 20, 50 or 100 mg/kg bw. At 100 mg/kg bw, two male rats and one female rat were found dead shortly after treatment, and four female rats were sacrificed due to their moribund condition. Adverse clinical signs noted in these rats prior to death or sacrifice included clonic convulsions, tonic extensor convulsions, continuous whole body tremors, intermittent whole body twitches, tachypnoea, prostration, lost righting reflex, soft or liquid faces and hyperpnoea.

Carcinogenicity

In two studies, rats were administered metofluthrin at doses of 0, 200, 900, 1800 or 3600 ppm via the diet, daily for seven days. In each study a positive control group was administered sodium phenobarbital (NaPB) at 1000 ppm via the diet daily for seven days. Overall, rats treated with metofluthrin exhibited affected enzyme induction at 900 ppm and above. Liver morphology was observed at 1800 ppm and above, as evidenced by increased liver weight, hepatocellular hypertrophy, hepatocyte cell DNA synthesis and CYP2B expression. In addition, a decrease in hepatocytic vacuolation and hepatic gap junction intracellular communication (GJIC) was observed. All of these effects diminished upon cessation of treatment. Generally, rats treated with NaPB at 1000 ppm displayed similar effects on the liver to those treated with metofluthrin. The mode of action for tumour induction in rats may be similar to that of NaPB. NaPB induces rodent liver tumours by a non-genotoxic mechanism characterised by increased cell proliferation, hypertrophy and the development of altered hepatic foci. Furthermore, NaPB is known to cause an increase in the activity of CYP P450 enzymes CYP2B1 and CYP2B2 in vivo. Enzyme induction of CYP2B in particular, due to the activation of nuclear receptors such as the constitutive androstane receptor (CAR), has been correlated with liver tumour formation in rodents and is accompanied by an increase in CYP mRNA and protein synthesis. NaPB is a barbiturate that has been widely used in humans as a sedative, hypnotic and anti-epileptic, and for which no increased incidence of liver tumours has been observed.

The effect of metofluthrin and NaPB on the induction of CYP2B forms (50 µM for each) and replicative DNA synthesis (10-1000 μM for each) was evaluated in cultured rat and human hepatocytes. Treatment of cultured rat and human hepatocytes with metofluthrin or NaPB induced expression of CYP2B, with NaPB producing a greater response than metofluthrin. These results are similar to the above in vivo studies where metofluthrin induced microsomal CYP2B in rat liver. In contrast to the above effects of metofluthrin and NaPB, a marked species difference was observed in the effects on replicative DNA synthesis (i.e. cell proliferation). Both metofluthrin and NaPB induced replicative DNA synthesis in rat but not human hepatocytes suggesting that one of the key events in the proposed MOA for metofluthrin (and NaPB) induced rat liver tumour formation (increased cell proliferation) does not occur in human hepatocytes in vitro.

The human relevance of the rat liver carcinogenic response was then discussed in relation to the human relevance framework. Treatment with high doses of metofluthrin (900 and 1800 ppm) for two years produced an increased incidence of hepatocellular adenomas and/or carcinomas in rats. Treatment with metofluthrin induced cytochrome P450 (CYP) CYP2B isoform (increased smooth endoplasmic reticulum), resulting in increased liver weights which were associated with centrilobular hepatocyte hypertrophy and induction of increased hepatocellular DNA replication. These key events in the metofluthrin induction of liver tumours were observed at or below tumourigenic dose levels. Induction of CYP2B by metofluthrin was shown to involve activation of CAR in rat hepatocytes. This MOA is similar to that of NaPB, which is known to be non-genotoxic, a CAR activator and inducer of liver CYP2B isoforms. In rodents, NaPB exhibits a clear threshold for the induction of hepatocellular tumours, and the available data indicates that metofluthrin is less potent than NaPB in its induction of rodent liver tumours. Furthermore, extensive epidemiological data for NaPB (a widely used anticonvulsant with a long history of use) indicates that it is not a human carcinogen. Limited studies in human hepatocytes in vitro suggest that NaPB does not increase hepatocellular proliferation indicating that the key event of NaPB induced liver tumour in rats (i.e. increased cell proliferation) does not occur in the human liver. Consequently, by analogy metofluthrin is not expected to produce an increase in hepatocellular proliferation in humans and therefore, would not result in liver tumour formation. Liver effects in rats occurred only after treatment at high doses of metofluthrin and human exposure to such dose levels is not expected. Therefore, metofluthrin is not expected to pose a carcinogenic risk to humans.

Reproduction and developmental toxicity

In a two-generation reproduction study, groups of rats (12/sex/dose) were fed diets containing 0, 50, 200, 1000 or 1800 ppm of metofluthrin for 70 days before pairing, throughout pairing, gestation and lactation and until termination. One F1 control male was found moribund and sacrificed during the post-weaning period. During lactation, there was an increase in the number of P-generation females with tremor and twitches at 1800 ppm, and F1 females with tremor, twitches and excessive salivation at 1000 and 1800 ppm. There were no treatment-related clinical signs of toxicity observed in F1 pups, however, tremor was observed in F2 pups on postpartum day 24 at 1800 ppm, and this was considered to result from pups eating the test substance. Among the P-generation, there was a transient reduction in female bodyweight gain at all dose levels during pre-cohabitation. Throughout lactation, bodyweight was reduced at 1000 and 1800 ppm and bodyweight gain was reduced at 1800 ppm and there was also a reduction in absolute and relative food consumption at 1800 ppm. There were no treatment-related changes in bodyweight, bodyweight gain or food consumption during gestation. In F1-generation animals, throughout the post-weaning period, there was a reduction in bodyweight for males at 1800 ppm and females at 1000 and 1800 ppm. Bodyweight gain was also reduced during the first two weeks of the post‑weaning period at 1800 ppm in males and at all dose levels in females. In F1 females, bodyweight gain was also reduced at 1800 ppm throughout post-weaning. Bodyweight was reduced in F1 females throughout gestation and lactation at doses of 1000 and 1800 ppm and bodyweight gain was reduced in early gestation. Food consumption was reduced in F1 females at 1000 and 1800 ppm during post-weaning period, gestation and lactation.

Observation in humans

No information was provided.

Public exposure

The product is intended only for domestic use as a personal mosquito repellent and not be used directly on food or food preparation areas or food utensils. Exposure to the product will be via the inhalational and dermal routes, with the potential for incidental oral exposure in children from touching (hand to mouth transfer) or mouthing the device or refills. Exposure can occur when using the product or when replacing the refill unit in the device.

The product is intended to be used on a person or next to a person during outdoor activities throughout the year. The public may be exposed to the product while replacing the refill unit. There is a potential risk to users and bystanders associated with repeat exposure to the product.

A total margin of exposure (MOE) derived by adding dermal and inhalation MOE values) of more than 100 was obtained in adults, 2 to less than 3 years old and 1 to less than 2 years old children (229, 654 and 546, respectively). A MOE of 100 or above is considered acceptable. The MOE takes into account both interspecies extrapolation and intra-species variability.

International regulations

No information was provided. The Scheduling Secretariat obtained the following information.

In the EU, metofluthrin is included in Annex I of the Directive 98/8/EC. Biocidal products containing active substances that have been included in Annex I or IA of the Biocides Directive are subject to product authorisation or registration, respectively, as per the requirements of the Biocides Directive.

In New York state (USA) two products, OFF! Insect Repellent Fan and OFF! Insect Repellent Fan Refill, containing metofluthrin have been registered with the following condition: 'The registrant is required to provide us with a summary of any adverse effects that have been associated with these products, including any FIFRA 6(a)(2) reports, on a quarterly basis'.

In Canada, a product of OFF! Clip-on Mosquito Repellent (Pest Control Product Registration Number 30211) was registered for use as a personal insect repellent in October 2011. Within the first year of its registration, the Pest Management Regulatory Agency (PMRA) received six human incident reports associated with this product. A wide range of symptoms such as dizziness, swelling, nausea, lethargy, muscular weakness, pruritus, irregular heart rate, or loss of consciousness was noted. The effects reported were considered to be either possibly or probably related to pesticide exposure. The product currently holds a registration that is conditional upon the submission of additional data on product exposure. The PMRA indicated that 'Although only a few incidents were reported, this is a new product and the PMRA will continue to monitor incidents reported in the following year'.

Scheduling status

Metafluthrin is listed in Schedule 6.

Other synthetic pyrethroids, namely transfluthrin (in Schedule 6), permethrin (in Schedules 4, 5 and 6), deltamethrin (in Schedules 5, 6 and 7), esfenvalerate (in Schedules 5 and 6) and alpha-cypermethrin (in Schedules 5, 6 and 7) are included in various schedules of the SUSMP.

Scheduling history

In 2011, the chemicals scheduling delegate, based on the advice from the ACCS, decided to include metofluthrin in Schedule 6.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS advice to the delegate

The ACCS recommended that the current Schedule 6 metofluthrin entry be amended to exempt impregnated fabric mosquito repellent preparations for use in a vaporizer containing 15 mg or less of metofluthrin per disk to Schedule 5.

The ACCS recommended an implementation date of 1 February 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reason for the recommendation is:

The packaging and presentation of the product mitigates the exposure risk and warrants Schedule 5 inclusion.

Delegate's interim decision

The delegate accepts the advice tendered by the ACCS and agrees to include a new entry for metofluthrin in Schedule 5 and to amend the current Schedule 6 entry. While metofluthrin is a moderately toxic pyrethroid insecticide, the packaging and presentation of the product mitigates the exposure risk and warrants Schedule 5 inclusion.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (c) toxicity and (d) dosage, formulation, labelling, packaging and presentation of a substance.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors;
  • Other relevant information.

Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate has confirmed 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.

Schedule entry

Schedule 5 - New entry

METOFLUTHRIN in impregnated fabric mosquito repellent preparations for use in a vaporizer containing 15 mg or less of metofluthrin per disk.

Schedule 6 - Amendment

METOFLUTHRIN except when included in Schedule 5.


Footnotes

  1. Santanu Mukherjee, Surendra Kumar, Anjana Srivastava and Prakash Chandra Srivastava (2011). Uptake and distribution of 14C-labeled Fosthiazate in tomato (Lycopersicon esculentum L.) Agricultural Sciences, Volume 2, No.3, p 308-312.
  2. Pope C. N (1999) Organophosphorus pesticides: do they all have the same mechanism of toxicity? Journal of Toxicology and Environmental Health, Part B Critical Review, 1999 April-June; 2(2):161-181.
  3. Available at: Taiwan Bans fosthiazate 75% EC and Restricts Other 3 Formulated Pesticides
  4. Metofluthrin Pesticide Fact Sheet. United States Environmental Protection Agency. Available at: Pesticide Fact Sheet
  5. Jerome J. Schleier and Robert K. D. Peterson (2011) Pyrethrins and Pyrethroid Insecticides. Chapter 3 RSC Green Chemistry No. 11 Green Trends in Insect Control. Edited by Oscar Lopez and Jose G. Fernfmdez-Bolafios Published by the Royal Society of Chemistry. Available at: Pyrethrins and Pyrethroid Insecticides

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