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Scheduling delegate's final decisions: ACCS/ACMS, April 2014

Scheduling medicines and poisons

14 April 2014

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Part B - Final decisions on matters not referred to an expert advisory committee - 4.1-4.4

4. Chemicals

4.1 Afoxolaner

The Chemicals Scheduling Delegate (the delegate) considered a proposal to include afoxolaner in Schedule 5.

The delegate decided to make a delegate-only decision. The Advisory Committee on Chemicals (ACCS) was not consulted.

Scheduling status

Afoxolaner, an isoxazoline group of chemical, is not specifically listed in the SUSMP. Another isoxazoline chemical, namely isoxaflutole is listed in Schedule 5.

Schedule 5

Isoxaflutole
Scheduling history

Isoxaflutole was first considered in May 1997 by the National Drugs and Poisons Schedule Committee (NDPSC). The NDPSC, based on its acute toxicity profile decided to include isoxaflutole in Schedule 5.

Substance summary

Afoxolaner, a member of the isoxazoline family, binds at a binding site to inhibit insect and acarine ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA)39. Afoxolaner, a new ectoparasiticide, is systemically active against ticks and fleas. The benefits of a product containing afoxolaner are its efficacy in the treatment of flea and tick infestations on dogs. The product is in general well tolerated at the recommended dose, adverse reactions (gastrointestinal effects) were only observed in overdoses40.

Toxicity of the technical grade active constituent

The summary of acute toxicity studies is shown in the table below.

End-point of toxicity Species Afoxolaner SPF* classification
Acute oral toxicity LD50 (mg/kg bw) Rats >1,000 (no deaths) Moderate to high toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rats >2000 (no deaths) Low toxicity
Inhalational - No study submitted Not applicable
Skin irritation Rabbits Non-irritant
Eye irritation Rabbits Non-irritant
Skin sensitisation Mice (local lymph node assay) Non-sensitiser

*SPF - Scheduling Policy Framework for Medicines and Chemicals (2010)

Repeat-dose toxicity potential

In repeat-dose toxicity studies, the most sensitive species was the rat, with reduced body weight gain and food consumption at 50 mg/kg bw/d in a 90-day study, with effects noted as early as week 2 of treatment. The NOEL for this study was 10 mg/kg bw/d.

Across repeat-dose toxicity studies, treatment-related reductions in body weight gain and/or body weight loss, as well as reduced food consumption were commonly found effects in all species tested. In most studies, a cascade of adaptive metabolic effects were noted and considered secondary to treatment-related decreased food consumption and decreased body weight gain.

Carcinogenic potential

No carcinogenicity studies were submitted in support of afoxolaner. In this case, noting the use pattern of substance in the product as a once-monthly treatment in a non-food-producing use situation, carcinogenicity studies were not required for the purposes of this risk assessment. The OCS notes that there was no evidence that afoxolaner would be an in vivo genotoxicant.

Genotoxicity potential

There was no evidence of a mutagenic and/or genotoxic potential in vitro with and without metabolic activation or in vivo.

Developmental and reproductive toxicity potential

Studies in rats and rabbits did not show any evidence of afoxolaner being a reproductive or developmental toxicant.

Neurological toxicity potential

No specific neurotoxicity studies were submitted, though in the single- and repeat-dose toxicity studies conducted, no evidence of neurotoxicity was observed.

Toxicity of the product

No acute studies were submitted on the formulated product. The potential acute toxicity was extrapolated from data on the excipients.

The summary of acute toxicity studies on the product is shown in the table below.

End-point of toxicity Toxicity of the product
Acute oral toxicity LD50 Low toxicity*
Acute dermal toxicity LD50 Low toxicity*
Inhalational No studies submitted**
Skin irritation Non-irritant
Eye irritation Non-irritant*
Skin sensitisation Not sensitising

* based on the toxicological profile of all ingredients in the product.

** expected to be low exposure by this route, due to nature of formulation.

Delegate's consideration

The delegate considered the following in regards to this application for re-scheduling.

  • evaluation report (not publically available);
  • section 52E of the Therapeutic Goods Act 1989;
  • scheduling factors41; and
  • other relevant information.
Delegate's interim decision

Afoxolaner had low acute toxicity profile to be consistent with the Scheduling Policy Framework for Medicines and Chemicals factors for listing in Schedule 5. More significant toxicity would be expected with repeated dosage, due to accumulation of active drug.

The acute poisoning risk to humans (in particular children) is low, partly associated with the proposed packaging of only six tablets in blister packaging.

The delegate also considered whether a Schedule 4 listing for afoxolaner could be more appropriate, providing for oversight of treatment by a veterinarian. The delegate indicated that because the treatment instructions are sufficiently clear that pet owners should be able to manage the required dosage regimen without a veterinarian's oversight.

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.

An early implementation date is proposed to facilitate marketing of the product when registered by the APVMA. The delegate therefore proposes an implementation date of 1 June 2014.

Scheduling entry
Schedule 5 - New entry

AFOXOLANER for the treatment and prevention of flea infestations and control of ticks in dogs in oral divided preparations each containing 140 mg or less of afoxolaner per dosage unit.

4.2 Fluensulfone

Scheduling proposal

The Office of Chemical Safety (OCS) evaluated the data provided in support of an application for the approval of a new active constituent fluensulfone. The OCS recommended that fluensulfone be included in Schedule 6 in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP).

The delegate decided to make a delegate-only decision. The Advisory Committee on Chemicals (ACCS) was not consulted.

Scheduling status

Fluensulfone is not specifically scheduled.

Scheduling history

As fluensulfone is not specifically scheduled, the scheduling history is not available.

Substance summary

Fluensulfone is a novel nematicide developed for agricultural use (soil incorporation) for the control of root knot nematodes in cucurbits and fruiting vegetables. Fluensulfone belongs to a new chemical class, namely fluoroalkenyle (-thioether).

Toxicity

Acute toxicity of the technical grade active constituent

The summary of acute toxicity studies is shown in the table below.

End-point Toxicity Species Fluensulfone SPF* Classification
Oral LD50 (mg/kg bw) Rats 671 Moderate to high
Dermal LD50 (mg/kg bw) Rats >2,000 Low toxicity
Inhalational LC50 (mg/m3/4h) Rats >5,100 Low toxicity
Skin irritation Rabbits Slight
Eye irritation Rabbits Non-irritant
Skin sensitisation Guinea pigs Sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Acute toxicity of the product

The summary of the acute toxicity studies on the product containing fluensulfone are listed in the below table.

Toxicity Species fluensulfone SPF* Classification
Oral LD50 (mg/kg bw) Rats >300 - < 2000 mg/kg bw Moderate to high
Dermal LD50 (mg/kg bw) Rats >2,000 Low toxicity
Inhalational LC50 (mg/L) Rats > 6.0 (equates to 6,000 mg/m3) Low toxicity
Skin irritation Rabbits Moderate
Eye irritation Rabbits Moderate eye irritant
Skin sensitisation Guinea pigs Sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Short-term toxicity

Oral toxicity

In a 4-week dietary study, mice (5/sex/dose) were fed with 0, 100, 500 and 2000 ppm (equivalent to 0/0, 30/41, 101/155, and 375/353 mg/kg bw/day in males/females, respectively). Food intake was decreased at 500 ppm (28-33%) and 2000 ppm (34-63%) in both sexes. Water consumption was slightly increased at 2000 ppm in females. Body weight loss was observed at 2,000 ppm in the first week of treatment in both sexes. At the end of treatment the mean body weight difference from the controls was -13% in males at 2000 ppm.

Dermal toxicity

In a dermal toxicity study, 10/sex/dose rats were exposed (for 6 hours each day for 5 consecutive days per week) to 0, 80, 400 or 2000 mg/kg bw/day.

No mortality occurred, and no clinical signs of toxicity were observed. Transient reductions in food consumption were noted in males at 400 mg/kg bw/day and in both sexes at 2000 mg/kg bw/day. A slight reduction in body weight gain, driven by a decrease in body weight gain during week 1 of the study, was noted in males at the 2,000 mg/kg bw/day dose level. In females dosed with 2000 mg/kg bw/day fluensulfone, slight alterations in haematological (increased red cell volume distribution width, decreased mean corpuscular haemoglobin concentration, and increased reticulocytes) and clinical chemistry (increased cholesterol, reduced serum ALAT) parameters were observed.

Sub-chronic toxicity

Oral toxicity

In a 90-day dietary toxicity study, 12/sex/dose mice received diets containing 0, 60, 300 and 1500 ppm (equivalent to 0/0, 11/18, 51/68 and 228/252 mg/kg bw/day in males/females, respectively) of fluensulfone for a period of 13 weeks.

There were several mortalities during the study: 2, 2, 4 and 4 males and 3, 0, 0 and 5 females for the control and treated groups in order of ascending doses. Apart from the death of a single female of the highest dose group, which was also the only animal in which clinical signs (piloerection, squatting position, poor general condition, and emaciation) were recorded, all mortalities were related to blood sampling.

Inhalational toxicity

In a 90-day inhalation toxicity study, groups of 10 male and 10 female rats were exposed nose-only to fluensulfone for 6 hours/day, 5 days/week for 13 consecutive weeks (resulting in 65 and 66 exposure days for males and females, respectively) to target concentrations of 0, 0.04, 0.2 or 1.0 mg/L.

Potentially adverse changes which were present at the lowest concentration consisted of weight loss on exposure days in males, prolonged prothrombin time in females, decreased thymus weight in males (without histopathological effects) and histopathological changes in the epiglottis (squamous metaplasia, epithelial hyperplasia, focal mononuclear cell infiltrate) in both sexes and in the nasal cavity (squamous epithelial hyperplasia) in males.

Long-term toxicity

In a 1-year oral toxicity study, fluensulfone was administered in the diet to groups of 4/sex/dose dogs at 0, 5, 50 100 and 500 ppm (0.0, 0.1/0.1, 1.5/1.5, 3.1/3.3. 16.0/16.2 mg/kg bw/day in male/females) for a period of 52 weeks.

Oral administration of fluensulfone dogs in the diet at a dose of 500 ppm resulted in transient changes in consistency of faeces, reductions in food intake in females and lower body weight gains, mean body weights and terminal body weights, effects on haematology and biochemistry parameters and on the liver.

Carcinogenicity

In an oral oncogenicity study, 4 groups of 50 male and 50 female mice (allocation a) were treated for 78 weeks with 0, 30, 200 or 1200 ppm of fluensulfone in their feed. Additionally, 6 males and 6 females were exposed to the same dietary concentrations and used for liver enzyme determination after 13 weeks of treatment. The average daily intakes of test material were 0, 4.2, 27.6 or 152.3 mg/kg bw/day for males and 0, 6.4, 39.0 or 188.4 mg/kg bw/day for females.

Absolute and relative (to brain weight) prostate weights were observed in males in the 200 and 1,200 ppm dose groups. Changes in other organ weights at 1,200 ppm (increased relative kidney, adrenal gland, epididymal, testes, heart, and brain weight in males; decreased absolute kidney weight in females, and increased relative liver weight in females) were likely secondary to the effect of fluensulfone exposure on body weight.

Neurotoxicity

In a subchronic dietary neurotoxicity study, groups of 12 male and 12 female rats received fluensulfone in their diet at concentrations of 0, 100, 500 and 2500 ppm (equivalent to 0/0, 6/7, 31/34, and 153/162 mg/kg bw/day in males/females) for at least 90 days.

All animals scheduled for neurohistological examination survived the scheduled study period. Treatment-related effects included lower food consumption and body weight gain in males and females at 2500 ppm, as well as reduced body weight in males.

Reproductive/Developmental toxicity potential

There were no treatment related effects on reproductive performance ina dietary 2-generation rat study up to and including dose levels producing parental toxicity.

Fluensulfone was not a developmental toxicant in oral gavage studies in the rat and rabbit.

Genotoxicity

Fluensulfone is non-mutagenic/genotoxic in in vitro studies with and without metabolic activation and non-genotoxic in in vivo studies.

Immunotoxicity

Fluensulfone was not an immunotoxicant in mice in an immunotoxicity study that evaluated anti-sheep red blood cell response.

Delegate's consideration

The delegate considered the following in regards to this application for re-scheduling.

  • Evaluation report (not publically available);
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors42; and
  • Other relevant information.
Delegate's final decision

The toxicological profile of fluensulfone is consistent with the SPF criteria for listing in Schedule 6, with the estimated lethal dose in the range 50-2000 mg/kg and some potential for skin/eye irritation and sensitisation. The systemic toxicity on repeated exposure to fluensulfone provides additional support for Schedule 6 listing. The evaluation report discusses, in some detail, the human significance of the lung alveolar/bronchiolar carcinogenic responses seen in female mice. While the proposed mode of action (MoA) and human relevance of these tumours is not established beyond reasonable doubt, there is no evidence of genotoxic potential and the MoA evidence is sufficiently strong that the observed carcinogenesis could be a response specific to female mice and have no human relevance. Therefore, listing in a more restrictive schedule (Schedule 7) is not warranted.

While the evaluation report did not supported the registration of a product for home garden use, this is not an issue that would negate listing in Schedule 6. However, the decision to NOT include a scheduling cut-off for the proposed product supports the OCS recommendation.

An early implementation date is proposed to facilitate marketing of the product when registered by the APVMA. The delegate therefore proposes an implementation date of 1 June 2014.

Schedule entry
Schedule 6 - New entry

fluensulfone.

4.3 Iron salt and calcium salt of chromates (including dichromates)

Scheduling proposal

On 17 September 2013, NICNAS under the Inventory Multi-tiered Assessment Prioritisation (IMAP) Tire II human health assessment process, recommended that the delegate consider a proposal to amend the current Schedule 6 chromates entry to add the iron and calcium salts to the list of chromate salts exempt from scheduling when included in paints and tinters at 5 per cent or les and to also amend the current Appendix I (Uniform Paint Standard) chromates entry to include additional chromate salts namely iron and calcium.

The delegate decided to make a delegate-only decision. The Advisory Committee on Chemicals (ACCS) was not consulted.

Scheduling status

Chromates are listed in Schedule 6, Appendices E, F and I (listed as chromium).

Schedule 6

CHROMATES (including dichromates) except in paints or tinters containing 5 per cent or less of chromium as the ammonium, barium, potassium, sodium, strontium or zinc chromate calculated on the non-volatile content of the paint or tinter.

Appendix E
Poisons Standard statements
Chromates

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 eyes 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 I
The First Schedule
The proportion of a substance for the purpose of this section Schedule is calculated as a percentage of the element present in the non-volatile content of the paint.
Substance Proportion
CHROMIUM as chromates of ammonia, barium, potassium, sodium, strontium or zinc more than 5 per cent
Scheduling history

In April 1963 the Poisons Advisory Panel decided to list chromates in Schedule 6. No reasons were given for this decision.

In August 2000, the National Drugs and Poisons Schedule Committee decided to amend the chromate entry to read: chromates (including dichromates) except in paints or tinters containing 5 per cent or less of chromium as ammonium, barium, potassium, sodium, strontium or zinc chromate calculated on the non-volatile content of the paint or tinter.

Substance details

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report available on from the NICNAS website.

Delegate's consideration

The delegate considered the following in regards to this application for re-scheduling.

  • Evaluation report (not publically available);
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors; and
  • Other relevant information.
Delegate's final decision

The delegate has decided to amend the current Schedule 6 and Appendix I (Uniform Paint Standard) entries for chromates to include additional chromate salts (iron and calcium) that might be present in paints sold in Australia. The toxicological profile of these salts is expected to be related to the valence state (VI) of the chromate component and comparable to those salts already listed in the Schedule 6 paint/tinter exemptions and Appendix I (Schedule 1) restrictions. The delegate has decided on an implementation date of 1 June 2014.

Scheduling entry
Schedule 6 - Amendment

CHROMATES (including dichromates) except in paints or tinters containing 5 per cent or less of chromium as the ammonium, barium, calcium, iron, potassium, sodium, strontium or zinc chromate calculated on the non-volatile content of the paint or tinter.

Appendix I - Amendment
Substance Proportion
CHROMIUM as chromates of ammonia, barium, calcium, iron, potassium, sodium, strontium or zinc more than 5 per cent

4.4 Sodium 5-nitroguaiacolate

Scheduling proposal

The Chemicals Scheduling Delegate (the delegate) considered a proposal to include sodium 5-nitroguaiacolate (Na-5NG), sodium o-nitrophenolate (Na-oNP) and sodium p-nitrophenolate (Na-pNP) in Schedule 6. As sodium ortho-nitrophenolate and sodium para-nitrophenolate are sodium salts of o-nitrophenol and p-nitrophenol respectively, the current Schedule 6 ortho- and para-nitrophenols entries may capture these substances.

The delegate decided to make a delegate-only decision. The Advisory Committee on Chemicals (ACCS) was not consulted.

Scheduling status

Sodium 5-nitroguaiacolate is not specifically scheduled.

Other nitrophenolates, such as sodium ortho-nitrophenolate and sodium para-nitrophenolate, are listed in Schedule 6.

Schedule 6

NITROPHENOLS, ortho-, meta-, and para-, except when separately specified in these schedules.

Scheduling history

Ortho-, meta- and para-nitrophenols were first considered by the Committee on Poisons Schedules (CPS) in May 1956. The CPS decided to include these substances in Schedule 1 (substances which are extremely dangerous to human life) and Schedule 2 (substances which are dangerous to human life if misused or carelessly handled). No rationale was given for this decision.

In November 1990, the National Drugs and Poisons Schedule Committee (NDPSC) considered translocating Schedule 1 entries appropriately in different schedules. In February 1991, the NDPSC decided to move some substances, including ortho-, meta- and para-nitrophenols, from Schedule 1 to other appropriate schedules. The translocation of Schedule 1 substances to other Schedules was completed in November 1994. Since February 1995 no substance is listed under Schedule 1.

Information on when and why nitrophenols entry was transferred from Schedules 1 and 2 to Schedule 6 was not available.

Substance details

Sodium 5-nitroguaiacolate, a nitrophenolate, is a plant growth regulator43. The substance is naturally found in plants and stimulate plant growth by altering the activity of specific antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and peroxidase (POX)44.

Acute toxicity

The summary of acute toxicity studies is shown in the table below.

End-point of toxicity Species Sodium 5-nitroguaiacolate SPF* classification
Acute oral toxicity LD50 (mg/kg bw) Rats

723 (Males)

706 (Females)

Moderate to high
Acute dermal toxicity LD50 (mg/kg bw) Rabbits >2000 Moderate to high

Acute inhalational toxicity

LC50 (mg/m3)

Rats > 2380 (no deaths) Moderate to high
Skin irritation Rabbits Non-irritant
Eye irritation Rabbits Severe irritant
Skin sensitisation Guinea pigs Non-sensitiser

*SPF - Scheduling Policy Framework for Medicines and Chemicals (2010)

Repeat-dose toxicity

Sodium 5-nitroguaiacolate was of low toxicity in a 90-day oral toxicity study in dogs, with a NOEL established at the highest dose tested of 60 mg/kg bw/day.

Carcinogenicity

No evidence of carcinogenicity was observed in long-term studies.

Neurotoxicity

No evidence of neurotoxicity in acute and repeat-dose toxicity studies.

Reproductive/Developmental toxicity

Sodium 5-nitroguaiacolate was not a reproductive toxicant in rats, or a developmental toxicant in rats and rabbits.

Genotoxicity

Sodium 5-nitroguaiaicolate was found to be positive in Saccharomyces cerevisiae cells for both aneuploidy and recombination. Sodium 5-nitroguaiacolate is likely to induce mitotic aneuploidy and mitotic recombination in S.cerevisiae cells, suggesting that sodium 5-nitroguaiaicolate may have genotoxic potential in mammalian cells. The long-term in vivo studies in rodents did not indicate a carcinogenic effect. The OCS report therefore notes that, overall the weight of evidence indicates that sodium 5-nitroguaiacolate is unlikely to be genotoxic.

Delegate's consideration

The delegate considered the following in regards to this application for re-scheduling.

  • evaluation report (not publically available);
  • section 52E of the Therapeutic Goods Act 1989;
  • scheduling factors; and
  • other relevant information.
Delegate's final decision

The toxicological profile of sodium 5-nitroguiaicolate is consistent with Scheduling Policy Framework for Medicines and Chemical's factors for Schedule 6 listing. Accordingly, the delegate decided to include 2-methoxy-5-nitrophenol (the IUPAC name for this chemical), with no cut-off, in Schedule 6. The delegate also decided to create a cross-reference in the Index for sodium 5-nitroguiaicolate to 2-methoxy-5-nitrophenol. The implementation date for this decision is 1 October 2014.

Schedule entry
Schedule 6 - New entry

2-METHOXY-5-NITROPHENOL.

Index - New entry

SODIUM 5-NITROGUAIACOLATE.

  • See 2-METHOXY-5-NITROPHENOL

Footnotes

  1. 4-Azolylphenyl isoxazoline insecticides acting at the GABA gated chloride channel. Lahm et al March 2013. Bioorganic and Medicinal Chemistry Letters 2013 May 15;23(10):3001-6.
  2. Committee for Medicinal Products for Veterinary Use Summary of opinion (initial authorisation) NexGard International non-proprietary name (INN): Afoxolaner. European Medicines Agency.
  3. Scheduling Policy Framework for Medicines and Chemicals (2010)
  4. Scheduling Policy Framework for Medicines and Chemicals (2010)
  5. Sodium 5- Nitroguaiacolate, Sodium o-Nitrophenolate and Sodium p-Nitrophenolate Fact Sheet (pdf,108kb).
  6. Field Evaluation of Nitrophenolate Plant Growth Regulator (Chaperone) for the Effect on Cotton Lint Yield. Bynum et al (2007) Available at: <http://www.cotton.org/journal/2007-11/1/upload/jcs11-20.pdf>

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