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Scheduling delegate's final decisions: ACCS, October 2014

Scheduling medicines and poisons

28 October 2014

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

3. Agriculture and veterinary chemicals

3.1 Fluralaner

Scheduling proposal

In August 2014, the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to register a new active ingredient and the approval of five different tablets that containing various concentrations of fluralaner, referred the following proposal to be considered by the delegate:

  • A proposal to create a new Schedule 5 listing for oral divided preparations, each containing 1400 mg or less of fluralaner per dosage unit, for the treatment and prevention of flea infestations and control of ticks in dogs.

The reasons for the request are that fluralaner:

  • has low oral toxicity in rats (LD50 >2000 mg/kg bw);
  • has low dermal toxicity in rats (LD50 >2000 mg/kg bw);
  • has no skin irritation or eye irritation in rabbits; and
  • is not a skin sensitiser in guinea pigs.

The OCS evaluation report indicated that no acute inhalational toxicity study was submitted for fluralaner. While the acute inhalational toxicity is unknown due to the general lack of specific toxicological data on the active constituent and formulation excipients, the lack of an acute inhalational toxicity endpoint is not considered a significant data deficiency, and does not affect the risk assessment of the product, noting that the formulated product is in a chewable form and is not expected to generate fine material of inhalational concern in this case.

Scheduling status

Fluralaner is not specifically scheduled.

Fluralaner belongs to a chemical group called isoxazolines. Isoxazoline substances, such as isoxaflutole and afoxolaner, are a partially saturated analogue of isoxazoles. Isoxaflutole is currently in Schedule 5. Afoxolaner, a chemical with a comparable use pattern and toxicology profile to that of fluralaner, in oral divided preparations each containing 140 mg or less of afoxolaner per dosage unit for the treatment and prevention of flea infestations and control of ticks in dogs, is also listed in Schedule 5.

Scheduling history

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

The scheduling history of a similar substance, afoxolaner, is provided below.

In April 2014, the delegate made a delegate only decision to list afoxolaner in Schedule 5. This decision was based on its low acute toxicity profile. The delegate noted that 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, in part due to the proposed packaging of only six tablets in a blister pack.

Substance summary

Fluralaner is a new molecular entity of the isoxazoline class that has shown potent acaricidal and insecticidal activity through a dual mechanism of binding to neuronal γ-aminobutyric acid (GABA)- and glutamate-gated chloride channels in susceptible invertebrates. Fluralaner has high selectivity for arthropods and a very favourable safety profile in vertebrates including dogs6. It is a potent inhibitor of parts of the arthropod nervous system by acting antagonistically on ligand-gated chloride channels (GABA receptor and glutamate-receptor). In molecular on-target studies on insect GABA receptors of flea and fly, fluralaner is not affected by dieldrin resistance7.

Figure 1. Structure of fluralaner

Figure 1. Structure of fluralaner

Acute toxicity

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

Toxicity Species Fluralaner SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat > 2000 (no deaths) Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat > 2000 (no deaths) Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Not provided Not provided Unable to be assessed.
Skin irritation Rabbits Non-irritant
Eye irritation Rabbits Non-irritant
Skin sensitisation (maximisation test) Guinea pig Non-sensitiser

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

The OCS evaluation report indicated that no studies on the formulated product have been provided. Estimation of its acute toxicity suggests that the product is expected to have low acute oral and dermal toxicity. While acute inhalational toxicity is unknown, the formulation presentation of the product as a tablet is unlikely to result in acute inhalational toxicity risks. It is not expected to be a skin sensitiser, although it is expected to be a slight skin and eye irritant based on the formulation composition.

The acute toxicity end-points of all the constituents in the product are listed in the below table.

Toxicity Species Preparations containing fluralaner SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat Not provided* Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat Not provided* Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Not provided Unknown (but likely to be low toxicity)** Unable to be assessed.
Skin irritation Rabbits Slight-irritant*
Eye irritation Rabbits Slight-irritant*
Skin sensitisation (maximisation test) Guinea pig Not expected to be sensitising*

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

** based on the formulation type as a chewable tablet.

Repeat-dose toxicity

In a number of short-term studies by both the oral and dermal route of exposure in rats, the main signs associated with treatment included minor variations in haematological and blood chemistry parameters, and organ weight changes. Of the organ weight changes, the liver was the most affected with increases in liver weights associated with fatty changes (diffuse and mid-zonal). The route of exposure did not markedly change the effects seen in treated animals, with similar haematological, blood chemistry and organ weight changes in both orally and dermally treated rats. Additional treatment-related findings in the oral toxicity study included thymic atrophy, zymogen depletion in the pancreas and diffuse vacuolation/hypertrophy in the adrenal cortices at high doses.

Mutagenicity

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

Genotoxicity

Fluralaner was not genotoxic in a standard suite of in vitro and in vivo genotoxicity studies.

Carcinogenicity

No carcinogenicity studies were submitted in support of fluralaner. The use pattern of the tablets as a quarterly treatment in a non-food-producing use situation, and noting the relatively minor effects seen in short-term studies and the lack of any positive genotoxicity potential, the long-term toxicity potential associated with the proposed use of the active constituent as a veterinary medicine for companion animals (dogs) is likely to be low.

Reproductive and developmental toxicity

In a target animal (dog), no effects were seen in reproductive parameters (including litter viability and fecundity) at up to three times the proposed therapeutic dose. In developmental toxicity studies in the rat, minor effects were seen in treated foetuses, such as a slight decrease in foetal bodyweights, increases in dilated renal pelvis and ureter, and supernumerary ribs. The effects, however, were at dose levels where maternal effects (decreased food consumption and bodyweight gain) were observed, suggesting foetal effects were secondary to maternal toxicity. The OCS notes that developmental toxicity studies in a second species were not conducted, although on available evidence, fluralaner is not considered to be teratogenic or a developmental toxicant.

Observation in humans

No information provided.

Public exposure

It is expected that administration of tablets will primarily be conducted by members of the public, as pet owners, and veterinarians. Pet owners or members of the household may be exposed to the product when administering the tablet into the mouth of dogs(s) or via excreta (vomitus, urine/faeces).

Overall exposure to fluralaner during dosing is likely to be low. Administration of a chewable tablet formulation to non-food-producing companion animals is a low exposure pattern, with only dermal exposure likely to occur. The presentation as a chewable tablet with the majority of the tablet being excipients, with low levels of active constituent, is expected to result in low fluralaner exposure to the person administering the tablet.

While exposure during dosing is likely to be negligible, there is an increased likelihood of exposure to small amounts of fluralaner following dosing of domestic dogs, via contact with wet or partly macerated tablets, or when cleaning vomitus or urine/faeces (noting that dermal toxicity studies have identified that systemic exposure does occur with dermal contact with fluralaner). Emesis is not uncommon in dogs, while exposure to small amounts of fluralaner in faeces may occur during disposal.

Exposure routes will be primarily dermal with a limited possibility of subsequent hand-to-mouth or hand-to-eye exposure. Such exposure is likely to be minimal, as contamination of hands via emesis or excreta is likely to be obvious to an adult. As it is expected that dog owners will take normal hygiene measures such as washing hands after touching vomitus or coming into contact with faeces, it is likely that fluralaner will only be in contact with the skin for a short period of time, which will limit the amount absorbed through the skin and possible oral and ocular exposure. Potential oral and ocular exposure is considered to be minimal.

There is the possibility of an accidental exposure, where a child gains access to the product after removal from packaging and before administration to the dog. It is expected that such exposure would be a single event, and may occur typically by the oral route, although dermal handling is also possible.

In a conservative worst-case scenario, where a 10 kg child gained access to a full package of very large tablets (4×1400 mg) and the product was consumed as an acute event, this would be equivalent to a total exposure of 560 mg/kg bw.

International regulations

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

In May 2014, the US Food and Drug Administration (US FDA) approved fluralaner with a condition that the products containing the substance may be dispensed only by or on the lawful order of a licensed veterinarian (Rx marketing status). Adequate directions for lay use cannot be written because professional expertise is required to advise dog owners regarding use in breeding dogs, to monitor for and respond to adverse reactions, and to define the appropriate treatment interval (8 vs. 12 weeks) based on the species of ticks the dog is likely to encounter.

In December 2013, the Committee for Medicinal Products for Veterinary Use (CVMP) of the European Medicines Agency recommended the granting of a marketing authorisation for the veterinary medicinal product Bravecto chewable tablets for dogs (112.5 mg, 250 mg, 500 mg, 1000 mg, 1400 mg) containing fluralaner.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • OCS evaluation report (not publicly available);
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors8;
  • Other relevant information.
Delegate's final decision

Fluralaner belongs to a novel class of ectoparasiticides (isoxazoline-substituted benzamide derivatives), two other members of which have been listed in Schedule 5 (isoxaflutole and afoxolaner). The toxicology package indicates that fluralaner also has a sufficiently low acute toxicity profile to be consistent with SPF criteria for listing in Schedule 5. The acute poisoning risk to humans (in particular children) is low, partly associated with the proposed packaging of only four tablets in blister packaging. The delegate considered whether S4 listing could be more appropriate, providing for oversight of treatment by a veterinarian, noting that this is a condition imposed for registration in the USA, but in the end decided against this, on the basis that the treatment instructions are sufficiently clear that pet owners should be able to manage the required dosage regimen.

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; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

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 February 2015.

Scheduling entry
Schedule 5 - New entry

FLURALANER for the treatment and prevention of flea infestations and control of ticks in dogs in oral divided preparations each containing 1400 mg or less of fluralaner per dosage unit.

3.2 Oclacitinib maleate

Scheduling proposal

In August 2014, the Office of Chemical Safety (OCS) referred, based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to register oclacitinib and to approve three different strengths of tablets, the following proposal to be considered by the delegate:

  • A proposal to create a new Schedule 4 entry for oclacitinib.

The reasons for the request are:

  • oclacitinib has moderate oral toxicity in rats (LD50 ~310 mg/kg bw in females);
  • it has low dermal toxicity in rats (LD50 >2000 mg/kg bw);
  • it has no skin irritation in rabbits;
  • it is a severe eye irritant in rabbits; and
  • it is not a skin sensitiser at concentrations ≤ 4% in mouse.

The OCS evaluation report indicated that no acute inhalational toxicity study was submitted for oclacitinib. While the acute inhalational toxicity is unknown, due to the general lack of specific toxicological data on the active constituent and formulation excipients, the lack of an acute inhalational toxicity endpoint is not considered a significant data deficiency and does not affect the risk assessment of the product, noting that the formulated product is in a film-coated tablet not expected to generate fine material of inhalational risk in this case.

Scheduling status

Oclacitinib is not specifically scheduled.

Scheduling history

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

Substance summary

Oclacitinib is an immunomodulator (a medicine that changes the activity of the immune system) that works by blocking the action of enzymes known as Janus kinases. These enzymes play an important role in the processes of inflammation and itchiness, including those involved in allergic and atopic dermatitis in dogs. By blocking the enzymes, the substance reduces the inflammation and itchiness associated with the disease9. The substance is intended for the treatment of clinical manifestations of pruritus associated with allergic dermatitis in dogs, and the treatment of clinical manifestations of atopic dermatitis in dogs.

Figure 2. Structure of oclacitinib

Figure 2. Structure of oclacitinib

Acute toxicity

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

Toxicity Species Oclacitinib SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 310 (females) Moderate to high toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 (no deaths) Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Not provided Not provided Unable to assess
Skin irritation Rabbit Non-irritant
Eye irritation Rabbit Severe irritant
Skin sensitisation (Local Lymph Node Assay - LLNA) Mice Non-sensitiser at concentrations ≤ 4%

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

The OCS evaluation report indicated that no acute toxicity studies for the tablet preparations (containing 3.6 mg, 5.4 mg and 16 mg of oclacitinib) have been submitted for evaluation. Estimation of product toxicity suggests that is a low acute oral and dermal toxicant, and not a skin irritant or sensitiser. Available data on eye irritation of the formulation components suggests that is likely to be irritating to eyes.

Repeat-dose toxicity

Repeat-dose oral toxicity studies in rats reported excessive toxicity and mortality at high doses (>100 mg/kg bw/day), with decreased red cell mass, myocardial degeneration, lymphoid depletion and hypocellularity in lymphoid tissue and bone marrow identified as treatment-related effects across all dose levels. Severity/frequency of findings showed broad dose level and/or dosing duration trends. Immunophenotyping reported changes in lymphocyte subpopulations, with alterations in cytotoxic T-cells, NKT and NK cells observed across dose levels attributable to the pharmacological effects associated with oclacitinib administration. A No Observed Effect Level (NOEL) was not established in rat studies, although it was noted that changes in clinical pathology, immunophenotyping and histopathology associated with lymphoid depletion generally occurred without evidence of clinical signs of toxicity at low doses.

In repeat-dose oral toxicity studies in dogs at up to 6 mg/kg bw/day, similar alterations in haematology, immunophenotyping and histopathology associated with lymphoid depletion and hypocellularity were consistently observed. No NOELs were established in dog studies. In an immunophenotyping study at 0.6 mg/kg bw for 15 weeks, treatment-related changes were observed in both blood and lymph node profiles, consistent with the pharmacological activity of the chemical. A short-term study in dogs dosed at 9 mg/kg bw twice daily reported clear T-cell inhibition and reticulocyte reductions associated with treatment, along with a range of other clinical pathology changes considered reversible after cessation of treatment.

A definitive margin-of-safety study in dogs (26 weeks at up to 5× the standard dose) suggested that oclacitinib was well tolerated in general, although observed effects in skin and lymph nodes were likely linked to the immunosuppressive nature of the chemical. Hypocellularity in lymphoid tissues and bone marrow was observed, consistent with other repeat-dose studies in the dog, although comparison of treatment-related effects in the repeat-dose dog studies suggested a general lack of progression in severity and frequency of identified effects.

Oclacitinib did not appear to affect the response of dogs to vaccination, with most immunosuppressive effects reversible after cessation of dosing; however, some clinical signs were still noted in some treated animals.

Mutagenicity

No information provided.

Genotoxicity

Oclacitinib was not genotoxic in an Ames and an in vivo micronucleus test. While no definitive carcinogenicity studies were available for evaluation, the lack of proliferative changes directly related to treatment in repeat-dose studies suggests that carcinogenicity is unlikely.

Carcinogenicity

No information provided.

Reproductive and developmental toxicity

Oclacitinib was not a developmental toxicant in both rat and rabbit. While skeletal variations and decreased foetal weights were identified in rat pups at 25 mg/kg bw/day (i.e. at doses where maternal toxicity was not observed), the OCS notes the lack of treatment-related malformations, and that treatment-related variations were consistent with developmental delays/maturity. In rabbits, malformations were identified only at doses with clear maternotoxicity (i.e. deaths and abortions at 60 mg/kg bw/day).

Observation in humans

No information provided.

Public exposure

Tablets containing oclacitinib for dogs will be administered primarily by pet owners and, therefore, management of potential domestic risks will need to be considered.

The main exposure to the substance will be by the dermal route. Residue levels resulting from the use of the product are expected to be negligible, as tablets are film coated and the excipients are widely used in approved veterinary/human pharmaceutical products. Noting that tablets are formulated such that formation of residues is unlikely, any resulting dermal-to-oral transfer of the product is also likely to be low. While the tablets are intended for division along the score line, the resulting exposure is also expected to be minimal, as formation of product dust is expected to be minimal.

The product is intended to be administered by adults and a tablet is not usually removed from the packaging until prior to administration. In addition, as the tablets will be contained in child resistant packaging, the likelihood of children accessing more tablets than the equivalent of a single dosing event is further limited. In the accidental oral ingestion scenario, where two 16 mg tablets (the maximum dose level as indicated for 55 to 80 kg dogs) are ingested by a 10 kg child, the exposure would be the equivalent of 3.2 mg/kg bw. For a 70 kg adult, the equivalent exposure is 0.46 mg/kg bw.

International regulations

No information provided. The Scheduling Secretariat has found the following information.

In May 2013, the US Food and Drugs Administration (FDA) approved the tablet preparations containing 3.6, 5.4 or 16 mg of oclacitinib as oclacitinib maleate per tablet. These preparations may be dispensed only by or on the lawful order of a licensed veterinarian (Rx marketing status). Adequate directions for lay use cannot be written because professional expertise is required to rule out other diseases in the diagnosis of allergic and atopic dermatitis, and to monitor the safe use of the product, including the treatment of any adverse reactions.

In September 2013, the European Commission (EU) granted a marketing authorisation valid throughout the European Union, for Apoquel (containing the active substance oclacitinib at 3.5 mg, 5.4 mg and 16 mg doses).

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • OCS evaluation report (not publicly available);
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors10;
  • Other relevant information.
Delegate's final decision

Oclacitinib, is an immunomodulator (a medicine that changes the activity of the immune system) that works by blocking the action of enzymes known as Janus kinases. These enzymes play an important role in the processes of inflammation and itchiness including those involved in allergic dermatitis and atopic dermatitis in dogs. By blocking the enzymes, the substance reduces the inflammation and itchiness associated with the disease. The substance is intended for the treatment of clinical manifestations of pruritus associated with allergic dermatitis in dogs, and treatment of clinical manifestations of atopic dermatitis in dogs. The listing of oclacitinib in Schedule 4 is based on the need for a veterinarian to diagnose and manage treatment of the condition. The OCS has recommended to the APVMA an appropriate set of label safety directions and warning statements about poisoning potential.

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.

An early implementation date is proposed to facilitate marketing of the product when registered by the APVMA. Therefore, the proposed implementation date is 1 February 2015.

Scheduling entry
Schedule 4 - New entry

OCLACITINIB.

3.3 Pyriofenone

Scheduling proposal

In September 2014, the Office of Chemical Safety (OCS) referred, based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to register a new active ingredient namely pyriofenone, the following proposal to be considered by the delegate:

  • A proposal to create a new Schedule 6 entry with no cut-offs for pyriofenone.

The reasons for the request are:

  • pyriofenone has low acute oral, dermal and inhalational toxicity in rats;
  • it is not a skin or eye irritant in rabbits;
  • it is a skin sensitizer in Guinea pigs (Maximization test); and
  • a reliable rabbit developmental toxicity study is not available.
Scheduling status

Pyriofenone, a fungicide in the aryl phenyl ketone chemical family, is not specifically scheduled. Another aryl phenyl ketone substance, metrafenone, is listed in Schedule 5 and Schedule 6. Preparations containing 50% or less of metrafenone are listed in Schedule 5 and all other preparations containing metrafenone are listed in Schedule 6.

Scheduling history

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

The scheduling history of metrafenone is provided below.

In February 2010, the National Drugs and Poisons Schedule Committee (NDPSC) considered a proposal to include metrafenone in a schedule. The NDPSC indicated that the key issue of concern was the carcinogenicity potential of metrafenone. Although carcinogenicity was observed in two species (which would normally indicate a Schedule 7 entry as being warranted), the carcinogenic response was only observed at very high dose rates and/or very high exposure rates. The NDPSC considered the relevance of the classification of metrafenone as a carcinogen to scheduling when such a high dose was required, and when, in practice, an individual would be highly unlikely to be exposed to such amounts. The NDPSC generally agreed, on the basis of the very low risk of being exposed to the quantities required for carcinogenicity, that the weight of evidence supported a Schedule 6, rather than Schedule 7 metrafenone parent entry. The NDPSC decided to include preparations containing 50% or less of metrafenone in Schedule 5 and all other preparations containing the substance was listed in Schedule 6.

Substance summary

Pyriofenone belongs to a new chemical family called benzoylpyridines, discovered and developed for use in grapevines (and other arable and vegetable crops)11.

Figure 3. Structure of pyriofenone

Figure 3. Structure of pyriofenone.

Acute toxicity

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

Toxicity Species Pyriofenone SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 (female, no deaths) Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 (male and female no deaths) Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >5180 (male and female, no deaths) Low toxicity
Skin irritation Rabbit Non-irritant
Eye irritation Rabbit Non- irritant
Skin sensitisation (Guinea pig maximization test) Guinea pig Sensitiser

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

Repeat-dose toxicity

For short-term to subchronic dietary studies with pyriofenone in rats, mice and dogs, the main target organs for toxicity were the liver and the kidneys (rats and mice only). At higher dosage levels, increases in caecum weight were also seen in rats. Mice were less susceptible to the toxicity of pyriofenone compared to rats and dogs, and kidney toxicity was seen at higher dose levels than liver toxicity. In rats and dogs, the no observed effect levels (NOELs) in subchronic dietary studies were 15.3 mg/kg bw/d and 20.6 mg/kg bw/d respectively, based on increased alkaline phosphatase activity and liver weight in dogs at 89.9 mg/kg bw/d, and increased activated partial thromboplastin time and decreased total bilirubin in rats at 69.0 mg/kg bw/d.

In chronic dietary studies, the liver and/or kidneys remained the main target organs in rat, mice and dogs, with treatment related effects also seen on blood clotting times in the rat and dog chronic studies. Additionally in dogs, at higher dose levels, vomiting and loose stool were observed.

The observed systemic toxicity and the dose levels at which these were observed do not warrant scheduling.

Mutagenicity

Pyriofenone was not mutagenic in bacteria and mammalian cells in vitro with and without metabolic activation, and did not induce chromosome aberrations or polyploidy in mammalian cells in vitro with and without metabolic activation at non-cytotoxic concentrations.

Genotoxicity

Pyriofenone did not induce micronuclei in vivo in the bone marrow of male and female mice up to and including the limit dose (2000 mg/kg bw). Thus, from the available data, pyriofenone is not an in vivo genotoxicant.

Carcinogenicity

In a rat 2-year dietary study, the overall incidences of all benign, malignant and combined benign and malignant tumours were comparable between treatment and control groups in both sexes. For specific tumour types, no statistically significant increase was seen, and a slight increase in the total incidence of combined hepatocellular adenomas and carcinomas in males at 5000 ppm (16% compared to 8% in controls) was seen at a dose level that produced an increase in unscheduled mortalities (i.e. liver tumours only seen in males at a dose level considered to have exceeded the maximum tolerated dose), and did not show a statistically significant dose-related trend when analysed by Peto's test.

In a mouse dietary 18-month study, for the total incidence of tumours, a statistically significant increase was seen in male mice only with ≥1 benign tumour(s) at 1800 (50%) and 5400 ppm (50%) compared to concurrent controls (31%). No historical control data on the laboratory incidence of such findings were provided, although historical control data were provided for specific tumour findings in the test laboratory. For specific tumour types, a statistically significant increase was only seen for combined hepatocellular adenomas and carcinomas in male mice at 5400 ppm (23.1% compared to 7.7% in controls), but this was within the historical control range (9.8 to 32.0% based on 11 studies), as were other (non-statistically significant) increases including the incidence of hepatocellular adenomas and carcinomas separately.

Consequently, there is no robust evidence that pyriofenone is carcinogenic in male and female rats and mice.

Reproductive toxicity

Pyriofenone was not a reproductive toxicant in a dietary 2-generation study in the rat up to and including dose levels that produced parental toxicity.

Developmental toxicity

In an oral (gavage) developmental toxicity study in rats, at 1000 and 300 mg/kg bw/d, an increased incidence was seen in the number of foetuses with skeletal variations (121/157 fetuses, 77.1% and 105/148 foetuses, 70.9% respectively). While no laboratory historical control data were provided on the incidence of foetuses with skeletal variations, such data were provided for specific skeletal variation in the strain of rat used in this developmental toxicity study. These historical control data have been used to interpret the observed skeletal findings and determine whether they are associated with pyriofenone treatment. Only the incidence of supernumerary rib at 1000 mg/kg bw/d (62.4%) was (slightly) outside the laboratory historical control range (35.7 to 61.0% based on 5 studies conducted from 2002 – 2008). Therefore, the findings at 1000 mg/kg bw/d were considered potentially treatment-related. However, these skeletal variations at the limit dose of 1000 mg/kg bw/d were seen in the presence of maternal toxicity (an increase in absolute and relative caecum weight) and are not sufficient for pyriofenone to be considered a hazard for developmental toxicity.

Only a preliminary dose-range finding developmental toxicity study (oral gavage) was available in the rabbit. In this study, observed abortions and premature deliveries at 1000 mg/kg bw/d, decreases in foetal and placental weight at 300 mg/kg bw/d and greater, and resorptions and foetal deaths at 100 mg/kg bw/d and greater, were seen in the presence of marked to severe maternal toxicity (i.e. during gestation, decreased body weight gain up to 16.2% at 100 mg/kg bw/d, and decreases in body weight gain >90.0% at 300 and 1000 mg/kg bw/d). Foetuses were only examined for external abnormalities, for which no treatment-related findings were seen. However, as this was a preliminary dose range finding study to identify dose levels for a subsequent definitive study (which was not submitted in the data package for this assessment), used low group sizes of 8 does per dose, and visceral and skeletal examination of the foetuses was not undertaken, it is not considered reliable for hazard identification. Thus, the absence of a developmental toxicity study in a second species constitutes a data gap (i.e. a deficiency in the data base) that needs to be taken into account when considering the potential scheduling of pyriofenone.

Observation in humans

No information provided.

Public exposure

No information provided.

International regulations

No information provided.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • OCS evaluation report (not publicly available);
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors12;
  • Other relevant information.
Delegate's final decision

The toxicological profile of pyriofenone is well characterised. Based on the OCS evaluation report, this profile is consistent with either listing in Schedule 5 or 6. The acute and chronic toxicity profile is not remarkable and there is no evidence of appreciable skin-eye irritancy. The primary reason for considering Schedule 6 to be more appropriate is potential for sensitisation, and an identified data gap in that a developmental toxicity study in a second species has not yet been submitted. The delegate has accepted the OCS recommendation that pyriofenone be listed in Schedule 6, with no cut-off.

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

An early implementation date is proposed to facilitate clearance of the active ingredient by the APVMA and prior to consideration of any products based on pyriofenone. Therefore, the proposed implementation date is 1 February 2015.

Scheduling entry
Schedule 6 - New entry

PYRIOFENONE.

Footnotes

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