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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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3.1 Isofetamid

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to create a new entry for isofetamid in Schedule 5 of the Poisons Standard, with no exemptions.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are:

  • Schedule 5 - New Entry
  • ISOFETAMID.

The applicant's reasons for the request are:

  • No product has been proposed for registration in this current application. However, isofetamid is a broad-spectrum fungicide whose mode of action involves the inhibition of succinate dehydrogenase in complex II of fungal respiration. Therefore, it is anticipated that isofetamid could be used to control diseases caused by Botrytis, Monilia, and Sclerotinia (and Rhizoctonia) fungi in a range of crops;
  • It is noted that isofetamid is a carboxamide fungicide and several carboxamide fungicides are currently listed in Appendix B of the poisons Standard (substances considered not to require control by scheduling), such as carboxin and boscalid. While recently (February 2012), the carboxamide fungicide fluxapyroxad with the same mode of action as isofetamid was listed in Schedule 5 of the Poisons Standard with no cut-off or exemptions, with the concern being slight skin irritation in rabbits;
  • Based on the observed slight eye irritation in rabbits, isofetamid meets the Scheduling Policy Framework (2015) criteria for scheduling it to Schedule 5 of the Poisons Standard with no cut-off or exemptions;
  • The toxicokinetic profile established in oral gavage doses in rats indicated that absorption of isofetamid was essentially complete at the low and high dose; i.e. >93%. Isofetamid was widely distributed to tissues with the highest concentrations being in the liver and kidneys. There was no evidence of accumulation in tissues following repeat oral dosing. Isofetamid is extensively metabolised, and the major routes of metabolism were O-dealkylation, hydroxylation and subsequent glucuronidation. Excretion was rapid with the majority of the administered dose eliminated in the urine (11% in males and 48% in females) and bile (85 – 88%) within 48 hours after administration. The difference between sex types with regard to the extent of excretion via urine and faeces was shown to be due to a quantitative difference rather than the presence of unique metabolites in bile or urine;
  • The observed systemic toxicity does not warrant scheduling. Additionally, there was no evidence that isofetamid was neurotoxic or immunotoxic. Therefore, isofetamid does not warrant scheduling for these endpoints;
  • There was no evidence that isofetamid was carcinogenic in mice and rats, and isofetamid was tested for genotoxicity in an adequate range of in vitro and in vivo assays and was negative. Therefore, isofetamid does not warrant scheduling for these endpoints;
  • In a study of developmental toxicity in rats, maternal (liver) toxicity was seen at the top (limit) dose of 1000 mg/kg bw/d. While rare major abnormalities to the heart and major vessels were seen in one and two foetuses (2 litters) at the mid and high dose respectively, the findings were seen at the same incidence in studies from the laboratories historical database with the exception of incomplete caudal vena cava with persistent cardinal vein. However, the singular occurrence of this finding at the mid- and high-dose was considered likely incidental to treatment. For minor visceral abnormalities, a low incidence of brain haemorrhage and left-sided umbilical artery was seen, that were stated by the study author to be within normal limits and of low biological significance and not adverse. However, no historical control data was provided, though obtained data on the background incidence of left-sided umbilical artery in rat foetuses in four other testing laboratories indicated they were likely incidental to treatment. No data on the background incidence of brain haemorrhages in rat foetuses was obtained and, therefore, this finding at the limit dose cannot be completely discounted. However, brain haemorrhages are not a structural abnormality per se, this non-statistical finding was seen (at a lower incidence) in concurrent controls, and was seen at a dose level producing maternal toxicity. Therefore, while this finding was considered potentially treatment-related, it was not considered to fully demonstrate an increased sensitivity of the embryo/foetus to isofetamid. While it is considered that the observance of a dose-related increase in ossification leading to fewer foetuses showing incomplete ossification/unossified is unlikely to be toxicologically significant; and
  • In a study of developmental toxicity in rabbits, marked maternal toxicity (that included a bodyweight loss over GD 6-9) was seen at the top (limit) dose of 1000 mg/kg bw/d, and skeletal malformations were seen in 1, 1, and 4 foetuses (4 litters) at 0, 300 and 1000 mg/kg bw/d, respectively. At the limit dose specific malformations were only seen in a single animal with the exception of fused sternebrae in 2 foetuses, and neither the incidence of individual or total malformations were statistically significant. Therefore, it is considered that the observed low incidences of skeletal malformations were likely incidental to treatment, and an increased sensitivity of the embryo/foetus to isofetamid has not been demonstrated. It was concluded that isofetamid was not teratogenic in rats and rabbits. Therefore, isofetamid does not warrant scheduling for this endpoint.

Current scheduling status and relevant scheduling history

Isofetamid is not currently scheduled and has not been previously considered for scheduling. Therefore, a scheduling history is not available.

Isofetamid is a carboxamide fungicide; several carboxamide fungicides (such as carboxin and boscalid) are currently listed in Appendix B of the Poisons Standard (substances considered not to require control by scheduling).

Boscalid

In June 2003, the National Drugs and Poisons Scheduling Committee (NDPSC) decided to include boscalid (first generation carboxamide) in Appendix B because of its low acute toxicity potential, i.e. low oral, dermal and inhalation toxicity and it was not a skin irritant in rabbits or a skin sensitiser in guinea pigs, but was a slight eye irritant in rabbits. The NDPSC therefore agreed to exempt boscalid from the requirements of scheduling.

Carboxin

In July 1987, the Drugs and Poisons Scheduling Committee (DPSC) decided to include carboxin in Appendix B on the basis of low acute oral, dermal and inhalation toxicity; and an absence of reproductive effects.

Fluxapyroxad

In February 2012, the carboxamide fungicide fluxapyroxad, with the same mode of action as isofetamid, was listed in Schedule 5 with no cut-off or exemptions, with the concern being slight skin irritation in rabbits.

Australian regulatory information

Isofetamid is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017, and is not an excipient or active in any products on the ARTG.

Isofetamid is not listed on the National Industrial Chemicals Notification and Assessment Scheme's (NICNAS) Australian Inventory of Chemical Substances (AICS).

International regulations

USA

Isofetamid 400SC Fungicide was listed as a pesticide by EPA in the USA in July 2015 under the Federal Insecticide, Fungicide and Rodenticide Act (EPA registration number 71512-22).[46])

Canada

In June 2016, Canada granted full registration for the sale and use of Technical Isofetamid Fungicide and Isofetamid 400 SC Fungicide, containing the active ingredient isofetamid, to control various Botrytis and Sclerotinia diseases on grape, lettuce (head and leaf), rapeseed, low growing berry and turfgrass on golf courses and sod farms.

EU

Isofetamid is approved for use in certain EU countries according to Regulation (EC) No 1107/2009.

Substance summary

The mode of action is inhibition of succinate dehydrogenase in complex II of the mitochondrial respiratory chain, resulting in inhibition of spore germination, germ tubes, and mycelial growth.[47])

Table 3.1.1: Chemical information for Isofetamid
Property Isofetamid
Chemical structure chemical structure of isofetamid
Molecular formula C20H25NO3S
Molecular weight 359.5 g/mol
CAS name N-[1,1-dimethyl-2-[2-methyl-4-(1-methylethoxy)phenyl]-2-oxoethyl]-3-methyl-2-thiophenecarboxamide
CAS number 875915-78-9
IUPAC and/or common and/or other names IKF-5411; N-[1,1-dimethyl-2-(4-isopropoxy-o-tolyl)-2-oxoethyl]-3-methylthiophene-2-carboxamide; N-[1,1-dimethyl-2-[2-methyl-4-(1-methylethoxy)phenyl]-2-oxoethyl]-3-methyl-2-thiophenecarboxamide.
Table 3.1.2: Acute toxicity end-points for Isofetamid
Toxicity Species Isofetamid SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >4820 Schedule 5
Skin irritation Rabbit Not irritant Appendix B
Eye irritation Rabbit Slight irritant Schedule 5
Skin sensitisation (LLNA) Mouse (LLNA) Not a sensitiser Schedule 5

Acute toxicity

Based on the available oral, dermal and inhalation data, isofetamid has low acute toxicity.

Skin irritation

Based on available data, isofetamid is not a skin irritant:

  • Three female rabbits received a single (semi-occlusive) topical application of 0.5 g isofetamid moistened with 0.5 mL de-ionised water for 4 h. Observation for skin irritation was performed at 1, 24, 48 and 72 h after patch removal. Observations for signs of toxicity were made once daily. As there was no irritating response at 72 h animals were sacrificed at that time.

Eye irritation

Based on available data, isofetamid is a slight eye irritant:

  • Six female rabbits were administered 0.1 g isofetamid (powder) by ocular instillation. The eyes of three rabbits were irrigated with lukewarm water after 20 seconds. Observation for ocular irritation was performed at 1, 24, 48 and 72 h after instillation. Observations for signs of toxicity were made once daily. As there was no irritating response at 72 h animals were sacrificed at that time. Redness of the conjunctivae (grade 1) was seen in all animals at 1 h, with discharge seen in 1 animal whose eyes were irrigated (grade 1) and in all animals whose eyes were not irrigated (grade 1, 2 and 3). Additionally, at 1 h chemosis of the conjunctivae was seen in all animals whose eyes were not irrigated (grade 1, 2 and 2). At 24 h, redness of the conjunctivae (grade 1) was still present in 2 animals whose eyes were not irrigated. Corneal opacity and iritis were not observed, and ocular irritation was absent in all animals at 48 h. No other treatment-related clinical signs were observed during the study. Under the study conditions described, isofetamid was a slight eye irritant.

Sensitization

Based on available data, isofetamid is not a skin sensitiser:

  • Five groups of 5 female mice received topical application of 0 (vehicle control), 10, 25 or 50% isofetamid in dimethylformamide (DMF), or 25% of the positive control α-hexylcinnamaldehyde in DMF, for 3 consecutive days to both ears. Observations for signs of toxicity and local irritation were made once daily. On test day 6 of the assay, mice received ³H‑methyl thymidine by tail vein injection and were sacrificed 5 h later. Cell proliferation in the draining lymph nodes of the ears of mice from the test substance and positive control groups was then evaluated and compared to the vehicle control group. The stimulation indices for cell proliferation were 1.0, 1.1 and 1.1 at 10, 25 and 50% of the test substance, respectively. The positive control demonstrated the sensitivity of the assay. No skin irritation or treatment-related clinical signs were observed during the study. Under the study conditions described, isofetamid was not a skin sensitiser.

Repeat-dose toxicity

In short- and long-term repeat-dose dietary studies in mice, rats and dogs, the primary target organ was the liver. If an increased liver weight occurred in the absence of a corresponding increase in plasma levels of some liver derived enzymes (gamma glutamyl transpeptidase (GGPT), alkaline phosphatase (ALP)) then it was considered to be an adaptive effect. This was observed in mice. However, in rats and dogs, increased liver weights with histopathological changes were consistently seen in the presence of clinical chemistry changes, specifically increased GGPT in both species and ALP in dogs, at the LOAEL in long-term repeat-dose dietary studies in rats. Additionally, in rats thyroid follicular cell hypertrophy was observed at dose levels producing liver toxicity. A prolongation in blood clotting time/potential was seen, in the absence of treatment-related changes in other haematology parameters, secondary to disturbances in liver function.

Genotoxicity and carcinogenicity

There was no evidence that isofetamid was carcinogenic in mice and rats. Further, isofetamid was tested for genotoxicity in an adequate range of in vitro and in vivo assays and based on these studies isofetamid is not genotoxic.

Reproduction and developmental toxicity

The reproduction toxicity studies on isofetamid showed no treatment related signs of toxicological significance. Therefore isofetamid was not a reproductive toxicant in rats. Further, the submitted studies on developmental toxicity showed that isofetamid was not teratogenic in rats and rabbits.

Toxicological data on metabolites and/or degradants

GPTC, the glucoside of 4HP and a significant plant metabolite, had an oral LD50 value > 2000 mg/kg bw in the rat, and was negative in a bacterial reverse mutation assay with and without S9 metabolic activation. The available toxicity data indicate that GPTC is of no greater toxicity than isofetamid.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that a new Appendix B entry for isofetamid be created as follows:

Appendix B - New Entry

ISOFETAMID

Reason for Entry - a, low toxicity

Area of Use - 1.3, fungicide

The committee also recommended an implementation date of 1 February 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice were:

  • Isofetamid is expected to be used for agricultural purposes as a broad spectrum fungicide. The use in Australia is unknown at this time, and therefore the risks and benefits are unknown.
  • The low toxicology profile of isofetamid does not appear to warrant scheduling. There is a risk of slight eye irritation, which is reduced by irrigation and is reversible within 48 hours.
  • The APVMA is well placed to develop suitable warning statements, safety directions and first aid instructions for the product label of future products containing isofetamid.
  • Isofetamid is similar to a number of carboxamide fungicides already listed in Appendix B.

Delegate's considerations

The delegate considered the following regarding this proposal:

  • Scheduling proposal
  • ACCS advice
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information

Delegate's interim decision

The delegate's interim decision is to create a new Appendix B entry for isofetamid. The proposed Schedule entry is as follows:

Appendix B – New Entry

ISOFETAMID

Reason for Entry – a, low toxicity

Area of Use – 1.3, fungicide

The proposed implementation date is 1 February 2018, as this is the earliest possible implementation date.

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

The reasons for the interim decision are:

  • Isofetamid is expected to be used for agricultural purposes as a broad spectrum fungicide. The use in Australia is unknown at this time, and therefore the risks and benefits are unknown.
  • The low toxicology profile of isofetamid does not appear to warrant scheduling. There is a risk of slight eye irritation, which is reduced by irrigation and is reversible within 48 hours.
  • The APVMA are well placed to develop suitable warning statements, safety directions and first aid instructions for the product label of future products containing isofetamid.
  • Isofetamid is similar to a number of carboxamide fungicides already listed in Appendix B.

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