You are here

Scheduling delegate's final decisions, March 2016

Scheduling medicines and poisons

17 March 2016

Book pagination

1.7 Amisulbrom

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

1. Scheduling proposals referred to the November 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#15)

1.7 Amisulbrom

Scheduling proposal

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

  • In August 2015, the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) for the approval of amisulbrom as a new active constituent and the registration of a product, containing amisulbrom, recommends that the delegate consider creating a new entry for amisulbrom in Schedule 6 of the SUSMP. No cut-off exemptions for amisulbrom were proposed by OCS.
Scheduling application

The reasons for the request were:

  • OCS considers amisulbrom meets the Scheduling Policy Framework criteria for Schedule 6, based on results from a rabbit eye irritation study and carcinogenicity and mechanistic studies in rats and mice.
  • The applicant did not nominate a Schedule for either amisulbrom or the product; in their APVMA application, the applicant indicated that they did not wish to nominate a Schedule proposal, but would defer to the outcome of the scheduling process.
  • The applicant has been provided a copy of the OCS draft report and considered the OCS Scheduling recommendation. In their correspondence, the applicant does not dispute the OCS Schedule 6 recommendation for amisulbrom and the FAISD recommended for the product. However the applicant does not agree with OCS in relation to the classification of eye irritation according to the NOHSC Approved Criteria (NOHSC:1008, 2004) or GHS (5th Edition, 2013).
  • In addition, although the applicant understands the logic for the R40 carcinogen category 3 classification for amisulbrom by OCS, the applicant has pointed out that the EU considered classification for carcinogenicity was not warranted as hepatocellular effects were seen at dose levels that exceeded the MTD.
  • The applicant concludes that the liver effects seen at high doses in animal studies are of little relevance to realistic human exposure levels.
  • In summary, the applicant, although agreeing with the OCS Scheduling recommendation is of the opinion that OCS has been overly conservative in their interpretation of both the eye irritation and carcinogenicity data.
Specific issues/questions raised by the delegate

The delegate asked the committee the following questions:

  • Does the ACCS support listing in Schedule 6, based on the OCS recommendations?
  • Does the ACCS agree with evaluation of the carcinogenic potential of amisulbrom, noting that the OCS evaluation does not believe that the evidence is sufficient to establish the proposed Mode of Action (MoA) suggesting a lack of human relevance for the proposed MoA?
  • Is there a basis for establishing a cut-off to Schedule 5, or exempt, on the basis of the currently submitted evidence? Is there are need for a cut-off at this time, given that the product contains enough copper sulphate for it to be classified in Schedule 6?
  • What name should be used for a listing in the Schedules - amisulbrom, or the IUPAC name 3-(3-bromo-6-fluoro-2-methylindole-1-ylsulfonyl)-N,N-dimethyl-1,2,4-triazole-1-sulfonamide?
Substance summary
Chemical structure of amisulbrom

Figure 6. Chemical structure of amisulbrom

Acute toxicity

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

Toxicity Species Amisulbrom SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >5000
(no deaths)
N/A
Acute dermal toxicity LD50 (mg/kg bw) Rat >5000
(no deaths)
N/A
Acute inhalational toxicity LC50 (mg/m3/4h nose-only) Rat >2850
(no deaths)
N/A
Skin irritation Rabbit Not irritating N/A
Eye irritation Rabbit Moderate Schedule 6
Skin sensitisation (GPMT) Guinea Pig Not sensitising N/A

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

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

Toxicity Species Amisulbrom SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat LD50 >2000
(no deaths)
N/A
Acute dermal toxicity LD50 (mg/kg bw) Rat LD50 >2000 N/A
Acute inhalational toxicity LC50 (mg/m3/4h nose-only) Rat LC50 >2153
(no deaths)
N/A
Skin irritation Rabbit Not irritating N/A
Eye irritation Rabbit Slight irritant N/A
Skin sensitisation (GPMT) Guinea Pig Not sensitising N/A

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

Repeat-dose toxicity

The systemic toxicity of amisulbrom in oral studies in rats, mice and dogs, consisted primarily of decreased body weight and body weight gain, food consumption and conversion efficiency and effects on the liver (e.g. serum liver enzyme changes, increased relative weights and hepatocyte hypertrophy), kidney (increased relative weights and cortical tubular pigmentation) and adrenals (increased relative weights and cortical hypertrophy). No treatment related adverse effects were seen in a short-term dermal toxicity study in the rat, except a small decrease in weight gain in males at the highest dose (1000 mg/kg bw/d). No repeat dose inhalational toxicity studies were available for assessment. The toxicity profile for amisulbrom in repeat-dose toxicity studies (excluding carcinogenicity studies) in rats, mice and dogs indicates a low health hazard from repeated exposure and there was no indication of irreversible toxicity in these studies, except at doses above the MTD.

Mutagenicity

Potential genotoxicity of amisulbrom was assessed in a bacterial reverse mutation assay (Ames test; adequate S. typhimurium and E. coli strains; with and without metabolic activation [S9]), in vitro mutagenicity assay in mammalian cells (tk assay; mouse lymphoma cells; with and without metabolic activation), in vitro clastogenicity assay (human peripheral blood lymphocytes; with and without metabolic activation), in vivo mouse bone marrow micronucleus test (oral and intraperitoneal dosing), in vivo hepatic micronucleus test in rats (oral dosing), in vivo unscheduled DNA synthesis (UDS) assay (rats; oral dosing), in vivo hepatic comet assays in mice and rats and gastric mucosal cell comet assay in rats (oral dosing). The potential genotoxicity of the primary amisulbrom metabolite, IT-4 was assessed in a bacterial mutation assay ((Ames test; adequate S. typhimurium strains; with and without metabolic activation [S9]),) and a mouse micronucleus test. There was no evidence of a genotoxic potential associated with amisulbrom or IT-4.

Carcinogenicity

In long-term toxicity/carcinogenicity studies with rats (104 weeks) and mice (78 weeks), the target organs of toxicity were the liver and kidney. In the 1-year dog study, the target organs were the liver and adrenals.

Neoplastic findings in these studies were confined to rats and mice, as follows:

  • an increased incidence of hepatocellular adenomas and carcinomas in male and female rats (i.e. ≥496 mg/kg bw/d in males, ≥697 mg/kg bw/d in females);
  • an increased incidence of hepatocellular adenomas in male mice (≥98 mg/kg bw/d); and
  • an increased incidence of squamous cell papillomas and carcinomas of the keratinised region of the forestomach in female rats and adenocarcinoma in males (i.e. ≥1008 mg/kg bw/d in males, ≥697 mg/kg bw/d in females).

Tumours of the forestomach were seen only at doses exceeding the MTD and appear to be related to chronic inflammatory changes caused by local irritation of the stomach mucosa. Histopathological lesions consistent with a local irritant effect in the gastrointestinal tract (epithelial hyperplasia, hyperkeratosis, ulceration and submucosal inflammation) were evident in animals at the same doses at which forestomach tumours were observed. Furthermore, consistent with a local inflammatory reaction in the gastrointestinal tract, sinus histiocytosis was seen in the mesenteric lymph nodes of females in the same dose groups. In addition, a rat forestomach gastric mucosa cell comet assay was negative. Given the high doses at which these effects occurred together with species differences in gastric fluid volumes and the fact that the anatomical target organ (the forestomach) is not present in humans, the forestomach tumours seen in rats are considered to have low relevance to humans.

Although liver tumours were only seen at high doses in rats, they were seen below the MTD in mice. The weight of evidence supports a non-genotoxic (epigenenetic) mechanism in rodents with a clear threshold for induction (i.e. no treatment-related induction of liver tumours occurred in male and female rats at 96 and 129 mg/kg bw/d, respectively, and mice at 11.6 mg/kg bw/d). Mechanistic studies, submitted by the applicant to elucidate the mechanism for liver tumours seen in both rats and mice, indicated a possible phenobarbital type mechanism for amisulbrom. However, although amisulbrom elicited similar DNA proliferative effects (RDS) and specific liver enzyme induction (mainly PROD activity) to phenobarbital, induction of CYP2B enzymes was not characterised and CAR/PXR activation was not demonstrated. Overall, the OCS considers the mechanistic data are only suggestive of a possible phenobarbital type MOA for hepatic tumour formation in rodents and not sufficiently comprehensive or robust to eliminate the possibility of other modes of action leading to liver tumour formation. Therefore liver tumours seen in rodents are considered potentially relevant to humans.

Reproduction and developmental toxicity

Amisulbrom was not a reproductive toxicant (rats) or developmental toxicant (rats and rabbits). However, in a 2-generation dietary reproductive toxicity study in rats, although no effects were seen in F0 females, prolonged or irregular oestrous cycles, impaired fertility and ovarian atrophy were evident in F1 females. No effects on fertility were seen in males. Mechanistic studies (including anti-oestrogenic uterotrophic assay; anti-aromatase assay, reproductive hormone levels together with cross-fostering and food restriction studies) submitted by the applicant, provided evidence that impaired fertility in F1 females was likely a secondary response to reduced food intake and impaired body weight gain, associated with poor palatability of amisulbrom. Therefore impaired fertility seen in rodents is considered to have low relevance to humans.

Neurotoxicity

No neurotoxic effects (clinical signs, anatomical brain measurements, gross pathology, neurohistopathology or functional observation battery (FOB)) were observed in rats (both sexes) in an acute gavage study (single oral administration of amisulbrom up to 2000 mg/kg bw) or in a follow-up sub-chronic 13 week dietary study (doses up to 860 mg/kg bw/d (males) and 1132 mg/kg bw/d (females) in the same rat strain. The NOEL for general toxicity in the sub-chronic study was 23 mg/kg bw/d in males and 29 mg/kg bw/d in females, based on decreased body weight gain.

Observation in humans

No information was provided.

Public exposure

No information was provided.

International regulations

Amisulbrom has recently been considered for registration by the US EPA and EU (EFSA).

Scheduling status

Amisulbrom is not specifically scheduled.

Scheduling history

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

Pre-meeting public submissions

One public submission was received. In general, the submission supported a Schedule 5 entry and would accept a Schedule 6 entry, as an entry in either schedule would not make any difference to end use product. The submission sought an expedient scheduling implementation date.

The public submission is available at Public submissions on scheduling matters.

ACCS advice to the delegate

The Committee recommended that a new Schedule 5 entry be created for amisulbrom as follows:

Schedule 5 - New Entry

AMISULBROM

The committee recommended an implementation date of 1 June 2016.

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

The reasons for the recommendations comprised the following:

  • the active constituent for use in fungicide products
  • the substance is a slight eye irritant
  • the substance meets the criteria for inclusion in Schedule 5
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 factors7;
  • Other relevant information.
Delegate's interim decision

The delegate notes, and accepts, advice from the ACCS that amisulbrom be listed in Schedule 5. The delegate agrees that the overall toxicological profile of amisulbrom is consistent with SPF criteria for listing in Schedule 5 and that the eye irritancy potential is more appropriately categorised as slight, rather than moderate. The delegate notes that the ACCS considers the evidence for the MoA producing liver tumours in rats and mice is sufficient to discount the relevance of these findings for humans.

Despite the apparent low toxicity profile of the product submitted for evaluation, an exemption cut-off for amisulbrom is not proposed at this time. The submitted product would require Schedule 6 controls since it includes copper sulphate at a concentration exceeding the Schedule 5 range of 5 - 15% that would qualify for the exemption from the Schedule 6 entry for copper sulphate.

The earliest practicable implementation of the scheduling decision will facilitate approval of the substance by the APVMA.

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

Schedule entry
Schedule 5 - New Entry

AMISULBROM

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

AMISULBROM

The proposed implementation date is 1 June 2016.


Footnotes

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

Book pagination