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Scheduling delegate's final decisions, March 2016

Scheduling medicines and poisons

17 March 2016

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3.4 Mandestrobin

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

3. Agricultural and Veterinary Chemicals

3.4 Mandestrobin

Scheduling proposal

In December 2015, the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) for registration of a new fungicide product, has referred the following scheduling proposal to be considered by the delegate:

  • A proposal to create a new entry for Mandestrobin in Schedule 5, with an exemption cut-off for preparations containing 25 per cent or less of mandestrobin.
Scheduling application

The Applicant has submitted a data package seeking approval of the new active constituent mandestrobin, a member of the strobilurin fungicide class of chemicals, a mitochondrial respiration inhibitor of fungal pathogens. As a new chemical for AgVet use, it will require consideration for scheduling prior to final registration of products containing this active constituent.

Substance summary
Chemical structure of mandestrobin

Figure 15. Structure of Mandestrobin (S-2200TG)

Acute toxicity

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

Toxicity Species Mandestrobin
(S-2200)
SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 (no deaths) Appendix B
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 (no deaths) Appendix B
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >4964 (no deaths) Appendix B
Skin irritation Rabbit Non-irritant Appendix B
Eye irritation Rabbit Moderate irritant Schedule 5
Skin sensitisation (Maximization Test) Guinea pigs Non-sensitiser Appendix B

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

Acute oral toxicity studies were conducted for technical grade mandestrobin (S-2200TG). Mandestrobin (S-2200TG) was found to be of low acute oral (LD50 of > 2000 mg/kg bw/d), low acute dermal (LD50 of >2000 mg/kg bw/d) and low acute inhalation (LC50 of >4964 mg/m3) toxicity.

Irritation

Mandestrobin was found to be a moderate irritant of the eye, and non-irritating to skin.

Sensitization

Mandestrobin was found to be non-sensitising to skin.

Repeat-dose toxicity

The systemic toxicity of mandestrobin in dietary studies consisted primarily of decreased bodyweight and bodyweight gain, liver toxicity such as increased liver weight and centrilobular hepatocellular hypertrophy with associated clinical chemistry seen at higher doses. This systemic toxicity profile was observed in subchronic and chronic studies in rats (54/61.1 mg/kg bw/d, M/F), mice (807.3/1111.2, mg/kg bw/d, M/F) and dogs (90.9/102.7, mg/kg bw/d, M/F), with the available data indicating that the rat was the most sensitive species. No short term oral studies were submitted for mandestrobin. No treatment-related adverse effects were seen in a short-term dermal toxicity study in the rat at the limit dose.

Study duration Species & Route Doses
(mg/kg bw/d)
NOEL/NOEC
(mg/kg bw/d)
LOEL & Toxic End-point
(mg/kg bw/d)
Short-term/Sub-chronic
28 days Rat, dermal 0, 100, 300, 1000 1000 No treatment-related effects observed
13 weeks Rat, dietary

800, 4000, 10,000, 20000 ppm

(0, 54/62, 283/320, 743/789, 1545/1887 M/F)

800 ppm

Males: 54.0 Females: 61.6

4000 ppm (283 mg/kg bw/d) and above for dose related clinical signs of including increased absolute and relative liver weight, large mottled liver, and hepatocyte proliferation, in both sexes.
13 weeks Mouse, dietary

0, 1750, 3500, 7000 ppm

(0, 204/252, 405/529, 807/1111 M/F)

7000 ppm

Males: 807.3 Females: 1111.2

No treatment-related effects observed
13 weeks Dogs

4000, 12000, 40000 ppm

(0, 90.9/102.7, 267.8/304.4, 933.1/820.4 M/F)

4000 ppm

Males: 90.9

Females: 102.7

12000 ppm (268/304 (M/F) mg/kg bw/d) and above for liver organ weight and liver histopathological findings.
Chronic
52 weeks Dog, dietary

0, 200, 800, 4000, 8000 ppm

(0, 4.3/4.5, 19.2/20.4, 92/92, 18.07/225.7 M/F)

800 ppm

Males: 19.2

Females: 20.4

4000 ppm (92 mg/kg bw/d M&F) for dark liver, centrilobular hepatocyte hypertrophy and pigmented hepatocytes
78 weeks Mouse, dietary

0, 700, 2000, 7000 ppm

(main group: 0, 82.5/99.2, 238.8/280.3, 823.9/99.4 M/F)

(satellite group: 0, 88.4/104.0, 255.0/325.0, 883.3/1045.1 M/F)

7000 ppm

Males: 883

Females: 1045

No treatment related effects
104 weeks Rat, dietary

400, 2000, 7000, 15000 ppm

(0, 21/26.7, 105/135, 375.6/475, 804/1016 M/F)

Males: 2000 ppm (105.1)

Females: 400 ppm (26.7)

7000 ppm (376 mg/kg bw/d, males) and above for hepatocyte hypertrophy, correlating with increases in relative liver weights and macroscopic findings of large liver. Increased total cholesterol.

2000 ppm (135 mg/kg bw/d, females) and above for decreased body weights and body weight gain. Hepatocyte hypertrophy in males, correlating with increases in relative liver weights and macroscopic findings of large liver.

Mutagenicity/Genotoxicity

Mandestrobin was not genotoxic in a bacterial reverse mutation test, and the results from the in vitro gene mutation assay (in Chinese Hamster V79 cells), chromosomal aberration (in Chinese Hamster lung cells CHL/IU) and micronucleus test (Mice bone marrow cells) were negative both with and without metabolic activation. Overall, mandestrobin is not considered genotoxic. There was no evidence of a mutagenic/genotoxic potential of mandestrobin or its primary metabolites in vitro with and without metabolic activation.

Carcinogenicity

No evidence of oncogenic potential was observed in mice treated with diets containing concentrations up to 7000 ppm or rats up to 15000 ppm. An increase in the sex-cord stromal tumours in the ovary of female rats was observed in animals offered 7000 or 15000 ppm. This was considered to be part of a continuum of change that was associated with sex-cord stromal hyperplasia. The sex-cord stromal hyperplasia was not statistically significant during pairwise comparison of treatment groups with controls; however, the incidence of benign sex cord stromal tumours were statistically significant in the treated versus control rats (p=0.005).

Study duration Species & Route Doses
(mg/kg bw/d)
NOEL/NOEC
(mg/kg bw/d)
LOEL & Toxic End-point
(mg/kg bw/d)
78 weeks Mouse, dietary

0, 700, 2000, 7000 ppm

(main group: 0, 82.5/99.2, 238.8/280.3, 823.9/99.4 M/F)

(satellite group: 0, 88.4/104.0, 255.0/325.0, 883.3/1045.1 M/F)

7000 ppm

Males: 883

Females: 1045

No treatment related effects
104 weeks Rat, dietary

400, 2000, 7000, 15000 ppm

(0, 21/26.7, 105/135, 375.6/475, 804/1016 M/F)

Males: 2000 ppm (105.1)

Females: 400 ppm (26.7)

7000 ppm (376 mg/kg bw/d, males) and above for hepatocyte hypertrophy, correlating with increases in relative liver weights and macroscopic findings of large liver. Increased total cholesterol.

2000 ppm (135 mg/kg bw/d, females) and above for decreased body weights and body weight gain. Hepatocyte hypertrophy in males, correlating with increases in relative liver weights and macroscopic findings of large liver.

Reproduction and developmental toxicity

Mandestrobin was not a reproductive or developmental toxicant. However, in the reproductive toxicity study in the rats, systemic toxicity signs including increased relative liver weights, moderate diffuse hepatocyte hypertrophy, increased thyroid weights in F0 males (3000 ppm). Significantly decreased relative and absolute spleen weight in males F1 pups at weaning were observed at >3000 ppm.

Study duration Species & Route Doses
(mg/kg bw/d)
NOEL/NOEC
(mg/kg bw/d)
LOEL & Toxic End-point
(mg/kg bw/d)
Reproductive, (range-finding) Rat, dietary

0, 5000, 10000, 20000 ppm

(F0 male: 318, 636, 1253

F0 female: 335, 667, 1326)

Not established 5000 ppm (equivalent to 244.1 mg/kg bw/d in males and 781.7 mg/kg bw/d in lactating females) based on treatment-related and toxicologically significant findings in liver and thyroid organ weight and histopathology in males.
Reproductive, 2-Generation Rat, dietary

0, 1000, 3000, 10000 ppm

(F0 male: 56.2, 166.3, 559

F0 female: 62.5, 195, 629

F1 male: 84.7, 254.5, 881

F1 female: 90, 274.9, 929.3)

Reproductive F0/F1

10000 ppm

male: 560/629

female: 881/930

Systemic F0/F1

1000 ppm

male: 56/62

female: 85/90

Developmental F1/F2 weanlings

1000 ppm

Reproductive

No reproductive toxicity was observed in F0 or F1 parental animals up to 10000 ppm.

General

3000 ppm (166 mg/kg bw/d) for increased relative liver weights, moderate diffuse hepatocyte hyopertrophy, increased thyroid weights in F0 males.

Developmental

≥ 3000 ppm (255/275 mg/kg bw/d, M/F) for significantly decreased relative and absolute spleen weight in males F1 pups at weaning

Developmental

GD 6-19

Rat, gavage 0, 250, 500, 1000 1000 No significant adverse signs of maternal or embryo-foetal toxicity.

Developmental

GD 7-28

Rabbit, gavage 0, 250, 500, 1000

Maternotoxicity

500

Developmental

1000

Maternotoxicity

1000 for decreased food intake.

Developmental

No effect of treatment on the mean incidence of external foetal variations and malformations.

Developmental

GD 6-19

Rat, gavage 0, 100, 300, 1000

Maternotoxicity

300

Developmental

1000

Maternotoxicity

1000 for decreased food intake.

Developmental

No effect of treatment on the mean incidence of external foetal variations and malformations.

Developmental

GD 7-28

Rabbit, gavage 0, 100, 300, 1000

Maternotoxicity/Developmental

1000

No treatment related effects.
Neurotoxicity and immunotoxicity

While no neurotoxic effects were observed in the short-term (28-days) and sub-chronic (90-days) dietary study in rats, the acute oral (gavage) neurotoxicity study identified neuro-functional changes, including decreased locomotor activity at peak effect time at the highest dose level of 2000 mg/kg bw tested in the acute neurotoxicity study, though no treatment-related neuro-histological changes were observed. Overall, when considered with the decreased locomotor activity noted in the rat acute neurotoxicity study in rats, the available data suggests that mandestrobin has mild neurotoxic potential.

Study duration Species & Route Doses
(mg/kg bw/d)
NOEL/NOEC
(mg/kg bw/d)
LOEL & Toxic End-point
(mg/kg bw/d)
28 days (screening study) Rat, dietary

0, 1500, 5000, 15000 ppm

(0, 135, 436, 1340)

Immunotoxicity

15000 ppm

(1340)

Neurotoxicity

15,000 ppm

1200(M)/1305(F)

No treatment-related immunotoxic/neurotoxic effects.
28 days immunotoxicity Rat, dietary

0, 1500, 5000, 15000 ppm

(0, 147, 471, 1419)

Immunotoxicity

15000 ppm

(1419)

No treatment-related immunotoxic effects.
Acute Neurotoxicity Rats, gavage 0, 300, 1000, 2000 2000 No treatment-related neurotoxic effects.
Acute Neurotoxicity Rat, gavage 0, 500, 1000, 2000 1000 2000 for decreased locomotor activity at peak effect time (8 hours post dose on Day 0.
90 days Neurotoxicity Rat, dietary

0, 1500, 5000, 15000 ppm

(Males: 0, 99, 338, 1024)

(Females: 0, 122, 415, 1223)

Females: 15000 ppm (1223)

Males: 5000 ppm (388)

Neurotoxicity

15000 ppm (1024/1223 M/F)

15000 ppm (1024 mg/kg bw/d, males) for significantly decreased bodyweight and bodyweight gain.

No treatment-related neurotoxicity effects observed.

Mode of action (moa)

Mechanistic studies suggest that mandestrobin is a hepatic enzyme inducer via CAR activation in rat similar to phenobarbital.

The applicant has provided discussion and analysis of the MOA data for evaluating higher incidence of ovarian sex-cord stromal tumour in female rats treated with S-2200TG in a 2-year carcinogenicity study. As there was no evidence of interaction with hormone receptors in mechanistic studies, no genotoxic effect, and the top dose level exceeded the maximum tolerated dose in the two-year chronic/carcinogenicity study, the sex-cord stromal lesions and tumours in female rat were not considered toxicologically significant.

Study type Method and doses Results (focussing on liver and thyroid changes) and conclusions
Effects of S-2200TG and its metabolites on human oestrogen receptor alpha and human androgen receptor (Suzuki 2012)

10, 100 pM

1, 10, 100 nM

1, 10 100, µM

No agonist or antagonist effects were observed.

Cytotoxicity apparent in HeLa cells treated with ≥ 6 µM 24 - 48 hours.

Effects of S-2200TG androgen and oestrogen levels in vitro (Kubo 2012)

Steroidogenesis assay

10, 100, 300 nM

1, 3, 10, 30, 100 µM

Cytotoxicity was observed at 100 µM dose level.

No effects on production of oestrogen or testosterone in human adrenocortical cells up to 30 µM in culture.

Dose response, time course, and reversibility for short-term study for mode of action analysis for rat liver and thyroid findings with S-2200TG (Asano 2012e) 0, 400, 2000, 7000, 15000 ppm At the highest dose (15000 ppm), a significant increase in absolute and relative liver weight with diffuse hepatic hypertrophy. Increased CYP2B activity. Increased thyroid weight in females at 7000 and 15000 ppm with diffuse thyroid follicular cell hypertrophy.
Toxicological relevance of liver and thyroid alterations in rats (Yamada 2012a) - Liver is the target organ in all species. Thyroid effects have been observed in the rat, but not in the mouse or dog. The observations in the both the liver and the thyroid have been limited to organ-specific hypertrophy. No carcinogenic findings for either of these target organs have been reported in rat or mouse carcinogenicity studies. Liver and thyroid hypertrophy were induced by S-2200TG treatment in experimental animals, the findings from a MOA analysis allow for the conclusion that S-2200TG does not pose a hazard to humans.
Dose-response, time course and reversibility of alterations at an early phase of treatment with S-2200TG (Yamada 2012b) 7000 ppm No effects on DNA replication in hepatocytes. Significant increase in relative liver weights, CYP2B activity and total liver protein. Visual changes in gross liver pathology in 3/10 treated animals. S-2200 is a weak CAR activator at 7000 ppm.
Interpretation of higher incidence of ovarian sex-cord stromal tumour in female rats treated with s-2200tg in a 2-year carcinogenicity study (Yamada and Miyata 2012) 0, 400, 2000, 7000, 15000 ppm

The aetiology of ovarian tumours (including SCST) may involve hormonal perturbations/interactions. S-2200TG was negative in both an oestrogen receptor reporter gene assay and an assay for steroidogenesis. In addition there was no evidence that S-2200TG causes endocrine disruption, nor was any abnormality observed in the rat reproduction study.

It is unlikely that S-2200 is carcinogenic.

Metabolites toxicology data

None of the metabolites of S-2200; 2-COOH-S-2200, 5-COOH-S-2200, 2-CH2OH-S-2200, 4-OH-S-2200 and De-Xy-S-2200 were considered to be mutagenic. All the metabolites except 5-COOH-S-2200 were of low acute oral toxicity (LD50>2000 mg/kg bw/d). 5-COOH-S-2200 was of moderate acute oral toxicity (300<LD50<2000 mg/kg bw/d).

Observation in humans

No information was provided.

Public exposure

At this time, the proposed agricultural use of mandestrobin is not expected to result in general public (i.e. domestic) exposure. Spray drift considerations have not been considered.

International regulations

Mandestrobin is currently under registration review by the US EPA in a joint review with Health Canada. The EFSA has reviewed mandestrobin as an active constituent, with the peer review document published in 2015.

Scheduling status

MANDESTROBIN is not specifically scheduled.

Scheduling history

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

Delegate's final decision
Schedule 5 - New Entry

MANDESTROBIN except in preparations containing 25 per cent or less of mandestrobin.

Implementation date: 1 June 2016.

The reasons for the final decision comprised the following:

  • The OCS evaluation suggests a low toxicity profile for mandestrobin and the associated product. The delegate notes that moderate eye irritancy is the only toxic endpoint that meets SPF criteria for listing in a Schedule (S5) and that the product containing 25% has no toxicity that merits scheduling. Accordingly, the delegate has determined to make a delegate-only decision, and to list mandestrobin in Schedule 5, with an exemption cut-off at 25%.
  • The delegate considered the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.
Delegates' considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • OCS evaluation report;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors26;
  • Other relevant information.

Footnotes

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

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