Propyzamide still safe for use in Australia according to the Australian Pesticides and Veterinary Medicines Authority

Australia’s pesticides and herbicides authority says the environmental chemical agent propyzamide remains safe for use as an active ingredient in herbicides in Australia.

This follows the release of a study last month in Nature that found propyzamide amplifies (but does not initiate) intestinal inflammation and could promote inflammatory bowel disease (IBD).

Read here: Scientists identify a readily available herbicide which might lead to IBD.

The Australian Pesticides and Veterinary Medicines Authority (APVMA) is responsible for assessing and registering agricultural and veterinary (agvet) chemicals for use in Australia.

Cosmos asked the APVMA if it was aware of the new research and whether it would impact the regulation of propyzamide in Australia?

A spokesperson for APVMA told Cosmos: “Products registered by the APVMA have been assessed against the statutory criteria – including safety, efficacy and trade – to protect Australia’s trade and the health and safety of people, animals and the environment.

“The Australian Pesticides and Veterinary Medicines Authority’s (APVMA) scientific staff, including senior toxicologists, conduct regular scans of scientific literature to identify new information associated with the safety and effectiveness of registered agricultural and veterinary chemicals.

“For the Nature study specifically, it was identified and reviewed by the APVMA’s relevant in-house expert, who is familiar with the new assessment methodologies utilised. Following their review, the expert’s opinion was that no further action was required at this time.”

So, how is propyzamide registered with APVMA?

According to the APVMA safety criteria, the use of a chemical product – in accordance with instructions approved by APVMA – is not or would not be:

• an undue hazard to the safety of people exposed to the product during its handling or people using anything containing its residues;
• likely to have an effect that is harmful to human beings;
• likely to have an unintended effect that is harmful to animals, plants or the environment.

“The APVMA uses a scientific, evidence-based approach and aligns its regulatory efforts with the risks associated with each active constituent or product. Risks are considered in terms of both the likelihood of exposure and the potential effects of exposure, and the label is used to communicate safe use,” an APVMA spokesperson said in an email to Cosmos.

“The current health-based guidance values for propyzamide, established in 2018, followed consideration of a range of studies in animals, are protective of the Australian population and can be found on the APVMA website.”

Those guidance values are as follows:

Chemical	ADI (mg/kg bw/d)	NOAEL (mg/kg bw/d)	Date	Study	Comments
Propyzamide	0.04	40 [LOAEL]	11 December 2018	Point of departure was derived using a weight of evidence approach based on:   Acute neurotoxicity LOAEL of 40 mg/kg bw in rats due to increased landing foot splay and decreased motor activity. Subchronic neurotoxicity NOAEL of 2.4 mg/kg bw/d based on decreased body weight and food consumption in males at the next highest dose. Chronic toxicity NOAEL of 8.5 mg/kg bw/day with hepatotoxicity, thyroid lesions and ovarian lesions occurring at higher doses.	Total uncertainty factor used was 1,000.

Toxicology is the field of science that helps us understand the harmful effects that chemicals can have on people, animals, and the environment. In toxicology, when plotting the relationship between the dose of a chemical and the response to it on a graph, the “point of departure” (POD) is the point on the curve on the graph that generally corresponds to an estimated no or low level of effect.

No-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) are both points of departure and are determined through experiments or observation.

The NOAEL is the level of exposure for an organism at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effects.

The LOAEL is the lowest amount of an ingested substance that causes an adverse alteration of morphology, function, capacity, growth, development, or lifespan of an organism, compared to normal organisms of the same species under defined conditions of exposure.

APVMA used a weight of evidence approach – gathering and assessing all available toxicological studies – to identify the LOAEL for propyzamide. The LOAEL is 40 mg of propyzamide per kilogram of body weight administered per day.

This number is then used to estimate the amount of propyzamide that can be ingested daily over a lifetime by humans without appreciable health risk – the Acceptable Daily Intake (ADI). In calculating the ADI, the LOAEL is divided by a safety or uncertainty factor that accounts for uncertainties in extrapolating animal data to humans, variation between humans, and the completeness of the toxicological database.

In the case of propyzamide, the uncertainty factor used was 1,000, taking into account that: humans may be 10 times more sensitive to propyzamide than rats; a proportion of the population may be 10 times more sensitive to propyzamide than the average person; and that the toxicity database is incomplete (no NOAEL has been identified in a pivotal study).

So, the ADI for propyzamide is 0.04 mg per kg of body weight administered per day. This is the same as determined by the United States Environmental Protection Agency.

Earlier this year the European Food Safety Authority (EFSA) completed a peer review of the pesticide risk assessment for propyzamide and found that the genotoxicity – ability to cause damage to genetic information in cells – of two of the products of its metabolic break-down could not be ruled out and further experimental data is needed.

Why is no further APVMA action needed for propyzamide?

The new Nature study found that administration of 100 mg of propyzamide per kg of body weight per day resulted in worsening of TNBS-induced intestinal inflammation in mice.

(TNBS) induced colitis is a chemically induced colitis animal model widely used in scientific research. So, there is a role for propyzamide in the amplification, but not the initiation, of intestinal inflammation.

But the amount administered daily to the mice in the study which caused this affect – 100 mg/kg – is greater than the LOAEL (40 mg/kg bw/d) and ADI (0.04 mg/kg bw/d) for propyzamide used by the APVMA to determine instructions for its safe use.

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