Chemical name: N-propyl-N-[2-(2,4,6- trichlorophenoxy)ethyl]imidazole-1-carboxamide trichlorophenoxy)ethyl]imidazole-1-carboxamide

Final regulatory action has been taken for the category: Pesticide

Final regulatory action: The chemical is Banned

Use or uses prohibited by the final regulatory action: All uses.

Pesticide use or uses that remain allowed: None.

The final regulatory action was based on a risk or hazard evaluation: Yes

Summary of the final regulatory action:

Prohibition of all technical and formulated products based on Prochloraz active ingredient.

The reasons for the final regulatory action were relevant to: Human health

Summary of known hazards and risks to human health:

Prochloraz is a non-systemic fungicide that was used in Brazil for foliar application on onion, carrots, barley, watermelon, rose, tomato and wheat and for post-harvest application on papaya and mango. There were three authorized formulations with Prochloraz in Brazil: Sportak 450 EC, Mirage 450 EC and Jade. In 2013 Brazilian Health Regulatory Agency (ANVISA) initiated the toxicological reassessment of Prochloraz due to a court order that suspected of its potential carcinogenic, teratogenic and endocrine-disrupting effects.

Brazilian law predicts that pesticides may have their registrations cancelled in the country when they fall under the following conditions related to human health: when they have no antidote or effective treatment in Brazil; if found teratogenic, mutagenic or carcinogenic; if they cause hormonal disturbances and damage to the reproductive system or if they are more dangerous to humans than demonstrated in tests with laboratory animals.

Hazard assessment

After analyzing studies performed by registrants and from the peer-reviewed scientific literature, ANVISA concluded Prochloraz interferes with the androgen signaling pathway by at least two mechanisms: androgen receptor antagonism and inhibition of steroidogenesis. When only classical parameters of toxicological studies (weight of sexual organs) are considered, the antiandrogenic effects of Prochloraz are observed only at high doses. However, after a more detailed analysis of some recent peer-reviewed articles (Noriega et al., 2005; Vinggaard et al, 2005a; Laier et al, 2006; Blystone et al, 2007a; Blystone et al, 2007b), it can be evidenced that other endocrine-mediated effects, more sensitive to an antiandrogenic mode of action, appear in doses well below the ones that cause changes in the weight of androgen-dependent organs.

Physically observable effects of developmental exposure to Prochloraz, as nipple retention, were observed at 30 mg/kg/day (Noriega et al., 2005; Vinggaard et al, 2005a), a dose about two times higher than the NOAEL from the rat Study of Two Generations (? : 13-16 mg/kg, ? : 14-18 mg/kg) conducted by registrant companies (Cozens et al., 1982). Moreover, Blystone et al (2007a), who evaluated hormonal levels after pubertal exposure (PND 23-42/43) of rats to Prochloraz, have already observed a significant reduction of testicular androstenedione at 7.8 mg/kg; and a significant decrease in serum and testicular testosterone, with a consequent increase in testicular 17α hidroxiprogesterone, at 15.6 mg/kg. Another study by Blystone et al (2007b) evaluated hormonal levels following exposure of rats during the fetal period of differentiation of androgen-dependent tissues (GD 14-18) and found hormonal changes at 7.8 mg/kg, the lower dose tested (significant increase in progesterone and in testicular 17α hydroxyprogesterone). Therefore, Blystone and colleagues (2007a, 2007b) have shown hormonal changes in doses approximately four times lower than those known to cause morphological changes resulting from the antiandrogenic action of Prochloraz. It is worth mentioning that these studies, which evaluated hormonal levels, cover only a short developmental period of the animals, since they aim to determine the Prochloraz mode of action. Thus, it can be expected that longer exposure periods would lead to even more pronounced hormonal changes or that they could be evidenced in even lower doses.

Although at the time of the evaluation, there was still no worldwide consensus on criteria to identify and evaluate the activity of endocrine disruptors (ECETOC, 2011), it was considered that there were three important uncertain aspects of substances with these types of effects, which need to be clarified (EFSA, 2013): (a) exposure to certain substances during critical periods of development can result in irreversible changes in organs/tissues; (B) exposure to multiple substances with endocrine effects can lead to combined toxicity; and (c) there is no consensus in the scientific community about the existence and/or relevance of effects at low doses and non-monotonic dose-response curves in Toxicology.

ANVISA believes that there is no guarantee that the doses of Prochloraz in which endocrine-mediated adverse effects could be observed are not relevant to humans and cannot be achieved in real conditions of use. There are no detailed toxicokinetic data, combined with biomonitoring data on exposed populations, which can provide this information. However, even if such data were available, there is a general uncertainty in the scientific community on the existence of thresholds for endocrine-disrupting effects and on the differences of susceptibility between species during developmental key stages, particularly in cases involving relevant endocrine endpoints to humans, such as those affected by Prochloraz.

ANVISA therefore concluded that Prochloraz causes hormonal disturbances and damages in the reproductive system, at doses that cannot be regarded as irrelevant to humans. Furthermore, exposure to Prochloraz during critical developmental periods of animals leads to particularly adverse irreversible effects, even upon discontinuation of administration of the substance. Additionally, the uncertainties about the possible synergistic effect of mixtures of substances in the environment with similar modes of action lead to regulatory concerns.

Risk assessment

From 2009 to 2014 Prochloraz was monitored by the Brazilian Program on Pesticide Residue Analysis in Food (PARA) in 9,212 samples, distributed in 21 crops. During this period, residues of Prochloraz were detected in 11 cultures (pineapple, lettuce, rice, cabbage, orange, strawberry, cucumber, grape, papaya, mango and tomato), despite having authorized use for only 3 of them (papaya, tomato and mango). Papaya samples had the largest number of detections of Prochloraz (157, ie 15.8% of analysed samples), and even with this crop having a high maximum residue level (1 mg/kg), 10 samples exceeded this limit. 8.5% of strawberry samples had Prochloraz residues, not authorized for this crop. Anvisa performed the risk assessment from acute dietary exposure for each sample in which Prochloraz was detected from 2009 to 2014, considering the Acute Reference Dose (ARfD) of 0.025 mg/kg recommended by EFSA. For the calculation of residue intake, there were used food consumption data and the average body weight of consumers of each crop, extracted from the Brazilian Family Budget Survey (POF / IBGE 2008-2009). 16 samples showed concentrations of Prochloraz above the ARfD (13 of papaya, 1 of citrus, 1 of pineapple and 1 of mango).

Conclusions

Therefore, from the reevaluation of the health effects of Prochloraz, completed in 2016, ANVISA concluded this active ingredient of pesticides causes hormonal disturbances and damage to the reproductive system, which are prohibitive criteria for registration of pesticides in Brazil. Additionally, the risk assessment carried out by ANVISA with Prochloraz monitoring data on food showed risks resulting from acute exposure to this active ingredient. Thus, Prochloraz was banned in Brazil in 2016.

Expected effect of the final regulatory action in relation to human health:

Eliminate the risks posed by Prochloraz.

Date of entry into force of the final regulatory action: 04/02/2016