Risk Assessment of the Plant Protection Product PROMAN – with the Active Ingredient Metobromuron

ABSTRACT

Proman is a new product containing the active substance metobromuron. The intended use is as a broad spectrum selective herbicide for potatoes grown outdoors. VKM’s Panel on Plant Protection Products has discussed the questions raised by The Norwegian Food Safety Authority in the Terms of reference and has stated the following opinion On the relevance of the carcinogenic effects observed in the rat carcinogenicity study; fibrosarcomas in females and pheochromocytomas and Leydig cell tumours in males It is the opinion of VKM’s Panel for Plant Protection Products that the relevance of the observed incidence in mammary gland tumours and Leydig cell tumours in the rat carcinogenicity study is strengthened by the fact that the tumours are observed in hormone responsive tissues. The panel concludes that the carcinogenic effects observed in the rat carcinogenicity study are likely to be relevant for tumours that are influenced by the endocrine system, also in humans. On the higher incidences of still dumbbell-shaped centres of thoracic vertebrae and nonossification of the 13th rib observed in the rat developmental toxicity study and whether these are considered to be malformations VKM’s Panel on Plant Protection Products has discussed the classification of the different types of incomplete ossifications and concluded that incomplete ossification of sternebrae and non-ossification of the 13th rib in rats should by itself be considered to be variations, and not adverse developmental effects. On the other hand, the Panel agrees with ECHA that the “thoracic vertebral centres still dumbbell-shaped” should be considered as malformations, due to limited data and understanding of the mechanism underlying the observed slow reversal of these anomalies. Furthermore, it is the view of the Panel that the different types of retarded ossification induced by the exposure of metobromuron should be considered as a whole when assessing for developmental effects. On the establishment of the NOAEL for the developmental toxicity study in rats and the reference value (ARfD) VKM’s Panel on Plant Protection Products supports the proposal of an ADI value of 0.008 mg/kg bw/day based on a NOAEL of 0.8 mg/kg bw/day from the 2-year study in mouse, and VKM Report 2015 03 5. AOEL of 0.016 mg/kg bw/day based on the NOAEL of 1.6 mg/kg bw/day from the 1-year feeding study in dog. An UF of 100 is applied. The panel suggests on the other hand an ARfD of 0.03 mg/kg bw based on a LOAEL of 10 mg/kg bw /day with the observations of incomplete ossification in the rat developmental study. An UF of 300 is applied. On the possible anti-androgenic potential of metobromuron It is the view of the Panel that the rat carcinogenicity study suggests that metobromuron may possess endocrine disrupting potency. The data from the Hershberger in vivo rat study and the in vitro studies is also suggestive of a weak anti-androgenic effect. Thus, it is the opinion of the VKM Panel on Plant Protection Products that an anti-androgenic effect of metobromuron cannot be excluded.