T- toxicological evaluation; R-residue and analytical aspects
TOXICOLOGY
Tebufenozide was first evaluated by the 1996 JMPR, which established an ADI of 0-0.02 mg/kg on the basis of NOAELs for haematotoxicity of 50 ppm, (equal to 1.8 mg/kg bw per day) in a 1-year study in dogs, and 25 ppm (equal to 1.6 mg/kg bw per day) in a two-generation study of reproductive toxicity in rats. At the 1999 JMPR, it was recommended that the acute toxicity of tebufenozide be evaluated as soon as possible. The 2001 JMPR evaluated the acute toxicity of tebufenozide on the basis of the available data. The Meeting established an acute reference dose (RfD) of 0.05 mg/kg bw, on the basis of a NOAEL of 5 mg/kg bw per day for haematotoxicity in a 2-week study in dogs. The Meeting noted that it might be possible to refine this estimate using the results of a study designed specifically for this purpose. After submission of data from such a study, the present Meeting reconsidered the acute RfD for tebufenozide.
Tebufenozide has low acute toxicity in rats and mice after oral (LD50 > 5000 mg/kg bw) or dermal (LD50 > 5000 mg/kg bw) exposure, and in rats after exposure by inhalation (LC50 > 4.3 mg/l air). In short-term studies of toxicity in mice, rats and dogs, the main effect was haematotoxicity, with signs of regenerative haemolytic anaemia and compensatory responses in haematopoietic tissues, accompanied by the formation of methaemoglobin. The dog was the most sensitive species, males showing slightly greater changes in several parameters than females (methaemoglobin, reticulocytes and Heinz bodies).
In the study evaluated by the present Meeting, male beagle dogs received tebufenozide in the diet such that intakes of 21.9 and 89 mg/kg bw were achieved. Animals were permitted 9 h to consume the test meal. The diet was not tested for homogeneity, stability or concentration of the test substance, but given the duration of the treatment period, this was not considered to be a serious limitation of the study. No necropsy or histopathology was undertaken but the study design was adequate for the evaluation of the acute haematotoxicity of tebufenozide (see general item 2.2 above). Blood samples were taken before, and 2, 8 and 15 days after exposure to tebufenozide. Treatment with tebufenozide had no significant effect on clinical signs or haematological parameters, including reticulocyte numbers or concentrations of serum total bilirubin. The NOAEL was 89.4 mg/kg bw, the highest dose tested.
In studies evaluated previously by the Meeting, it had been concluded that tebufenozide and its metabolites are not genotoxic. It was also concluded that tebufenozide is not embryo- or fetotoxic, or teratogenic in rats or rabbits at doses of up to 1000 mg/kg bw per day.
Toxicological evaluation
The Meeting considered that the above study in dogs was adequate for the establishment of an acute RfD for tebufenozide. Accordingly, an acute RfD of 0.9 mg/kg bw was established, based on a NOAEL of 89.4 mg/kg bw (the highest dose tested) and a safety factor of 100.
An addendum to the toxicological monograph was prepared.
RESIDUE AND ANALYTICAL ASPECTS
At the 35th Session of the CCPR, the Delegation of Australia requested the JMPR to consider the extrapolation of recommendations for MRLs for tebufenozide in cattle commodities to all mammalian species.
The Meeting recalled that tebufenozide was evaluated by the JMPR in 2001, while in 2002 the Meeting decided that it would generally use cattle feeding studies to estimate maximum residue levels for mammalian commodities to cover the potential exposure of an animal to a pesticide in the diet (Item 2.11, Report 2002). With hindsight, the case of tebufenozide was not consistent with this approach.
The Meeting recommended the withdrawal of the draft MRLs for cattle kidney (0.02* mg/kg), cattle liver (0.02* mg/kg), cattle meat (fat) (0.05 mg/kg) and cattle milk (0.01* mg/kg), to be replaced by recommendations of 0.02* mg/kg for edible offal (mammalian), 0.05 mg/kg (fat) for meat (from mammals other than marine mammals) and 0.01* mg/kg for milks.
DIETARY RISK ASSESSMENT
Long-term intake
The International Estimated Daily Intakes of tebufenozide for the five GEMS/Food regional diets, based on the STMRs estimated for 43 commodities by the 1996, 1997, 1999, 2001 and present Meeting, were in the range of 1 to 20% of the ADI (Annex 3). The Meeting concluded that the long-term intake of residues of tebufenozide resulting from its uses that have been considered by JMPR is unlikely to present a public health concern.
Short-term intake
In the 2001 Meeting, International Estimated Short Term Intake (IESTI) calculations showed an exceedence of the acute RfD for leafy vegetables, cabbage, pomefruit and grapes. In the present Meeting, based on a study better suited to assess acute toxic affects, the acute RfD of 0.05 mg/kg bw was refined to 0.9 mg/kg bw (see Toxicology comments). Therefore the IESTIs for tebufenozide were recalculated for the food commodities for which maximum residue levels were estimated and for which consumption data were available. The results are shown in Annex 4.
The IESTI represented 0-10% of the acute RfD for the general population and 0-40% of the acute RfD for children. The Meeting concluded that the short-term intake of residues of tebufenozide resulting from its uses that have been considered by JMPR is unlikely to present a public health concern.
