T- toxicological evaluation; R-residue and analytical aspects
TOXICOLOGY
Pyrethrins (pyrethrum extracts) derived from chrysanthemum flowers of the genus Chrysanthemus have been used as insecticides for a long time. Pyrethrum, the active principle containing pyrethrin isomers, was evaluated toxicologically by the JMPR in 1965, 1966, 1967, 1968, 1969, 1970 and 1972. In 1999, the compound was re-evaluated on the basis of new studies that used a blend of refined pyrethrum extracts from plants in four major growing areas, with a total pyrethrin content of 57.6%. The 1999 JMPR established an ADI of 0-0.04 mg/kg bw on the basis of the NOAEL for liver effects in a new 2-year study in rats, and a safety factor of 100. At the same Meeting, an acute RfD of 0.2 mg/kg bw was established on the basis of the NOAEL in a study of acute neurotoxicity in rats, and a safety factor of 100.
The 1999 JMPR concluded that the increased incidences of liver and thyroid tumours observed in rats are threshold phenomena of negligible relevance to the low doses of pyrethrins to which humans are exposed. In order to confirm this, the Meeting recommended that additional studies be performed to investigate the mechanism by which pyrethrins cause tumorigenesis in the liver and thyroid. The 1999 Meeting also suggested that a test for gene mutation in mammalian cells and more detailed information on case reports of adverse health effects in humans, for which only an abstract was available, should be submitted for evaluation.
The following information was made available to the present Meeting: a new test for gene mutation in mammalian cells, the full report of the mechanistic studies on liver and thyroid tumorigenesis in rats; and the full report of the analysis of case reports of human exposures to consumer products containing pyrethrins and/or pyrethroids.
In the gene mutation test evaluated by the present Meeting, pyrethrins did not induce mutations at the thymidine kinase (TK) locus in mouse lymphoma L5178Y cells. The Meeting reaffirmed the conclusion of the 1999 JMPR that pyrethrins are not genotoxic.
In mechanistic studies of liver and thyroid tumorigenesis, treatment of rats with pyrethrins at doses of 3000 and 8000 ppm for 7, 14 and 42 days resulted in significant induction of a number of hepatic microsomal cytochrome P-450 enzyme activities, thyroxine UDPglucuronosyltransferase activity, decreased T3 and T4 and increased thyroid-stimulating hormone (TSH) activity. Additionally, increased liver and thyroid weights in association with increased BrdU labelling indices in the liver and thyroid, and liver cell and thyroid follicular cell hypertrophy were observed. The studies were somewhat limited in that the choice of doses used did not thoroughly assess the dose concordance of the mechanistic events with the induction of tumours (e.g. a dose of 1000 ppm, which produced thyroid follicular adenoma in the long-term study of carcinogenicity in rats, was not tested). Nonetheless, the Meeting concluded that pyrethrins induce the formation of liver and thyroid tumours by mechanisms that appear to be similar to those used by other non-genotoxic, mitogenic substances, e.g. phenobarbital, which produce tumours in rodents that are not predictive of hazard in humans at relevant exposures. The Meeting thus concluded that the increased tumour incidences caused by pyrethrins are threshold phenomena of negligible toxicological relevance to humans.
Although the data on human exposure (based on case reports of 81 838 patients exposed by a variety of routes to consumer products containing pyrethrins and/or pyrethroids) did not permit ready distinction between exposure to natural pyrethrins and synthetic pyrethroids, important inferences can be made about the safety of pyrethrins. Of 49 331 cases with known medical outcomes, > 90% of patients had symptoms that were unrelated to exposure, were asymptomatic, or reported symptoms of minor severity. Major effects of exposure were reported in 114 cases, but only in 28 cases (including 7 cases of people exposed to pyrethrins) could these be confirmed as major outcomes after thorough review of the case reports. Among these 28 cases, respiratory and neurological symptoms were reported most frequently (18 and 15 cases, respectively). There was no evidence that having a history of asthma was disproportionately associated with major adverse outcomes after exposure to pyrethrins.
Toxicological evaluation
The Meeting concluded that the ADI of 0-0.04 mg/kg bw established by the 1972 JMPR and reaffirmed by the 1999 JMPR, and the acute RfD of 0.2 mg/kg bw established by the 1999 JMPR are supported by the new data.
An addendum to the toxicological monograph was prepared.
RESIDUE AND ANALYTICAL ASPECTS
Pyrethrins were evaluated for residues in a periodic review by the JMPR in 2000. The JMPR recommended withdrawal of the CXL of 3 mg/kg Po for cereal grains because no residue data were available. The 34th Session of the CCPR in 2002 decided to retain the CXL for cereal grains under the periodic review procedure since it was informed by the delegation of Germany that data would be made available. The 2003 JMPR received information on GAP for cereals from the government of Germany. New supervised residue trials for the post-harvest use of pyrethrins on wheat and maize were reported by the manufacturer.
Results of supervised trials on crops
Cereal grains. The current German label indicates that pyrethrins may be applied to stored cereal grains by cold fogging in mills and warehouses either 3 times at 2.4 g ai/100 m3 or 10 times at 0.4 g ai/100 m3. Four supervised trials each were available for stored wheat and maize grains according to maximum German GAP (3 x 2.4 g ai/100 m3). The residues of pyrethrins were <0.05 (3) and 0.19 mg/kg in wheat and <0.05 (3) and 0.05 mg/kg in maize. The combined residues of wheat and maize in rank order (median underlined) were <0.05 (6), 0.05 and 0.19 mg/kg.
The Meeting estimated a maximum residue level of 0.3 mg/kg, an STMR of 0.05 mg/kg and an HR of 0.19 mg/kg for the post-harvest use of pyrethrins on cereal grains, and recommended withdrawal of the existing CXL for cereal grains of 3 mg/kg Po.
Residues in animal commodities
The 2000 JMPR considered that an estimate of maximum residue levels for pyrethrins in animal commodities was impossible because of the lack of adequate animal feeding studies. As cereal grains are feed items, residue concentrations in cereals must be considered in the animal dietary burden calculations when feeding studies with ruminants and poultry become available in the future.
FURTHER WORK OR INFORMATION
Desirable
1. Feeding studies with ruminants (from 2000 JMPR)
2. Feeding studies with laying hens
DIETARY RISK ASSESSMENT
Long-term intake
The International Estimated Daily Intakes (IEDI) of pyrethrins, based on the STMRs estimated by the 2000 and 2003 JMPR for 11 commodities, for the five GEMS/Food regional diets were 1% of the maximum ADI of 0.04 mg/kg bw/day (Annex 3). The Meeting concluded that the long-term intake of residues of pyrethrins resulting from the uses considered by the JMPR is unlikely to present a public health concern.
Short-term intake
The International Estimated Short Term Intake (IESTI) for pyrethrins was calculated for 9 food commodities for which maximum residue levels were estimated by the JMPR in 2000 and 2003 and for which consumption data were available. These results are shown in Annex 4.
The IESTI represented 0-2% of the acute RfD (0.2 mg/kg bw) for the general population and 0-5% of the acute RfD for children. The Meeting concluded that the short term intake of residues of pyrethrins resulting from the uses considered by the JMPR is unlikely to present a public health concern.
