Toltrazuril
(endorsed 2011)
Guideline
Based on human health concerns, toltrazuril in drinking water should not exceed 0.004 mg/L.
Related chemicals
Toltrazuril (CAS 69004-03-1) belongs to the triazinetrione class of chemicals. There are no other pesticides in this class (Tomlin 2006).
Human risk statement
With good water quality management practices, the exposure of the general population is expected to be well below levels that may cause health concerns.
If present in drinking water as a result of a spillage or through misuse, toltrazuril would not be a health concern unless the concentration exceeded 0.004 mg/L. Excursions above this level even for a relatively short period are of concern, as the health-based guideline is partially based on short-term effects.
With good water quality management practices, pesticides should not be detected in source waters used for drinking water supplies. Persistent detection of pesticides may indicate inappropriate use or accidental spillage, and investigation is required in line with established procedures in the risk management plan for the particular water source.
General description
Uses: Toltrazuril is a coccidiostat for the control of protozoa infection (coccidiosis) in poultry, young cattle and piglets.
There are registered products that contain toltrazuril in Australia. The products are intended for professional use and are available as concentrated formulations to be applied to drinking water and feed provided to animals. Data on currently registered products are available from the Australian Pesticides and Veterinary Medicines Authority.
Exposure sources: The main source of public exposure to toltrazuril is residues in food. Residue levels in food produced according to good agricultural practice are generally low.
The veterinary use of toltrazuril provides some potential for contamination of drinking water through the washing of equipment near dams, streams or watercourses.
Typical values in Australian drinking water
No published reports on toltrazuril occurrence in Australian drinking water supplies were found. However, there is an identified risk that toltrazuril may reach groundwater after spreading of contaminated poultry manure on agricultural land. (EMEA 2008).
Treatment of drinking water
There is insufficient information on the treatment of toltrazuril in drinking water, but it is expected that advanced treatment methodologies such as ozonation, reverse osmosis and advanced oxidation would be effective.
Measurement
Toltrazuril is a veterinary product and the majority of analytical methods have been developed to determine residue concentrations in animal tissues. A high performance liquid chromatography (HPLC) analytical method based on fluorescence detection has been used to determine toltrazuril concentrations in tissues and plasma (EMEA 2008). Determination of toltrazuril in eggs by HPLC with ultraviolet detection or HPLC with tandem mass spectrometric detection can achieve a limit of quantitation of 30 µg/kg and 1 µg/kg respectively (Mulder et al. 2004). No published reports on methods for analysis of toltrazuril in drinking water were found.
History of the health values
The current acceptable daily intake (ADI) for toltrazuril is 0.01 mg per kg of bodyweight (mg/kg bw), based on a lowest-observed-effect level (LOEL) of 1 mg/kg bw/day from a 2-year dietary study in rats. The LOEL is based on the occurrence of pre-neoplastic uterine lesions. The ADI incorporates a safety factor of 100, and was first established in 1993.
A health value has not been previously established by NHMRC.
Health considerations
Metabolism: Toltrazuril is rapidly and moderately well absorbed via the gastrointestinal tract. It is extensively metabolised by sulfoxidation of the trifluoromethyl-thio group to form sulfoxide and sulfones. Excretion is in faeces and urine, and is almost complete within 7 days.
Acute effects: Toltrazuril has low acute oral and dermal toxicity. It is not a skin sensitiser.
Short-term effects: In 3-month dietary studies in rats and dogs, there was anaemia and organ weight changes (testes, liver and kidney) at 4.2 mg/kg bw/day in rats and dogs; decreased prostate weights at 13.5 mg/kg bw/day in dogs; and decreased bodyweight gain and effects on the liver at 16.6 mg/kg bw/day in rats.
Long-term effects: Long-term dietary studies were conducted in mice and rats. In rats, there was an increased incidence of pre-neoplastic nodular changes in the uterus at 1 mg/kg bw/day and decreased bodyweight gain and increased uterine fluid and distension of the uterus at 3 mg/kg bw/day. In mice, anaemia was seen at 41 mg/kg bw/day. No other effects were seen. The LOEL of 1 mg/kg bw/day is the basis for the current ADI.
Carcinogenicity: There was an increase in pre-neoplastic lesions in the rat uterus at the lowest dose tested of 1 mg/kg bw/day and above. This dose level is well in excess of the likely level of human exposure. Uterine adenomas were observed at the next highest dose tested of 3 mg/kg bw/day and above.
Genotoxicity: Toltrazuril is not considered to be genotoxic, based on in vitro and in vivo short-term studies.
Reproductive and developmental effects: A 2-generation reproduction study in rats reported evidence of maternotoxicity (decreased bodyweight gain) and pup toxicity (increased pup mortality and decreased bodyweight gain) at 4 mg/kg bw/day. A developmental toxicity study in rabbits reported maternotoxicity, and increased foetal death and abortion rates at 3 mg/kg bw/day, but no evidence of teratogenicity.
Poisons Schedule: Toltrazuril is included in Schedule 5 of the Standard for the Uniform Scheduling of Medicines and Poisons No.1, 2010 (the Poisons Standard)(DoHA 2010). Current versions of the Poisons Standard should be consulted for further information.
Derivation of the health-based guideline
The health-based guideline of 0.004 mg/L for toltrazuril was determined as follows:
where:
1 mg/kg bw/day is the LOEL based on a long-term (2-year) dietary study in rats, and is the NOEL from the reproduction study in rats and the developmental toxicity study in rabbits.
70 kg is taken as the average weight of an adult.
0.1 is a proportionality factor based on the assumption that 10% of the ADI will arise from the consumption of drinking water.
2 L/day is the estimated maximum amount of water consumed by an adult.
1000 is the safety factor applied to the NOEL derived from animal studies. This safety factor incorporates a factor of 10 for interspecies extrapolation and 10 for intraspecies variation, with an additional safety factor of 10 to account for the uncertainty in the ADI, which is based on a LOEL for pre-neoplastic uterine lesions.
References
NOTE: The toxicological information used in developing this fact sheet is from reports and data held by the Department of Health, Office of Chemical Safety.
DoHA (2010) The Poisons Standard; Schedule 1-Standard for the Uniform Scheduling of Medicines and Poisons, Department of Health and Ageing, Commonwealth of Australia, Canberra.
EMEA (European Medicines Agency) (2008). Committee for Medicinal Products for Veterinary Use – Opinions on Veterinary Medicinal Products. Lomdon.
Mulder PPJ, Balzer-Rutgers P, Brinke EM, Bolck YJC, Berendsen BJA, Gerçek H, Schat B, JA v Rhijn (2004). Deposition and depletion of the coccidiostats toltrazuril and halofuginone in eggs. Analytica Chimica Acta, 29(1-2):331-337.
Tomlin CD (ed) (2006). The Pesticide Manual: a world compendium, 14th Edition, British Crop Production Council, UK.
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