Molinate

(endorsed 2011)

Guideline

Based on human health concerns, molinate in drinking water should not exceed 0.004 mg/L.

Related chemicals

Molinate (CAS 2212-67-1) belongs to the thiocarbamate class of pesticides. Other herbicides in this class include EPTC, methiobencarb, pebulate, thiobencarb and vernolate (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, molinate would not be a health concern unless the concentration exceeded 0.004 mg/L. Excursions above this level even for a short period are of concern as the health-based guideline is 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: Molinate is a post-emergence herbicide for the control of grass weeds in rice only.

There are registered products that contain molinate in Australia. The products are intended for professional use. The chemical is available as concentrated solutions to be applied in diluted or undiluted form to rice crops soon after sowing. It may be applied by aerial application, or directly to flooded rice bays by drip applicators mounted on a tractor or a four-wheel drive spray bike. Data on currently registered products are available from the Australian Pesticides and Veterinary Medicines Authority.

Exposure sources: The possible sources of public exposure to molinate and its metabolites are residues in rice and drinking water. Residue levels in rice produced according to good agricultural practice are generally low and maximum residue limits (MRLs) are at the level of detection.

The agricultural use of molinate involves direct application into water bays of rice crops, which may then enter source waters for drinking water.

Typical values in Australian drinking water

Molinate was the most commonly applied herbicide to rice crops in southern New South Wales in 1994-1995. It was detected in irrigation drains after application to rice fields at levels up to 0.7 mg/L (Bowmer et al. 1998). Molinate was detected on two occasions in the Mulwala supply offtake on the Murray river, at 0.0072 and 0.0005 mg/L (7.2 and 0.5 µg/L). Over a 55-day period of monitoring supply water in the irrigated areas, molinate was found in 90% of the analysed samples, with a maximum concentration of 0.0036 mg/L (3.6 µg/L) (Bowmer et al. 1998). The high frequency of molinate detection was due to samples being taken in early summer, when the herbicide is used in rice crops.

Rice-growing areas are within the Murray Darling Basin on the Murrumbidgee and Murray rivers in south-western New South Wales and Victoria. Molinate has been detected in the Coleambally irrigation area, Murrumbidgee region, New South Wales and Murray irrigation area (Ball 2001).

Treatment of drinking water

Ozonation, granular activated carbon, preoxidation by chlorine and preoxidation by chlorine combined with activated carbon adsorption removes 100% of molinate during drinking water treatment (Ormad et al. 2008).

Measurement

Capillary gas chromatography with a selective nitrogen–phosphorus detector for the determination of molinate can achieve a limit of quantitation (LOQ) of 0.03 µg/L (Worthing and Hance 1991). United States Environmental Protection Agency (USEPA) method 525.2 for the determination of organic compounds in drinking water by liquid-solid extraction and capillary column gas chromatography–mass spectrometry (GC/MS) can achieve a LOQ of 0.05 µg/L to 0.087 µg/L for molinate (Munch 1995a). USEPA method 507 can achieve a LOQ of 0.15 µg/L (Munch 1995b). Molinate can be extracted from water by liquid/liquid extraction with dichloromethane and analysed by gas chromatograpy–mass spectometry in selected ion monitoring mode, with a LOQ of 0.5 µg/L. Liquid chromatography–mass spectrometry with direct injection can achieve a LOQ of 2.2 µg/L (Yu et al. 2003). Solid phase extraction and high performance liquid chromatography with ultraviolet detection can achieve a LOQ of 0.1 µg/L. Solid phase micro extraction followed by gas liquid chromatography employing either a nitrogen-phosphorus detector or mass spectrometry can achieve LOQ of 0.11 µg/L and 0.02 µg/L respectively (Choudhury et al. 1996).

History of the health values

The current acceptable daily intake (ADI) for molinate is 0.002 mg per kg of bodyweight (mg/kg bw), based on a no-observed-effect level (NOEL) of 0.2 mg/kg bw/day from a 3-generation rat reproduction study. The NOEL is based on reduced litter numbers, litter size and pup survival at the next highest dose of 0.63 mg/kg bw/day. The ADI incorporates a safety factor of 100, and was established in 1986.

The previous ADI of 0.0001 mg/kg bw established in 1984 was based on the same NOEL of 0.2 mg/kg bw/day from the 3-generation rat reproduction study, but included a safety factor of 2000 due to the absence of long-term studies. Following the review of long-term studies in 1986, the NOEL of 0.2 mg.kg bw/day remained the lowest available, but the safety factor was reduced to 100 and the current ADI was established.

The previous health value was 0.005 mg/L (NHMRC and NRMMC 2004).

Health considerations

Metabolism: Molinate is readily and extensively absorbed via the gastrointestinal tract in rats. It is metabolised to more polar products such as molinate sulfoxide (35%) and hydroxymolinate (26%). The majority of an administered dose is excreted within 48 hours, with 82% in urine, 11% in faeces and less than 1% expired as carbon dioxide.

Acute effects: Molinate is of moderate acute oral toxicity and low dermal toxicity. It is not a skin sensitiser.

Short-term effects: A 3-week dietary study in rats reported weakness in the hind limbs, and depressed bodyweight and food consumption at 80 mg/kg bw/day. Interference in blood clotting occurred at higher dose levels. Three-month dietary studies in rats reported pathological changes in the liver, kidney, testis, ovary and adrenal glands at 70 mg/kg bw/day. In 3-month dietary study in dogs, there were increases in thyroid gland weight at 60 mg/kg bw/day.

Long-term effects: Long-term dietary studies in rats reported increased testes weight at 2 mg/kg bw/day and above, and decreased bodyweight gain and increased kidney weight at 6 mg/kg bw/day.

Carcinogenicity: Based on a 2-year study in rats, there is no evidence of carcinogenicity for molinate.

Genotoxicity: Molinate is not considered to be genotoxic, based on in vitro and in vivo short-term studies.

Reproductive and developmental effects: A 3-generation reproduction study in rats noted a reduction in the number of litters, with an associated reduction in litter size and pup survival, in all generations at the highest dose, 0.63 mg/kg bw/day. No effects were noted at the next lowest dose, 0.2 mg/kg bw/day. This NOEL is the basis for the ADI. Further detailed studies have shown that molinate causes infertility in rats through its effects on sperm membranes, interfering with sperm maturation and causing some degeneration of seminiferous tubules.

In a developmental toxicity study in mice, there were no effects on foetal development. In rabbits, there were maternotoxic and foetotoxic effects at dose levels well in excess of the likely level of human exposure. There were no teratogenic effects in the rabbit. Developmental and reproduction studies in rats evaluated by the USEPA (not evaluated in Australia) have reported effects on brain weight at 0.4 mg/kg bw/day and on reproductive parameters at 0.2 mg/kg bw/day (USEPA 2002).

Neurotoxicity: Degeneration and demyelination of the sciatic nerve (combined with muscle atrophy) in a long-term study in rats have been reported at the lowest dose of 0.3 mg/kg bw/day by the USEPA (not yet evaluated in Australia).

Poisons Schedule: Molinate is included in Schedule 7 of the Standard for the Uniform Scheduling of Medicines and Poisons No.1, 2010 (the Poisons Standard)(DoHA 2010), with an Appendix J rider limiting availability to authorised or licensed persons. 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 molinate was determined as follows:

$$\text{ 0.004 mg/L } = \dfrac{\text{ 0.2 mg/kg bodyweight/day x 70 kg x 0.1 }}{\text{ 2 L/day x 200 }}$$

where:

• 0.2 mg/kg bw/day is the NOEL based on a 3-generation reproduction study in rats.

• 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.

• 200 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 factor of 2 to take into account the uncertainty resulting from the new data on neurotoxicity and developmental effects, which have yet to be evaluated in Australia.

The World Health Organization has a health-based guideline value of 0.006 mg/L for molinate (WHO 2004).

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.

Ball J (2001). Australia State of the Environment Report 2001 Inland Waters Theme Report. CSIRO on behalf of the Department of the Environment and Heritage.

Bowmer KH, Korth W, Scott A, McCorkelle G, Thomas M (1998). Pesticide Monitoring in the Irrigation Areas of South-Western NSW 1990-1995. CSIRO Land and Water, Canberra, Australia.

Choudhury TK, Gerhardt KO, TP Mawhinney (1996). Solid-phase microextraction of nitrogen- and phosphorus-containing pesticides from water and gas chromatographic analysis. Environmental Science and Technology, 30(11):3259–3265.

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.

Munch JW (1995a). Method 525.2 Determination of Organic Compounds in Drinking Water by Liquid-Solid Extraction and capillarity Columns Gas Chromatography/Mass Spectrometry Revision 2.0. Environmental Monitoring Systems Laboratory, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, Ohio.

Munch JW (1995b). Method 507 Determination of Nitrogen and Phosphorus Containing Pesticides in Water by Gas Chromatography with a Nitrogen Phosphorus Detector. National Exposure Research Laboratory, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, Ohio.NHMRC (National Health and Medical Research Council), NRMMC (Natural Resources Management Ministerial Council) (2004). Australian Drinking Water Guidelines. National Water Quality Management Strategy, Paper 6. NHMRC and NRMMC.

Ormad MP, Miguel N, Claver A, Matesanz JM, Ovelleiro JL (2008). Pesticides removal in the process of drinking water production. Chemosphere, 71(1):97-106.

Tomlin CD (ed) (2006). The Pesticide Manual: a world compendium, 14th edition, British Crop Production Council, UK.

USEPA (United States Environmental Protection Agency) (2002) Molinate: Reregistration Eligibility Decision (RED). USEPA, Washington DC.

WHO (World Health Organization) (2004). Guidelines for Drinking-water Quality. 3rd Edition, WHO, Geneva, Switzerland.

Worthing CR, Hance RJ (eds) (1991). The Pesticide Manual, 9th Edition. British Crop Protection Council, Farnham, Surrey.

Yu K, Krol J, Balogh M, Monks I (2003). A fully automated LC/MS method development and quantification protocol targeting 52 carbamates, thiocarbamates, and phenylureas. Analytical Chemistry, 75(16):4103-12.