Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

105 Toxicokinetics

Generally, glycol ethers and their acetates are readily absorbed and distributed throughout the body following inhalation or oral administration and no substantial accumulation of the parent compound has been observed (ECETOC 1995).

No in vivo dermal absorption data were found in the literature for DPGME, but toxic effects observed in rabbits and rats after dermal application of the substance indirectly indicate skin uptake (Rowe et al. 1954).

Propylene glycol ethers follow the following major metabolic pathways:

Beta isomers, which are primary alcohols, are oxidised to carboxylic acids. Alpha isomers, being secondary alcohols, are oxidised to carbon dioxide after cleavage of the ether bond and O-demethylation. Both alpha and beta isomers are in addition conjugated with sulphate and glucuronic acid. (A&H 1990).

Commercial information from manufacturers states compositions of DPGME to be:

50-55% 1-(2-methoxy-1-propoxy)-2-propanol (CAS no. 13429-07-7),

40-45%1-(2-methoxy-1-methylethoxy)-2-propanol (CAS no. 20324-32-7),

3-5% 2-(2-methoxy-1-methylethoxy)-1-propanol (CAS no. 55956-21-3) and

2-5% 2-(2-methoxy-propoxy)-1-propanol (CAS no. 13588-28-8) (BUA 1995). Miller states that commercial grade DPGME in the US contains at least 95% of the two first-mentioned isomers (Miller 1987).

Analysis of a DOW DPGME-product showed predominance of CAS no. 13429-07-7 (approximately 85%), and only up to 1.6% of each of the primary alcohols (A&H 1990).

Primary alcohol isomers of DPGME, are theoretical substrates for alcohol dehydrogenase with the formation of methoxypropionic acid (ECETOC 1995). However, excretion of methoxypropionic acid in rat urine was not observed in metabolic studies with DPGME (Breslin et al. 1996).

The distribution, metabolism and excretion of DPGME were investigated in three rats dosed orally with 8.7 mmol (1289 mg/kg) radio-labelled material. 60 % of the radioactivity was eliminated in urine, the vast majority (54.3 %) being recovered during the first 24 h after dosing. 27% was recovered in the expired air as ¹⁴CO₂. 2.7% was excreted in faeces, and less than 3% remained in the carcass after 48 h. Levels of ¹⁴C in the liver (0.5%) and the skin (1.3%) were higher than in other organs and tissues (kidney, blood, brain and fat). There were no indications of accumulation of radioactivity in adipose tissue, testes or main body tissues. The urine metabolites were identified to be propylene glycol methyl ether and dipropylene glycol (jointly making up 28.8% of the dose) and propylene glycol (9.6%). Sulphate and glucuronide conjugates accounted for respectively 9 and

9.6% of the given dose. 3% of the dose was found in urine as the unchanged parent compound. The authors concluded that microsomal O-demethylation is a significant route of bio-transformation of DPGME. (Miller et al. 1985).

105.1 Mode of action

Propylene glycol ethers and their acetates only show developmental toxicity if the ether bond is present on the secondary carbon atom (e.g. 1PG2ME, 1PG2EE); this allows the primary alcohol to be oxidised to an alkoxypropionic acid. Propylene glycol ethers with the ether bond on the primary carbon atom (e.g., 2PG1ME, 2PG1EE) are secondary alcohols and are not metabolised to alkoxypropionic acids; these ethers and their acetates have not shown developmental toxicity. (ECETOC 1995).

DPGME contains four isomers, a small percentage of which are primary alcohols which could be metabolised to the toxic metabolite methoxypropionic acid (ECETOC 1995). However, metabolic studies carried out with DPGME did not identify the formation of methoxypropionic acid in rat urine (Breslin et al. 1996).