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Report on the Health Effects of Selected Pesticide Coformulants

4 Discussion

The results of this project on hazard assessment of 18 selected coformulants give information on two levels: data availability and toxicological effects observed for the 18 substances according to the public available literature.

4.1 Data availability on the selected coformulants

The literature searches performed on the 18 coformulants clearly demonstrate, that the toxicological database for this class of substances is limited.

Data are available on all end-points (acute toxicity, irritation, sensitisation, repeated dose toxicity, toxicity to reproduction, mutagenicity and genotoxicity, and carcinogenicity) for 8 substances: Hexamethylenetetramine, isopropyl myristate, ethylene glycol (EG), propylene glycol (PG), ethylene glycol mono-n-butyl ether (EGBE), 1-methoxy-2-propanol (2PG1ME), cyclohexanone, and 1-methyl-2-pyrrolidone (NMP).
For 6 substances, data are available on four to six end-points: Manganese (II) sulphate / manganese (II) sulphide, dimethyl ether (DME), diammonium sulphate, diethylene glycol mono-n-butyl ether (DEGBE), dipropylene glycol monomethyl ether (DPGME), and 4-hydroxy-4-methyl-2-pentanone (HMP).
For 3 substances, the data are limited to a few information about one to three end-points: sodium ligninsulphonate, calciumdodecylbenzene sulphonate (CaDBS), and polyethylene glycol dodecyl ether (polyEGDE).
For 1 substance, no relevant data were found at all: 1-methyl-1,2-ethanediyl dioleate.

Human data are available for 16 of the selected substances; however for most of these substances, the data are scarce. The 2 substances for which no human data were found are sodium ligninsulphonate and CaDBS. For one substance (1-methyl-1,2-ethanediyl dioleate), the human data are not considered as being relevant for the hazard assessment of this substance. For most of the substances, data have been found primarily on irritative effects (14 substances), and in some cases also on acute toxic effects (7 substances). Reports on skin sensitisation in humans are present for 9 substances, but most of these are case reports on very few individuals; for one of these substances (hexamethylenetetramine), data on sensitisation by inhalation is also available. Human data were found on effects following repeated exposure for 7 substances, while reporting on toxicity to reproduction is only available for two substances. No data are available in humans for mutagenicity and genotoxicity, or for carcinogenicity.
The available human data are in most cases obtained from case reports (e.g., poisonings), clinical examinations, studies on volunteers, and experiences from the working environment; no epidemiological studies have been located for any of the substances. For the major part of substances and end-points, the information is qualitative and do not relate to specific exposure levels. Furthermore, the data are often not very well reported, and mixed exposures cannot always be excluded. Consequently, a hazard assessment could not be performed for any of the selected substances based on the human data only.

Animal data are available for all of the 18 substances, but one (1-methyl-1,2-ethanediyl dioleate). For one substance (CaDBS), the animal data are not specifically describing the selected substance, but a mixture (LAS) containing the substance, and the relevance of the data is therefore questionable. For the remaining substances, animal data are available on acute toxicity (16 substances) and local irritation (15 substances). Data for sensitisation are very scarce, with only 7 substances reported tested for skin sensitisation. Repeated dose toxicity data are available for 15 substances and data for toxicity to reproduction are available for 12 substances. In vitro mutagenicity/genotoxicity data are available for 15 substances and in vivo genotoxicity tests for 10 substances. Data on carcinogenicity in animals are available for 10 substances.
A large number of the available animal studies have been performed many years ago and therefore not in accordance with GLP or with agreed test guidelines as e.g., OECD test guidelines or the testing methods (Annex V Part B) adopted within the EU. The reporting of the studies is in many cases not appropriate, leaving out some information that would have been useful for the interpretation of the results. For several of the substances, most of the various end-points have not been examined thoroughly and therefore, data gaps exist. The problem of data gaps is most important for end-points such as sensitisation, repeated dose toxicity, toxicity to reproduction, in vivo mutagenicity/genotoxicity, and carcinogenicity.
The relatively high percentage of data on developmental toxicity and/or adverse effects on fertility may be due to the overrepresentation of glycol ethers, a chemical class including known reproductive toxicants.
The selected coformulants used in low tonnage are poorly documented with respect to effects following repeated administration, e.g. polyEGDE, HMP, and 1-methyl-1,2-ethanediyldioleate. However, this is also the case for several coformulants used in higher tonnage as e.g., DPGME, CaDBS, and sodium ligninsulphonate. Thus, there is no consistent relation between data availability and tonnage, and the adverse health effects of coformulants used in Denmark in high tonnage are not necessarily studied more extensively than coformulants used in low tonnage.

4.2 Toxicological effects of the selected coformulants

The toxicological evaluations of the 18 coformulants selected for this project showed that these substances have various toxicological effects:

The most common critical effect indicated by the available data is local effects - predominantly irritation of the eye, the skin, and/or the respiratory tract. For 13 of the coformulants, irritative effects are identified as the critical effect based on results from animal studies and/or from human experience.
However, the severity of the irritative effects is difficult to evaluate as an effect level could only be derived for 3 of these irritative coformulants (EG: respiratory tract; EGBE: respiratory tract; DEGBE: skin).
One other coformulant (hexamethylenetetramine) is associated with development of allergic asthma in humans by inhalation; this coformulant is also a skin sensitiser in humans and in guinea pigs.
Another coformulant (manganese (II) sulphate) is shown to be a serious neurotoxicant at low exposure levels by inhalation, while a number of coformulants, predominantly organic solvents, have CNS-depressing effects following acute exposure to relatively high concentrations and/or following repeated exposure.
One coformulant is nephrotoxic (EG), one causes haemolytic anaemia (EGBE), and one affects the liver (DME).
One coformulant (EG) is probably a developmental toxicant following exposure at very high concentrations (above 1000 mg/m³).
None of the 18 selected coformulants are considered to possess a mutagenic and/or genotoxic potential although it is acknowledged that some positive results have been obtained in some test systems for two of the selected coformulants (manganese (II) sulphate, hexamethylenetetramine) and no data are available for 3 of the coformulants.
A carcinogenic potential has not been identified for any of the 10 coformulants for which this end-point has been examined.

Thus, none of the selected coformulants can be considered as harmless based on the hazard assessments performed in this project. A number of the coformulants had even serious adverse health effects. This finding is especially alarming as the data availability was very limited for a number of coformulants. Some of the coformulants selected may thus have additional toxicological effects than the ones identifiable on the available database.

4.3 Present regulation

Eight of the 18 selected coformulants are classified for health effects by the EU. Three substances are classified for acute toxicity (EG, EGBE, cyclohexanone), 4 substances for irritative effects (EGBE, DEGBE, NMP, HMP), 1 substance for sensitisation (hexamethylenetetramine), and 1 substance for effects following repeated exposure (manganese (II) sulphate). For 10 of the 18 coformulants, an occupational exposure limit has been established in Denmark and for 9 of the coformulants, a C-value (quality criteria value in air) has been set in Denmark.

According to the present regulation, classification of a pesticide for health effects will reflect the toxicological effects of the coformulants with respect to acute toxicity and local irritation, which are the end-points where data are required for the pesticide product. However, classification will not include information on effects following repeated exposure as well as on a number of specific effects (sensitisation, toxicity to reproduction, mutagenicity/genotoxicity, carcinogenicity) unless the coformulants themselves are adopted on the list of dangerous substances.

4.4 Limitation of the project

The limited number of coformulants included (18 substances) in this project in comparison to the very high number of different coformulants used in Denmark makes the project vulnerable to bias. It is difficult to ensure that the prioritisation of the coformulants does not introduce parameters that influence the results with respect to the two elements investigated in this project, namely the data availability and the toxicological assessments of the coformulants. Also, the criteria for prioritisation of coformulants set under point 2.1 give rise to the following comments on the representativity of the coformulants evaluated in the project:

1. By setting tonnage as the primary criteria for selection, the many different functions of coformulants are probably not represented among the 18 selected substances as some functions can be fulfilled by only small amounts of coformulants, (e.g., perfume) while other functions require large amount of the chemical (e.g., fillers, dispersing agents, solvents). Thus, there is a risk that the latter functions are over represented in the project.
   It can be seen from Table 1 that a number of glycol ethers are included in the project. Many solvents, including glycol ethers, are irritative to the eyes, the skin and the respiratory tract, and some are CNS-depressants. These effects are all represented among the coformulants selected in this project; however, because of the possible overrepresentation of a certain chemical class in the project, it is not possible to use this knowledge on coformulants in general.
2. The criteria exempting substances classified as mutagens, carcinogens or toxic to reproduction may have biased the representativity of the results both on data availability and on toxicological effects.

The purpose of this project was to compile and evaluate the available toxicological information on the 18 selected coformulants in order to perform a hazard assessment for these substances. Therefore, proper risk assessments cannot be performed for these substances as no exposure assessments have been carried out in this project. Thus, no conclusions can be made exclusively based on the results obtained in this projects whether exposures to these coformulants in pesticides may constitute a risk for humans of experiencing adverse health effects during the use of these pesticides.

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