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Toxicology (Part 3)
This chapter sets out the guidelines for submitting toxicology data—or scientific argument in the absence of data—as part of applications for approval of new active constituents, registration of agricultural chemical products, variation of currently registered agricultural chemical products, or permits to use agricultural chemical products.
Toxicology data and/or scientific argument provide information on the potential human health hazards arising from proposed uses of agricultural chemical products. This information is important in establishing relevant health recommendations for safe use of agricultural chemical products, including:
- acceptable daily intakes
- acute reference doses
- poison scheduling
- first aid instructions
- safety directions
- warning statements
- re-entry/re-handling statements
- other limitations on use (for example, restraints, restrictions).
1.1. Reference materials
We have provided details of documents referred to in this chapter (including codes and standards) in the ‘References’ section. You should be aware that many of these documents are updated regularly and for this reason we have not supplied dates in the text. Therefore, it is important to ensure that you use the latest editions of reference materials.
2. Types of applications
The toxicology data elements that you should address in your application depend on the nature of the application. The nature of the application determines which Part 3 (toxicology) data module is appropriate.
Each module has a number of toxicology data elements, which are described in detail in the “Relevant data for module levels – agricultural chemical products.” A comprehensive assessment comprises a full toxicology data package, containing all of the data elements listed in ‘Data elements for a comprehensive Part 3 (toxicology) submission’. A reduced assessment or limited assessment comprises a subset of the data elements contained in a comprehensive assessment.
3. Data elements and guidelines
The data you generate and submit for evaluation is assessed to identify the immediate hazards to the user, and to enable the classification for poison scheduling or to ensure that the poison scheduling remains appropriate, and to set directions for the safe use of the product.
3.1. General recommendations
You should submit toxicity data in accordance with the procedures outlined in the regulatory guidelines. The data elements for a comprehensive part 3 toxicology submission are shown below. All data elements should be addressed with the submission of data or scientific argument.
The documentation you submit to us should be complete and well organised. It should be presented in sufficient detail to allow independent scientific assessment (for example, you should provide individual animal data when available). You should supply copies of original reports. Summaries, abstracts and published material alone usually do not contain adequate detail for independent scientific evaluation. Data submitted that do not enable independent evaluation may be of reduced or limited regulatory value, or determined to be inappropriate for regulatory purposes.
In certain cases, you may provide scientific argument based on accepted scientific principles or data published in peer-reviewed journals in lieu of submission of toxicology studies.
If you do not believe that a particular data element is necessary, you may request a data waiver. In such cases, you should maintain the data headings and provide a valid scientific argument as to why the data element should not be included. The regulatory value of scientific arguments will be determined based on their merits. .
For some applications, certain studies may not be relevant because of the type of active constituent or product being proposed for registration, or because of the specific agricultural situation where the product is intended for use. For specific types of products (for example, biological products, adjuvants), specific?guidelines may be available, which provide guidance on which of the data elements listed in ‘Data elements for a comprehensive toxicology submission’ are appropriate for registration or approval.
You should not omit any relevant data that could influence the toxicology assessment of the substance.
3.1.2. Applications and/or assessment involving other regulatory bodies
You should include details of any applications for the same active constituent or product lodged with other regulatory agencies, either in Australia or overseas. Where available, you should provide the same data relied on by the other regulatory agency (noting the general recommendations and guidance outlined in previous sections of this guideline) in determining the results of these applications and coming to subsequent regulatory decisions. Where available, you should also provide any other reports or documentation related to the active constituent or product. If use of the active constituent or product has been considered unfavourably by an overseas regulatory body, you should provide all details and submit a scientific argument discussing this information in the context of the Australian approval of the active constituent or registration of the chemical product.
3.1.3. Conduct of studies
Unpublished toxicity studies suitable for regulatory agencies around the world usually comply with test guidelines established by the Organisation for Economic Co-operation and Development (OECD) or similar—for example, the US Environmental Protection Agency’s Office of Chemical Safety and Pollution Prevention health effects test guidelines, the European Union’s guidelines or the Japanese Ministry of Fisheries and Food guidelines. Studies which follow these guidelines are usually also conducted in accord with the principles of Good Laboratory Practice (GLP). Signed certificates which attest adherence to the principles of GLP should accompany each study.
All studies should provide information on:
- selection of animal species, housing and feeding conditions, and preparation and randomisation of animals
- a description of the study procedure including route of administration, number and characteristics of animals in the main and any interim, satellite or recovery groups; dose selection rationale and dose preparation
- all parameters studied
- the frequency at which parameters were studied
- the duration and frequency of dosing and any recovery period
- the time of administration in relation to the observations and effects observed.
Reports should include detailed results for the individual animals in the studies, together with statistical analyses of results. Summary tables or diagrams can be useful to assist in reviewing data (for example, body weight, haematology, metabolite profile) or where they will permit sets of data to be compared on the same page (for example, those for control and treated animals). Studies should also include summarised reports of histopathological examinations, in tabular form, so that the incidence of observations can be studied in relation to dosage, sex and duration of treatment. You should also provide historical control data, if available.
Studies should be conducted using active constituents, the formulation for which registration is sought, or read-across from a formulation that has similar physicochemical and toxicological properties to the formulation for which registration is being sought. These similarities between the two formulations may be due to:
- a common active constituent functional group
- common breakdown products via physical and/or biological processes that result in structurally similar compounds
- a constant pattern in physicochemical and/or biological properties.
A valid scientific argument for a read-across approach will be considered.
You should include additional toxicity studies on individual metabolites or degradation products in situations where the metabolites or degradation products are formed through plant metabolism, photodegradation or other mechanisms that differ from those identified in mammalian metabolism studies, or a scientific rationale as to why such studies are not necessary. ?These studies are used to judge which compounds should be included in the residue definition, and may also be used to assess the risk to humans from a toxic degradation product during application.
3.1.4. OECD format
An acceptable format to receive data packages is the OECD format; however, submissions as used by other regulatory agencies (for example, the US Environmental Protection Agency) are acceptable if they contain the data elements in the relevant toxicology module, and are appropriately indexed.
3.2. Animal testing
Experiments involving animals should be conducted using the minimum number of animals recommended in the appropriate OECD Guidelines for the Testing of Chemicals or other recognised test guidelines. ?Applicants are encouraged to submit data obtained from appropriate OECD Guidelines for the Testing of Chemicals (or other recognised test guidelines) in vitro assay systems or alternative methods which use fewer animals according to the ‘3Rs’ principle (reduce, refine, replace).
Each application should contain complete reports of all animal investigations and in?vitro studies. These data should cover each of the elements listed under the heading ‘Data elements for a comprehensive Part 3 (toxicology) submission’ that are relevant to the application. You should also provide any available human data.
3.3. Chemistry and manufacture
Applications that include toxicological data should be accompanied by Part 2 - Chemistry and manufacture data. This is because details of the chemical and physical properties of the active constituent, the profile of impurities and the constituents of formulations are important in carrying out a complete toxicological evaluation of the product.
Impurities present in an active constituent used in the formulation of an agricultural product may be important both toxicologically and environmentally. Consequently, you should identify any impurity present in the active constituent at a concentration that may be toxicologically significant, in addition to identifying all impurities present in the active constituent at a concentration of one?gram per kilogram or more.
Formulation constituents should be clearly identified by name and Chemical Abstracts Service registry number. The use of trade names or proprietary names alone is not acceptable. You should provide all available information relevant to the hazard assessment of non-active constituents used in the product. This information should include, but is not limited to, a safety data sheet for each of the constituents.
For further details, refer to Part 2—Chemistry and manufacture.
3.4. Extrapolation of data
In certain cases, it may be possible to estimate the acute toxicity of a formulation by considering acute toxicity data on the active constituent (for example, a simple dilution in water, or a powder formulation in an inert material), or by read-across from a reference product formulation that has similar physicochemical and toxicological properties to the formulation for which registration is sought. Estimates of the potential hazard by extrapolation and read-across should take into consideration the acute toxicity of the active constituent as well as the acute toxicity of the individual non-active constituents (or excipients). However, toxicity data based on the product to be registered is always preferable as it usually results in more reliable estimates of overall product toxicity.
Where you do not provide six acute toxicity studies (ie. oral, dermal and inhalational toxicity together with eye and skin irritation and skin sensitisation) on the proposed product formulation, then the minimum information is a safety data sheet for each constituent in the product formulation.
3.5. Approval of a new source of an approved active constituent
Registrants may apply for approval of a new source of an approved active constituent. This may necessitate the APVMA to undertake a full assessment, a limited assessment or no assessment, depending on the impurity profile of the active constituent from the new source. If you apply for approval of a new source of an approved active constituent which is not equivalent to the approved source in terms of its impurity profile (ie. levels > 0.1% w/w), then the following points should be considered.
Is the impurity also a metabolite formed through in vivo metabolism of the active constituent in a laboratory animal model? If not, the genotoxic potential of the impurity should be assessed using in silico (computation) models. Two types of in silico (computational) methodologies must be used: a rules based method and a statistically based method. If any of the in silico analyses are positive then it is necessary to conduct genotoxicity testing on the active constituent as described in section 3.7.11
Scientific arguments for not undertaking studies on a new source of active constituent can be submitted for consideration.
3.6. Guideline for pesticides intended for domestic use
Poisoning by pesticides can and does occur from products sold for use in and around the house. Domestic-use pesticide products should be relatively harmless or capable of causing only mild illness if accidental poisoning occurs.
Appropriate consideration of inherent toxicity, formulation, packaging and labelling can reduce the hazard to householders and especially to young children. The following guidelines, when applied to experimental animal data, should reduce the hazards of household, home garden and domestic pesticides.
3.6.1. Acute oral toxicity
Any domestic pesticide formulation that may be ingested should not be expected to be acutely toxic to a child at doses up to 1500?milligram per kilogram body weight. Recognising that acute toxicity may reflect a range of adverse effects, the use of the term ‘acutely toxic’ here is intended to mean life-threatening.
3.6.2. Acute dermal toxicity
Any domestic pesticide formulation should not be acutely toxic at dermal doses up to 2000?milligram per kilogram body weight.
3.6.3. Acute inhalational toxicity
Any domestic pesticide formulation should not be acutely toxic at inhalational doses up to 2000?milligram per cubic metre (four-hour exposure) for a gas, 20?milligram per litre (four-hour exposure) for a vapour and 5?milligram per litre for dusts and mists (four-hour exposure).
3.6.4. Irritancy potential
The irritancy to skin and eyes of domestic pesticide formulations should be low. The formulation and application methods of a product will be taken into consideration on a case-by-case basis. You should provide any relevant information regarding any risk mitigation measures available for the proposed product.
3.6.5. Repeated exposure
Domestic pesticide products should present a low risk from repeated use. For instance, such products should be unlikely to induce irreversible toxicity.??
3.6.6. Directions for safe use
Safe use of domestic pesticide products should not require safety equipment that is not readily available to the householder. Safety equipment other than gloves is not considered an appropriate mitigation option for users of domestic pesticide products, because users are not trained in handling hazardous substances and compliance is not expected. Domestic pesticide products may not be supported for domestic use if safety equipment other than gloves is required for their safe use.
3.6.7. First aid directions
The product label affixed to the container and any associated leaflets should carry appropriate first aid directions in the event of poisoning. Domestic-use pesticide products should not require specific antidotes or aggressive first aid measures.
3.7. Data elements
The data elements for a comprehensive assessment of toxicology data are shown below. Unless specified, all studies should be conducted with the active constituent for which approval is sought.
If you believe that a specific data element is not relevant to your application, you should justify the absence of studies by providing a valid scientific argument under the heading for the data element(s) in question. Similarly, a valid scientific argument to justify the absence of acute toxicity studies should be provided under the heading of the data element when read-across is proposed from a formulation that has similar physicochemical and toxicological properties to the product formulation for which registration is sought.
Data elements for a comprehensive Part 3 toxicology submission
The data elements for a comprehensive assessment of toxicology data are:
- Table of contents
- Data summary
- Absorption, distribution, metabolism and excretion (toxicokinetics, pharmacokinetics)
- Acute toxicity studies:
- Studies on the active constituent
- Studies on the product
- Short-term toxicity studies (repeat dose)
- Sub-chronic toxicity studies (repeat dose)
- Long-term (chronic) toxicity studies (repeat dose):
- Chronic toxicity studies
- Carcinogenicity studies
- Combined chronic toxicity and carcinogenicity studies
- Reproduction studies
- Developmental studies (including developmental neurotoxicity)
- Genotoxicity studies
- Neurotoxicity studies
- Additional studies:
- Toxicity of metabolites and impurities
- Other adverse effects
- Toxicity of mixtures
- Mechanistic studies and mode of action
- Human toxicological data
- No observed-adverse effect level
- Acceptable daily intake
- Acute reference dose
- First aid instructions and safety directions
- Toxicological database/bibliography
A table of contents should be provided.
3.7.2. Data summary
Your application should include an overall summary of the toxicological information provided in relation to the active constituent or product, as well as rationale for any conclusions made. The summary should contain:
- a brief description of the active constituent or product (including hazard classification and packaging)
- a brief description of the pattern of use of the product. A detailed description of the data elements that you should provide is given in Part 6—Occupational health and safety (Part 6).
All principal treatment-related changes, such as biochemical and morphological changes observed in the studies should be identified in the data summary, with proper cross-referencing to the detailed data. Where your application claims that:
- findings are not toxicologically significant, you should provide evidence of their reversibility and a scientific argument in support of the proposal. By anticipating such possibilities from early tests, it may be possible to include subgroups for recovery trials in later studies
- findings are not treatment related, you should provide a scientific argument supporting the claim, supported by historical control data if available, preferably from the testing laboratory and by the route of administration tested
- findings are considered to be of low relevance to humans, you should provide a scientific argument based on mechanistic data identifying the mode of action and using a weight-of-evidence approach for the relevance of the identified mode of action to human health based on the Bradford Hill criteria. This approach is contained within the International Programme on Chemical Safety Mode of Action framework?for analysing the relevance of a cancer mode of action for humans.
The regulatory value of scientific arguments that findings were not toxicologically significant, not treatment related or of low relevance to humans, will be determined based on their merits and reliability. If you have submitted metabolism and kinetics data under Part 4, you should summarise these data with argument as to how they relate to relevant aspects of toxicology. In most cases, the data summary need not exceed two to three pages.
3.7.3. Absorption, distribution, metabolism and excretion (toxicokinetics, pharmacokinetics)
You should provide studies examining the absorption, distribution, metabolism and elimination of active constituents in appropriate laboratory animals (see Part 4—Metabolism and kinetics for further details). The route of administration for these studies should be carefully considered, and take into account routes of likely exposure to the active constituent in question.
3.7.4. Acute toxicity studies (active constituent)
Acute toxicity studies examine the adverse effects arising from administration of a single oral dose or a single dermal or inhalation exposure of a substance over a specified period or multiple doses given within 24?hours.
Acute oral toxicity studies should be performed in at least one mammalian species. Rats are the preferred rodent species for oral studies unless a species more representative of human toxicity is known. You should also provide acute dermal and inhalation studies in at least one species. For skin and eye irritation studies, rabbits are an acceptable species, but alternatives from adopted OECD guidelines for the testing of chemicals (or other recognised guidelines) to the usual in?vivo test may be suitable. In?vivo eye irritation tests may not be appropriate in certain circumstances. If you do not believe an eye irritation study is appropriate, you should provide a valid scientific argument as to why these studies should not be included. For example, if the results from a skin irritation study or validated in?vitro study demonstrated corrosivity or severe irritation, it is acceptable not to test the product in an eye irritation study, as it is presumed that the product will be corrosive to the eye. Similarly, products with pH extremes of 2 or less, or 11.5 or more are considered corrosive to the eye, unless the acid or alkaline reserve (buffering capacity) of the product suggests otherwise.
A skin sensitisation study is performed to test for possible hypersensitivity reactions to the substance. Guinea pigs are normally used for sensitisation studies. Internationally validated alternative methods, such as the murine local lymph node assay, are also acceptable.
3.7.5. Acute toxicity studies (formulated product)
For each new agricultural chemical product, you should submit a ‘six-pack’ of acute toxicological data. This consists of the following studies on the product:
- acute oral toxicity
- acute dermal toxicity
- acute inhalation toxicity
- eye irritation
- skin irritation
- skin sensitisation
If such data are not available, a toxicological evaluation of the product may be conducted by taking the known toxicological properties of the active constituents and excipients in the formulation and extrapolating these to estimate the acute toxicity of the product.
3.7.6. Short-term toxicity studies (repeat-dose studies of less than 90?days duration)
Short-term toxicity studies involve multiple administration of a substance for periods of less than 90?days. Such studies, including those which investigate dermal toxicity, provide information on the possible health effects likely to arise from repeated exposures over a limited period of time.
3.7.7. Sub-chronic toxicity studies (90?days to less than 12?months)
Sub-chronic toxicity studies are performed to assess possible effects observed in short-term repeated exposure and as preliminary dose range-finding studies before chronic studies are started. They should demonstrate a range of activity, from the no-observed adverse-effect levels through to a toxic effect level. Often this range can be encompassed in a single study using one control and three test groups.
Sub-chronic toxicity studies should be performed in two species, a rodent and a non-rodent species. Dogs are the commonly used non-rodent species. Rabbits are not considered an acceptable non-rodent species unless available data suggest that they are more relevant for the prediction of health effects in humans.
3.7.8. Long-term (chronic) toxicity studies (12?months or longer)
220.127.116.11. Chronic toxicity studies
You should provide long-term (chronic) studies to assess long-term toxic effects (chronic toxicity) that may not be demonstrable in sub-chronic studies (for example, from cumulative toxicity). Chronic toxicity studies normally consist of long-term, continuous, daily oral administration of the test compound to two species. The use of both a rodent and non-rodent species is desirable to provide an adequate assessment of interspecies variation. Rats and dogs are the preferred species. If a three-month toxicity study dog has been provided (see section 3.7.7), then it is not necessary to submit a 12-month study in dogs as it has been shown that such studies do not provide additional information. However, if a 12-month study in dogs has been completed then it should be submitted. The absence of chronic toxicity studies in? a rodent may be considered a significant data omission or may require an additional uncertainty factor to be applied.?
In chronic toxicity studies, it is desirable to have a dose–response relationship as well as a no-observed-adverse-effect level. To this end, normally one control and at least three test groups should be used. At least one dosage level should result in no observed toxic effects. Where a no-observed-adverse-effect level is not achieved and the study is identified as the key study for risk assessment purposes and/or establishing an acceptable daily intake value, an additional uncertainty factor may be implemented to account for the uncertainty regarding a lower limit of toxicity.
18.104.22.168. Carcinogenicity studies
Carcinogenicity studies are normally performed in two species. Such studies should be regarded as relevant whenever biologically significant residues of the compound or its metabolites occur, or when human exposure to the compound results from the normal use pattern of the compound.
Carcinogenicity studies involve administration of the test material, usually in the feed, throughout the major portion of the life span of the species. An adequate number of animals should be included at each dose level to enable suitable statistical evaluation of the results (that is, most of the animals should survive for the duration of the study). It is recommended that rodent species such as rats and mice be used. The use of non-rodent species may be considered when available data suggest that they are more relevant for the prediction of health effects in humans.
You should present historical data describing the normal occurrence of a finding in the particular species and strain of animal in the testing laboratory for the route of administration tested. This assists in deciding whether or not a tumour or lesion is compound related. The submission of historical control data not from the testing laboratory, and/or not by the route of administration that the test used, may be of reduced or no regulatory value.
Where a tumour is considered to be of low relevance to humans, you should provide a supporting scientific argument, based on mechanistic data identifying the mode of action and using a weight-of-evidence approach for the identified mode of action to human health based on the Bradford Hill criteria. The regulatory value of scientific arguments that tumour findings were of low relevance to humans, will be determined based on their merits and reliability.
22.214.171.124. Combined chronic toxicity and carcinogenicity studies
A combined chronic toxicity and carcinogenicity study may provide information on the possible chronic and carcinogenic effects likely to arise for a period lasting up to the entire life span of the species. However, careful design is suggested because information for each objective may differ.
You should present historical data describing the normal occurrence of a finding in the particular species and strain of animal in the testing laboratory for the route of administration tested. This assists in deciding whether or not a tumour or lesion is compound related. The submission of historical control data not from the testing laboratory, and/or not by the route of administration that the test used, may be of reduced or no regulatory value.
Where a tumour is considered to be of low relevance to humans, you should provide a supporting scientific argument, based on mechanistic data identifying the mode of action and using a weight-of-evidence approach for the identified mode of action to human health based on the Bradford Hill criteria. The regulatory value of scientific arguments that tumour findings were of low relevance to humans, will be determined on their merits and reliability.
3.7.9. Reproduction studies
Reproduction studies involve the administration of a substance over one or more generations (multi-generation studies) to provide information on the effects of the substance on male and female reproductive systems, including gonadal function, the oestrus cycle, mating behaviour, conception, gestation, parturition, lactation, and weaning, and the growth and development of the offspring.
Such studies may also provide information about the effects of the test substance on neonatal morbidity, mortality, and preliminary data on prenatal and postnatal developmental toxicity, and serve as a guide for subsequent tests. These studies should be conducted with at least three dose groups and a concurrent control group, and would normally be conducted using rodents, preferably rats. If other species are used, justification should be given and the test parameters should be modified as appropriate.
3.7.10. Developmental studies
Developmental studies involve administration of a substance to pregnant animals over a specified period of gestation (organogenesis) to provide information on prenatal exposure on the pregnant test animal and on the developing foetus, and may include assessment of maternal effects as well as death, structural anomalies and abnormalities, or altered growth in the foetus. Functional deficits, although an important part of development, are generally assessed in reproduction and developmental neurotoxicity studies.
Developmental toxicity studies should be performed in a rodent and non-rodent species. Rats are the preferred rodent species and rabbits are the preferred non-rodent species. You should provide justification if another species is used.
3.7.11. Genotoxicity studies
It is now known that some substances can cause changes to the genetic material. These changes may involve a single gene, or whole chromosomes (structural and/or numerical), and damage to deoxyribonucleic acid (DNA) via effects such as unscheduled DNA synthesis, DNA strand breaks, DNA adduct formation or mitotic recombination. A set of well-validated tests able to detect different classes of genetic toxicants will demonstrate the potential of a compound to induce genetic damage in humans. Tests (1) and (2) described below should be conducted in the first instance:
- a test designed to demonstrate the induction of point mutations (base-pair substitution and frameshift) in a microbial assay (for example, salmonella reverse mutation test), with and without the use of appropriate metabolic activation systems
- a test designed to demonstrate the production of chromosome damage in an in?vitro mammalian cell assay (for example, Chinese hamster ovary assay), with and without the use of appropriate metabolic activation systems.?
An in?vivo test is also recommended.
If (1) or (2) are positive, two of three tests described below under (3), (4) and (5) should be carried out in rodents (rats or mice) in order to characterise the genotoxic potential in?vivo in somatic cells:
- a test designed to demonstrate the production of cytogenetic damage (for example, micronuclei) in the bone marrow or other proliferative cells of intact animals
- a test designed to demonstrate genotoxic damage, involving other than cytogenetic endpoints (for example, unscheduled DNA synthesis or P32-post-labelling adduct formation) and preferably in a suspect or known target tissue for the substance
- a test designed to demonstrate mutations in transgenic rats or mice that have transgenes containing reported genes for the detection of various types of mutations in somatic tissues.
If (3), (4) or (5) are positive, a test described below under (6), (7) or (8) should be carried out in rodents (rats, mice or Chinese hamsters) in order to better characterise the genotoxic potential in?vivo in germ cells:
- a test designed to demonstrate a dominant lethal event in a germ cell that does not cause dysfunction of the gamete, but which is lethal to the fertilised egg or developing embryo
- a test designed to demonstrate the production of chromosome aberrations in spermatogonial cells
- a test designed to demonstrate mutations in transgenic rats or mice that have transgenes containing reporter genes for the detection of various types of mutations through the germline.
3.7.12. Neurotoxicity studies
A neurotoxic effect is an adverse change in the structure or function of the nervous system (central or peripheral) that results from exposure to a substance. A neurotoxic effect may arise in offspring from exposure of the mother during pregnancy and lactation. Adverse changes may result from single or repeat exposure to a substance.
Tests should be designed to detect or characterise major neurobehavioural and neuropathological effects in test animals. While behavioural effects—even in the absence of morphological changes—can reflect an adverse impact on the organism, not all behavioural changes are specific to the nervous system. Therefore, any changes observed should be evaluated in conjunction with correlative histopathological, haematological or biochemical data as well as data on other types of systemic toxicity. A developmental and delayed neurotoxicity study should be considered based on all the available information. A developmental neurotoxicity study should be conducted when neurotoxicity is observed in acute or repeat dose studies. Delayed neurotoxicity studies (acute and repeat dose) are required if the substance is an organophosphorous compound.
Relevant testing (acute, sub-chronic, developmental and delayed neurotoxicity) should be conducted in accordance with appropriate test guidelines.
3.7.13. Additional studies
126.96.36.199. Toxicity of metabolites and impurities
Although it is recognised that toxicity studies usually examine the toxicity of the active constituent, impurities or metabolites may contribute significantly to the toxicity of the compound. In general, studies employing the active constituent provide an overall estimate of toxicity of the parent compound and its metabolites. However, where metabolites produced in target plants and animals are significantly different from those produced in laboratory animals, you should provide toxicity studies on those metabolites. Submitted data should allow an assessment of what metabolites should be included in the residue definition for risk assessment purposes.
All impurities with concentrations of one gram per kilogram or greater (or those impurities with concentrations of less than one gram per kilogram that are toxicologically significant) in the active constituent should be identified and, where necessary, subjected to appropriate toxicological studies or a scientific argument (see ‘Approval of a new alternative source of an agricultural approved active constituent’ above for information on scientific arguments).
If you will be providing toxicological studies these should be outlined under the heading 3.5 Approval of a new source of an approved active constituent. The studies should be conducted on the listed impurities and metabolites and if these are demonstrated to be more hazardous than the active constituent, they may be identified as toxicologically relevant for risk assessment purposes and require further toxicological qualification.
188.8.131.52. Other adverse effects
Individual compounds that show specific toxicological effects (for example, immunotoxicity, neurotoxicity) during normal repeat dose testing should be further investigated using appropriate tests for the particular abnormalities induced to enable definitive hazard characterisation to be established. Similarly, new compounds that belong to chemical classes known to produce particular toxicological effects should also be tested appropriately; for example, delayed neurotoxicity with organophosphorus insecticides. In the absence of such information, the toxicity profile of a compound may be deemed incomplete. The regulatory impact of an incomplete toxicity profile will be determined on a case-by-case basis.
184.108.40.206. Mechanistic studies and mode of action
Mechanistic studies may be undertaken to supplement data obtained from standard studies conducted in accordance with the adopted OECD guidelines for the testing of chemicals, or other recognised test guidelines, so as to explain the process involved in, or responsible for, an observed toxicological finding. Together, the data may identify the overall mode of action by which a substance produces its toxicological effect, from a subcellular level through to histopathological changes.
When proposing that the observed toxicological effect is of low relevance to humans, you should provide a scientific argument based on the available data, identifying the mode of action and using a weight-of-evidence approach for the relevance of the identified mode of action to human health based on the Bradford Hill criteria.
An immunotoxic effect is an adverse effect on the components and/or function of the immune system from exposure to a substance, resulting from either direct or indirect actions reflecting either permanent or reversible toxicity.
While OECD test guidelines for short-term, sub-chronic and chronic toxicity studies may provide data to give an indication of immunological effects, there is no specific OECD test guideline to determine functional immunotoxicity. If such studies provide an indication of an immunological effect, you should consider further testing to investigate immunotoxicity using appropriate tests. The US Environmental Protection Agency has a functional immunotoxicity test guideline designed to evaluate the immunosuppressive potential of a substance (OPPTS?870.7800).
3.7.14. Human toxicological data
You should provide all available information relating to human experience with the substance. The information may arise as a result of voluntary intake, occupational exposure during the manufacture of the substance, worker exposure during field use, or reports of accidental poisoning.
You should include studies relating to occupational and/or worker exposure in the Occupational health and safety (Part?6) section of your application.
3.7.15. No-observed adverse effect level
The no-observed adverse effect level (NOAEL) is the highest dose of a substance at which there is no detectable adverse alteration of morphology, functional capacity, growth, development, or lifespan of the target organism under defined conditions of exposure compared to those observed in control (untreated) animals, and which are observed or measured at higher dose levels used in the study.
The no-observed adverse effect level is expressed in milligrams of substance per kilogram of body weight per day (mg/kg?bw/day) or, in a feeding study, as parts per million (ppm) in food. For feeding studies, conversion to mg/kg?bw/day should be made, calculated from substance intake by measured or estimated food intake over the study period.
Where the test substance is given in feed, and problems with the stability of the test compound occur, the feed should be analysed at frequent intervals.
3.7.16. Lowest-observed adverse effect level
The lowest-observed adverse effect level (LOAEL) is the lowest dose of a substance at which there is a detectable adverse alteration of morphology, functional capacity, growth, development, or lifespan of the target organism under defined conditions of exposure compared to those observed in normal (untreated) animals.
The lowest-observed adverse effect level is expressed in milligrams of substance per kilogram of body weight per day (mg/kg?bw/day) or, in a feeding study, as parts per million (ppm) in food. For feeding studies, conversion to mg/kg?bw/day should be made, and where problems with the stability of the test compound occur in feed, the feed should be analysed at frequent intervals.
3.7.17. Acceptable daily intake for humans
The acceptable daily intake for humans is the level of intake of a substance that can be ingested daily over an entire lifetime without appreciable risk to health on the basis of the available information at the time of evaluation. It is expressed in milligrams of the substance per kilogram of body weight per day (mg/kg?bw/day).
For this purpose, ‘without appreciable risk’ means that adverse effects are unlikely to result even after a lifetime of exposure. The acceptable daily intake is intended to give a guide to the maximum amount of a substance that can be ingested daily in the food without appreciable risk to the consumer. Accordingly, the figure is derived as far as possible from feeding studies in animals.
You can view a list of current acceptable daily intakes on the APVMA website.
3.7.18. Acute reference dose
The acute reference dose of a substance is an estimate of the amount of a substance in food and/or drinking water, expressed in milligrams of substance per kilogram of body weight (mg/kg?bw), that can be ingested over a short period of time, usually in one meal or during one day, without appreciable health risk to the consumer, on the basis of all known facts at the time of the evaluation. For some substances, an acute reference dose may not be necessary because the substance is not considered to cause appreciable acute risk after a single dose or exposure (that is, 24 hours or less).
You can view a list of current acute reference doses on the APVMA website.
3.7.19. First aid instructions and safety directions
You may propose first aid instructions and safety directions applicable for each formulation. You should use standard phrases as published in the APVMA’s First aid instructions and safety directions handbook.
You should note, however, that first aid instructions and safety directions are established by the APVMA, taking into account the hazard profile of an active constituent or chemical product, as well as the occupational and/or residential risks associated with the proposed use patterns for the product.
3.7.20. Toxicological database and bibliography
Every application (including supplementary applications) should include a toxicological database comprising a full bibliography of all studies provided in the application. Every application (including supplementary applications) that contains toxicological data should include a list of all studies on the active constituent and/or chemical product. You should clearly identify studies lodged as part of the application.
For each listed study, you should provide the following information:
- identity and the concentration or purity of the material tested (for example, active constituent, product)
- type of test (for example, acute oral study, two-year dietary study)
- species and strain of animal used
- study laboratory and names of authors
- study sponsor
- good laboratory practice status (including certification where applicable)
- title of the report, report number and date of report
- date the study was submitted in Australia
- location in the application (volume, page number).
3.8. Poison schedules
You may include a scheduling proposal when submitting a toxicology data package. Your scheduling proposal will be assessed against the scheduling factors described on the Therapeutic Goods Administration website. The scheduling factors ensure that public health objectives are consistently met when making scheduling decisions.
The schedules accompanying the states’ and territories’ Poisons Acts listing the various poisons under categories, which are based on the recommendations published in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP, produced by the Australian Government Department of Health). Active constituents intended for agricultural use and agricultural chemical products generally fall into one of the following categories:
3.8.1. Schedule 5
Substances with a low potential for causing harm, the extent of which can be reduced through the use of appropriate packaging with simple warnings and safety directions on the label.
3.8.2. Schedule 6
Substances with a moderate potential for causing harm, the extent of which can be reduced through the use of distinctive packaging with strong warnings and safety directions on the label.
3.8.3. Schedule 7
Substances with a high potential for causing harm at low exposure and which require special precautions during manufacture, handling or use. These poisons should be available only to specialised or authorised users who have the skills necessary to handle them safely. Special regulations restricting their availability, possession, storage or use may apply.
3.8.4. Appendix B
Those substances that do not require control by scheduling because of low toxicity, or where other factors suggest that the potential public health risk would be minimal, are listed in Appendix?B of the SUSMP. This appendix should be read in conjunction with Appendix?A (general exemptions).
We have provided below details for current editions at the time of publication. You should always ensure that you obtain the most recent edition of any publication.
Australian Government Department of Health, Standard for the Uniform Scheduling of Medicines and Poisons.
Organisation for Economic Co-operation and Development, OECD guidelines for the testing of chemicals.
Australian Pesticides and Veterinary Medicines Authority, Acceptable daily intakes for agricultural and veterinary chemicals.
Australian Pesticides and Veterinary Medicines Authority, Acute reference doses for agricultural and veterinary chemicals.
Australian Pesticides and Veterinary Medicines Authority,?First aid instructions and safety directions handbook.
World Health Organization/Food and Agriculture Organization Joint Meeting on Pesticide Residues 2004, ‘General considerations: Guidance on the establishment of acute reference doses’, in Pesticide Residues in Food, FAO Plant Production and Protection Paper, vol. 178, pp. 3–9.