Part 3 – Toxicology

1.   INTRODUCTION

This chapter sets out the requirements and guidelines for submitting toxicology data as part of applications for registration or variation of registration of agricultural chemical products, or applications for a permit.

The toxicology data are evaluated by the Office of Chemical Safety (OCS) within the Department of Health and Ageing. The data provide information on the potential human health hazards arising from proposed uses of the agricultural chemical product. This information is important in establishing:

• acceptable daily intakes (ADIs)
• acute reference doses (ARfDs)
• poison schedule classifications
• first aid instructions
• safety directions
• any necessary warning statements.

1.1.   Reference materials

The details of documents referred to in this chapter (including codes and standards) are given in the References section. Bibliographic details and where appropriate, ISBN and purchase information are given. Applicants should be aware that many of these documents are updated regularly and for this reason dates are not supplied in the text. Therefore, it is important to ensure that the latest edition of reference materials is used.

2.   TYPES OF APPLICATIONS

The toxicology data elements required for an application depend upon the nature of the application. The nature of the application determines which Part 3 (Toxicology) data module will be required; each module requires a number of Toxicology data elements.

2.1.   Modular categories

There are three modules in Part 3. Each module is relevant to different types of products. The modules which are associated with each product type may be seen in Volume 3: Module levels for modular categories.

The data elements for Modules 3.1, 3.2 and 3.3 relate to data requirements for a particular type of application and are related to the degree of toxicological risk posed by the application. The modules are more fully explained in Volume 3: Module levels for modular categories and also in the individual category chapters in Volume 2: Category requirements and guidelines.

Comprehensive assessment (Module 3.1) requires submission of a full toxicology data package, containing all of the data elements listed in the column titled ‘Data required’ in Volume 3: Module levels for modular categories, according to the type of product or application in the column title ‘Type of application.

Reduced assessment (Module 3.2) and limited assessment (Module 3.3) comprise a sub-set of the data elements contained in Comprehensive assessment (Module 3.1).

2.2.   Fixed categories

Applications which are evaluated under a fixed category (eg Category 4) may require submission of toxicology data. The level of data corresponds to Modules 3.1, 3.2 or 3.3 depending on the application category, and is provided in the relevant category chapter in Volume 2:  Category requirements and guidelines.

3.   DATA REQUIREMENTS AND GUIDELINES

Assessment of data on products based on approved active constituents is carried out to identify the immediate hazards to the user, and to enable the establishment of a poison schedule classification and directions for the safe use of the product.

3.1.   General requirements

Submission

Toxicology data packages must be submitted according to the procedures outlined in Volume 1: Application procedures.

A template for submission of Part 3 data for comprehensive assessment (Module 3.1) of toxicology data is provided at 4. This template may also be used for reduced assessment (Module 3.2) and limited assessment (Module 3.3) by deleting the headings of data elements which are not required by the module.

The documentation must be complete and well organised. It must be presented in sufficient detail to allow independent scientific assessment (eg individual animal data must be provided). Copies of original reports should be supplied. Summaries and reprints of published material alone usually do not contain adequate detail.

Applications must include all the available toxicological data and details of studies planned or in progress, together with their projected completion dates. An initial application must be sufficiently complete to allow detailed assessment. Additional studies which could significantly expand the assessment or provide new information relevant to human health standards (including but not limited to the ADI, ARfD or poisons scheduling) must be provided if and when they become available. However, judgment should be exercised, so that studies that do not have a significant bearing on human health and safety could be held over for submission until there is a reasonable package of information to evaluate.

In certain cases (eg commodity chemicals), scientific argument based on accepted scientific principles or data published in peer-reviewed journals may be provided.

If an applicant does not believe a particular data element is necessary, the applicant must maintain the data heading, but may provide valid scientific argument as to why the data element should not be included. For some applications, studies included under the heading ‘Related Studies’ would not be required because of the active constituent, or the crops for which the product is intended. For other products, specific product guidelines may be available, which provide guidance on which of the data elements listed in Table 1 are required for that type of product.

A report which could influence the assessment of the safety of the substance must not be omitted.

Overseas applications

The application must include details of any regulatory applications for the same product made to other regulatory bodies either in Australia or overseas. Where available, the results of these applications and subsequent regulatory decisions must be provided. If any data in the submission have been rejected by an overseas regulatory body, the applicant must identify this and submit scientific argument against the rejection.

Conduct of studies

All toxicity studies must be conducted in accordance with the OECD Guidelines for the Testing of Chemicals or other recognised test guidelines eg US Environment Protection Agency, Japanese Ministry of Fisheries and Food, and with an acceptable code of Good Laboratory Practice (GLP). Certification to this effect must be provided.

Studies should use testing regimes which cover the most likely routes/modes of human exposure. Non-GLP or non-Guideline-compliant studies will be considered on their scientific merit, but their value may be reduced.

Each study must clearly identify the name and address of the laboratory which performed the study, the names of the responsible scientists, the report number, the dates when the study was performed and the date the report was written.

Studies should be designed to assist in the establishment of no-observed-effect levels (NOELs) and to provide evidence of potential short- and long-term hazards, from which an estimate of the chemical's relative safety can be deduced.

Studies must be conducted using active constituents or formulations containing an impurity level comparable to that present in the commercial product. All toxicity studies must include details on the composition of the material used in the study, including solvents and vehicles. For chiral compounds the enantiomer ratio used in all toxicity studies must be clearly indicated.

Details of studies must include:

• route of administration
• dose levels
• the number of animals per dose level, their origin, sex, weight and maturity, all parameters studied
• the frequency at which observations were made
• the duration of each study
• time of administration in relation to the observations and effects observed
• the rationale for dose selection.

Reports must include detailed results for the individual animals in the studies, together with statistical analyses of results. Summary tables or diagrams should be included where these will assist in reviewing data (eg bodyweight, haematology) or where they will permit sets of data to be compared on the same page (eg those for control and treated animals). Studies also should 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.

Each study must clearly identify the name and address of the laboratory which performed the study, the names of the responsible scientists, the report number, the dates when the study was performed and the date the report was written.

For more detailed guidelines for undertaking toxicity studies, see the OECD Guidelines for the Testing of Chemicals or other recognised guidelines.

Additional toxicological studies on individual metabolites will be necessary in situations where the metabolites formed through plant metabolism or photodegradation differ from those identified in mammalian metabolism studies. These studies are required so that a judgement can be made regarding which compounds should be included in the residue definition for risk assessment purposes.

OECD format

Data packages in the OECD format (as used in the European Union) or the United States are acceptable if they contain the data required by the relevant application category or toxicology module, and are appropriately indexed.

3.2.   Animal studies

Experiments involving animals must be conducted using the minimum number of animals necessary to allow statistically-valid conclusions to be made. Applicants are encouraged to submit data obtained from in vitro assay systems, or from alternative methods which use fewer animals according to the ‘3Rs’ principle (reduce, refine, replace).

Each application must contain complete reports of all animal investigations and in vitro studies. These data must cover each of the elements in Table 1 which are relevant to the application. Any available human data also should be provided.

3.3.   Chemistry and manufacture

Applications which require toxicological data will also require 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 necessary to allow 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, all impurities present in the active constituent at a concentration of 1 g/kg or more must be identified. Any impurity present at any concentration that may be toxicologically significant must also be identified.

Formulation constituents must be clearly identified by name and Chemical Abstracts Service (CAS) registry number; the use of trade names alone is not acceptable. All available information relevant to the hazard assessment of non-active constituents used in the product must be provided. This information must include, but not be limited to, a material safety data sheet (MSDS).

3.4.   Extrapolation of data

In certain cases it may be possible to estimate the toxicity of a formulation by extrapolation from data on the active constituent, eg a simple dilution in water, or a powder formulation in an inert material. Estimates of the potential hazard by extrapolation should take into consideration the toxicity of the active constituent as well as the toxicity of the individual non-active constituents. However, data based on the product to be registered is always preferable.

3.5.   Approval of an alternative source of an agricultural approved active constituent

Registrants may apply for approval of a new source of an approved active constituent. If the APVMA considers that the active constituent from the new source may not be equivalent to an approved source in terms of its purity and impurity profile, toxicological data will be required for assessment by OCS.

3.6.   Pesticides intended for domestic use

Household, home garden and domestic animal pesticide products must be relatively harmless or capable of causing only mild illness if accidental poisoning occurs. Poisoning by pesticides can and does occur from products sold for use in and around the house. Unfortunately, young children are often the group most at risk of poisoning by pesticides.

Appropriate consideration of inherent toxicity, formulation, packaging and labelling can reduce the hazard to the 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 animal pesticides.

Acute oral toxicity

Any domestic pesticide formulation that may be ingested should not be expected to be acutely toxic¹ to a child at doses up to 1,500 mg/kg bodyweight.

Acute dermal toxicity

Any domestic pesticide formulation should not be acutely toxic at dermal doses up to 1,000 mg/kg bodyweight.

Irritancy potential

The irritancy to skin and eyes of domestic pesticide formulations should be low.

Repeated exposure

Domestic pesticide formulations should present a low hazard from repeated use. For instance, such products should be unlikely to induce irreversible toxicity.

Directions for safe use

Safe use of domestic pesticide products should not require safety equipment that is not readily available to the householder.

First aid directions

There should be appropriate directions for first aid measures to be taken, should poisoning occur in the household. Household, home garden and domestic animal pesticide products should not require specific antidotes or aggressive first aid measures.

3.7.   Data elements

The data elements required for a comprehensive assessment (Module 3.1) of toxicology data, are shown in Table 1.

If an applicant believes that the requirement for a data element is irrelevant, a brief explanation to justify the absence of the required information must be provided under the heading of the data element.

Table 1:  Data elements for a comprehensive Part 3 (Toxicology) submission

CONTENTS

A table of contents is essential.

DATA SUMMARY

The application must include an overall summary of the toxicological information provided in relation to the product as well as rationale for any conclusions made. The summary should contain:

• a brief description of the product (including hazard classification and packaging)
• a brief description of the pattern of use of the product.

All principal biochemical and morphological changes observed in the studies must be identified in the data summary, with proper cross-referencing to the detailed data. Where it is claimed that manifestations are not toxicologically significant, evidence of their reversibility may be required. By anticipating such possibilities from early tests, it may be possible to include sub-groups for recovery trials in later studies.

Tables may be used as a means of summarising the information. Where studies are cited, they should be cross-referenced in the main body of the application.

If metabolism and kinetics data have been submitted under Part 4, these data should be summarised with argument as to how they relate to relevant aspects of toxicology.

In most cases the summary need not exceed two to three pages.

TOXICOKINETICS AND METABOLISM

Studies examining the absorption, distribution, metabolism and elimination of active constituents in target animals are required (see Part 4: Metabolism and Kinetics for further details).

An investigation of the extent of human absorption of the product after dermal application is desirable. The vehicle chosen for the dermal study should resemble closely that proposed for the product. Submission of in vitro dermal absorption studies using rat and human skin in conjunction with an in vivo rat dermal study is acceptable to enable likely human dermal absorption to be calculated.

ACUTE TOXICITY STUDIES

Acute toxicity studies examine the adverse effects arising from administration of a single dose of a substance or multiple doses given within 24 hours. The substance is usually administered by the oral, dermal and inhalation routes.

The degree of hazard presented by chemicals depends on many complex factors. Although no single factor is completely reliable, the acute toxicity of a chemical probably gives the most useful immediate indication of the potential acute hazards to human users and bystanders and probably also to domestic animals. Poison scheduling is primarily based on acute toxic and irritancy effects and therefore demands, amongst other things, data on acute oral, dermal and inhalation toxicities. Additional specialised studies are used to assess the skin and eye irritancy and skin sensitisation potential of the substance.

To permit assessment of the acute toxicology of a chemical to exposed humans, studies in animals should examine the most likely routes and forms of exposure. They should be performed with both the active constituent and the products to be marketed in Australia.

Acute oral toxicity studies should be performed in at least one mammalian species. The rat is the preferred rodent species for oral studies. Acute dermal and inhalation studies in at least one species are also required.

LD₅₀² and LC₅₀³ values are normally not required and estimates of the lethal dose using alternative procedures are sufficient for hazard classification purposes. Reports should include details of the observed toxic signs, reasons for death and other data which will enable assessment of acute toxic potential.

For skin and eye irritation studies, the rabbit is an acceptable species but properly validated alternatives to the usual in vivo test would be suitable. Eye irritation tests may be unnecessary in the case of substances or formulations where chemical or physical properties suggest this form of toxicity is likely, eg pH above 11.5 or below 2.

A skin sensitisation study is also required to test for possible hypersensitivity reactions to the chemical. Guinea pigs are normally used for sensitisation studies. Internationally validated in vitro alternative methods, such as the murine local lymph node assay (LLNA), are also acceptable.

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 less than 90 days. Such studies provide information on the possible health hazards likely to arise from repeated exposures over a limited period of time.

For classes of chemicals which cause cholinesterase inhibition, short-term oral (gavage) studies in animals, incorporating frequent monitoring of cholinesterase levels, are desirable.

SUB-CHRONIC TOXICITY STUDIES (90 days to less than 12 months)

Sub-chronic toxicity studies are performed to assess possible effects of 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 NOEL through to a clear effect level. Often this range can be encompassed in a single study using one control and three test groups.

Sub-chronic toxicity studies must be performed in two species, one a non-rodent. The rabbit is not considered an acceptable species unless satisfactory evidence of its suitability is provided.

The test material should be given continuously in the feed, or daily by gavage or capsule. Sub-chronic studies with administration of the test material by the inhalation route may be required if there is a likelihood of repeated inhalation exposure to the chemical as a gas, vapour, aerosol or dust.

Evidence of the stability of the compound as formulated for the test conditions should be provided.

Each group should contain sufficient numbers of animals surviving at the end of the trial to produce meaningful results which can be subjected to statistical analysis.

Observations must be made throughout the study on growth, behaviour, food consumption, clinical abnormalities and mortality. All animals which die during the test must be examined for macroscopic and microscopic pathological changes. At the conclusion of the study, surviving animals (other than those allocated for recovery) must be sacrificed and organ weights, gross pathology and histopathology must be recorded. Analytical tests such as haematology, blood chemistry, urinalysis and enzyme studies must be performed. These should include tests to monitor any suspected target organ toxicity.

It must be borne in mind that the objective of a sub-chronic study is to demonstrate responses of biological importance. Where statistical analyses are used in the judgment process, the study must demonstrate an awareness of the validity of the test method and the degree of certainty (confidence) pertaining to it within the context of the study.

LONG-TERM (CHRONIC) TOXICITY STUDIES (12 months or longer)

Long-term (chronic) studies are required for two reasons:

• to assess long-term toxic effects (chronic toxicity) that may not be demonstrable in sub-chronic studies, (eg from cumulative toxicity); and
• to test the material's carcinogenic potential.

Chronic toxicity studies normally consist of long-term continuous daily oral administration of the test compound to two species. The use of a non-rodent species is desirable to provide an adequate assessment of interspecies variation. Rats and dogs are the preferred species.

Chronic toxicity studies normally include one control and three test groups. The highest dosage must induce a recognisable toxic response, or be the maximum dosage that can practically be achieved without causing death or decreasing bodyweight by more than 10% relative to controls. At least one dosage level should result in no observed effects.

Sufficient numbers of animals must survive the full term of the study to permit meaningful interpretation of the results and, wherever necessary, statistical analyses. The monitoring procedures are similar to those for sub-chronic studies.

The interpretation of chronic toxicity studies, particularly interspecies differences, can be greatly influenced by toxicokinetic considerations and wherever necessary, plasma levels of the test compound (or metabolites) must be determined during a study.

Carcinogenicity studies

Carcinogenicity studies will usually be required in two species. Such studies should be regarded as mandatory whenever biologically significant residues of the compound or its metabolites occur, or human exposure 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 lifespan of the species. An adequate number of animals must be included at each dose level to enable suitable statistical evaluation of the results (ie most of the animals should survive for the duration of the study). It is recommended that rodent species such as rats, mice or hamsters should be used.

The highest dose level should be chosen according to the principles on dose selection contained in the relevant Test Guidelines, and be as high as possible without producing manifest toxicity, or confounding the interpretation of carcinogenic effects.

Historical data describing the normal occurrence of a finding in the particular species and strain of animal in the testing laboratory should be presented. This assists in deciding whether or not a tumour or lesion is compound-related.

Chronic toxicity/carcinogenicity studies

A combined chronic toxicity/carcinogenicity study may provide adequate data with which to identify the majority of chronic and carcinogenic effects. However, careful design is necessary because requirements for each objective may differ. For example, a dosage sufficiently high to induce a detectable degree of chronic toxicity, and use of interim sampling techniques (blood collection, interim sacrifice), may add confounding variables to mitigate against detection of tumours, either by reducing the number of animals available at termination or by altering their physiological status (eg lower weight gain leads to fewer tumours).

REPRODUCTION STUDIES

Reproduction studies involve the administration of a substance over one or more generations (multigeneration studies) to provide information on the effects of the substance on male and female reproductive performance such as gonadal function, spermatogenic and oestrous cycles, mating behaviour, fertility, fecundity, parturition, pre- and postnatal growth, development, and maturation of the offspring.

Such studies may also provide preliminary data on teratogenesis, and serve as a guide for subsequent studies. These studies are usually conducted with one control and three test groups and would normally use rats or mice.

DEVELOPMENTAL STUDIES

Developmental studies involve administration of a substance to pregnant animals over a specified period of gestation (organogenesis) to provide information on embryotoxicity and foetotoxicity, developmental anomalies and abnormalities, and altered growth.

Developmental toxicity studies are required in at least two mammalian species. Tests for any functional deficits (for example post-natal behaviour) are desirable.

Signs of maternal toxicity must also be included to provide an indication of whether results suggest a selective action on the developing offspring. Developmental toxicity studies in the rat and rabbit are preferred unless a more appropriate species can be justified for a specific substance. Historical data describing the normal occurrence of abnormalities in the particular species and strain of animal in the testing laboratory should be presented. These data assist in deciding whether a developmental effect is compound-related.

It is recognised that there are short-term (in vitro) tests for teratogenicity but as yet, these have not been validated for regulatory purposes.

GENOTOXICITY STUDIES

It is now known that some chemicals, without DNA-damaging capacity or mutagenic potential, can alter the patterns of gene expression, for example by modifications of methylation and acetylation of DNA and histones. The ability of chemicals to affect so-called ‘epigenetic’ mechanisms means that in vitro testing paradigms alone cannot be seen as providing adequate assurance about the non-carcinogenicity of a chemical.

To determine the potential of a compound in contributing to genetic damage in humans, a set of well-validated tests able to detect different classes of genotoxins will generally be required. Tests (i) and (ii) described below should be conducted:

1. a test designed to demonstrate the induction of point mutations (base-pair substitution and frameshift) in a microbial assay (eg Salmonella reverse mutation test), with and without the use of appropriate metabolic activation systems;

2. a test designed to demonstrate the production of chromosome damage in an in vitro mammalian cell assay (eg Chinese hamster ovary assay), with and without the use of appropriate metabolic activation systems.

If tests (i) and (ii) are negative, no further genotoxicity studies are required.

If (i) or (ii) are positive, tests described under (iii) and (iv) should be carried out in order to better characterise the genotoxic potential:

3. a test designed to demonstrate the production of cytogenetic damage (eg micronuclei) in the bone marrow or other proliferative cells of intact animals;
4. a test designed to demonstrate genotoxic damage, involving other than cytogenetic end points (eg unscheduled DNA synthesis [UDS] or P32-post-labelling adduct formation) and preferably in a suspect or known target tissue for the chemical substance.

ADDITIONAL STUDIES

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, toxicity studies on those metabolites are required. Submitted data should allow an assessment to be made on what metabolites should be included in the residue definition for risk assessment purposes.

All impurities with concentrations of 1 g/kg or greater (or those with concentrations of less than 1 g/kg that may be toxicologically significant) should be identified and where necessary, subjected to appropriate toxicological studies.

Other adverse effects

Individual compounds that show specific toxicological effects (eg immunotoxicity, neurotoxicity, testicular abnormalities) must be further investigated using appropriate tests for the particular abnormalities induced. Similarly, new compounds that belong to classes known to produce particular toxicological effects must also be tested appropriately, eg delayed neurotoxicity with organophosphorus insecticides.

Toxicity of mixtures

Where two or more active constituents are formulated together, toxicity studies must be performed with the formulated product to investigate the possibility of synergism or potentiation. Acute toxicity studies are usually sufficient for this purpose.

Where synergism or potentiation are found, further studies to clarify their toxicological significance may be required.

HUMAN TOXICOLOGICAL DATA

All available information relating to human experience with the chemical must be provided. The information may arise as a result of voluntary intake, occupational exposure during the manufacture of the chemical, worker exposure during field use, or reports of accidental poisoning.

Studies relating to occupational and/or worker exposure should be included in Part 6 (Occupational Health and Safety) of the application.

NO-OBSERVED-EFFECT LEVEL (NOEL)

The no-observed-effect level (NOEL) is defined as the highest concentration or amount of a substance, found by study or observation, to cause no detectable (usually adverse) alteration of morphology, functional capacity, growth, development or life span of the most sensitive test organism.

The NOEL is expressed in milligrams of chemical per kilogram of bodyweight per day (mg/kg bw/day) or, in a feeding study, as parts per million (ppm) in food.

Where the test chemical is given in feed, the dose must be calculated from the food intake of the animals and the concentration of the chemical in food. Where problems with the stability of the test compound occur, it is essential to make up feed and analyse it at frequent intervals.

ACCEPTABLE DAILY INTAKE (ADI) FOR HUMANS

The acceptable daily intake (ADI) of a chemical is the daily intake which during an entire lifetime, appears to be without appreciable risk on the basis of the available information at the time. It is expressed in milligrams of the chemical per kilogram of bodyweight per day (mg/kg bw/day).

For this purpose, ‘without appreciable risk’ is taken to mean that adverse effects will not result even after a lifetime of exposure. Furthermore, for a pesticide residue, the ADI is intended to give a guide to the maximum amount that can be taken daily in the food without appreciable risk to the consumer. Accordingly, the figure is derived as far as possible from feeding studies in animals.

A list of current ADIs can be found in the Therapeutic Goods Administration’s ADI List (Acceptable Daily Intakes for Agricultural and Veterinary Chemicals), published on its ‘Chemicals’ website and periodically updated at www.tga.gov.au/docs/html/adi.htm

ACUTE REFERENCE DOSE (ARfD)

The Acute Reference Dose (ARfD) of a chemical is an estimate of the amount of a substance in food and/or drinking water, normally expressed on a body-weight basis, that can be ingested in a period of 24 hours or less, without appreciable risk to the consumer, on the basis of all known facts at the time of the evaluation.

A list of current ARfDs can be found in the Therapeutic Goods Administration’s ARfD List (Acute Reference Doses for Agricultural and Veterinary Chemicals), published on its ‘Chemicals’ website and periodically updated at www.tga.gov.au/docs/html/arfd.htm

Establishment of an ARfD

While no specific guidelines for a study to establish an ARfD have been developed, the concept of ARfDs is now well established and sponsors are encouraged to submit relevant studies which may aid in the establishment of valid ARfD values, if they are required.

Guidance on the establishment of ARfDs has been published by the WHO/FAO Joint Meeting on Pesticide Residues (JMPR, 2004). This includes discussion of a possible single-dose study protocol which would support the establishment of an ARfD, Unlike a classic lethal dose study, this protocol is not intended to investigate mortality or significant morbidity but to evaluate effects on more subtle endpoints which may arise after single exposures or during one day’s dietary exposure.

FIRST AID INSTRUCTIONS AND SAFETY DIRECTIONS (FAISD)

Applicants may propose first aid instructions and safety directions applicable for each formulation. Standard phrases should be used as published in the Therapeutic Goods Administration’s FAISD Handbook (Handbook of First Aid Instructions and Safety Directions for Agricultural and Veterinary Chemicals) at http://www.tga.gov.au/docs/html/faisd.htm

TOXICOLOGICAL DATABASE

Every application (including supplementary applications) must include a toxicological database comprising a full bibliography of all studies provided in the application. This database should be submitted in electronic format.

Every application (including supplementary applications) which contains toxicological data must include a list of all studies on the chemical. Studies lodged as part of the current application should be clearly identified.

For each listed study, the following information must be provided:

• identity of the material tested eg active constituent, product
• type of test eg acute oral study, 2-year dietary study
• the species and strain of animal used
• study laboratory and names of authors
• study sponsor
• title of the report, report number and date of report
• the date the study was submitted in Australia
• location in the application (volume, page number).

4.   TEMPLATE FOR SUBMISSION OF PART 3 TOXICOLOGY DATA

TABLE OF CONTENTS

OVERALL SUMMARY

ACUTE TOXICITY STUDIES

Studies on the active constituent

Studies on the product

SHORT TERM TOXICITY STUDIES (REPEAT DOSE)

SUB-CHRONIC TOXICITY STUDIES

LONG TERM (CHRONIC) TOXICITY STUDIES (REPEAT DOSE)

Carcinogenicity studies

Chronic toxicity and/or carcinogenicity studies

REPRODUCTION STUDIES

DEVELOPMENTAL STUDIES

GENOTOXICITY STUDIES

ADDITIONAL STUDIES

Toxicity of metabolites and impurities

Other adverse effects

Toxicity of mixtures

HUMAN TOXICOLOGICAL DATA

NO-OBSERVED-EFFECT LEVEL (NOEL)

ACCEPTABLE DAILY INTAKE (ADI)

ACUTE REFERENCE DOSE (ARfD)

FIRST AID INSTRUCTIONS AND SAFETY DIRECTIONS

TOXICOLOGICAL DATABASE

5.   GLOSSARY

Acceptable daily intake (ADI)

The daily intake of a chemical which, during an entire lifetime, appears to be without appreciable risk to the health of the consumer on the basis of all the known facts at the time.

The ADI is expressed in milligrams of the chemical per kilogram of body weight per day (mg/kg/day). It is derived from the no-observed-effect level (NOEL) observed in the most sensitive animal species, utilising an appropriate safety factor.

Acute Reference Dose (ARfD)

The ARfD of a chemical is an estimate of the amount of a substance in food and/or drinking water, normally expressed on a body-weight basis, that can be ingested in a period of 24 hours or less, without appreciable risk to the consumer, on the basis of all known facts at the time of the evaluation.

The ARfD is expressed as milligrams per kilogram of body weight.

CAS registry

A database of the Chemical Abstracts Service (CAS) in which numbers are randomly assigned to compounds and are unique for each compound.

Impurity

Any constituent other than an active constituent or an intentionally-added non-active constituent. Impurities include intermediates, reaction products, degradation products, contaminants or chemicals added for purposes of extraction or purification.

LC₅₀

The concentration of a substance in air that produces death by inhalation in 50 per cent of a population of experimental organisms. It is usually expressed as milligrams per litre (mg/L) or milligrams per cubic metre (mg/m³) of air.

LD₅₀

The dose of a substance that produces death in 50 per cent of a population of experimental organisms. It is usually expressed as milligrams per kilogram of body weight (mg/kg bw).

Manufacturing concentrate

A product containing active constituents and possibly non-active constituents intended for use in the manufacture of a product after further formulating and repackaging.

Material safety data sheet (MSDS)

Data sheets produced by manufacturers or importers of a substance which describes the properties and uses of the substance, ie its identity, chemical and physical properties, health hazard information, precautions for use and safe handling information.

The data sheets also provide the information needed to allow the safe handling of hazardous substances used in an occupational setting.

See the NOHSC/ASCC National Code of Practice for the Preparation of Material Safety Data Sheets at http://www.nohsc.gov.au/ohslegalobligations/nationalstandards/COP_MSDS.htm

No-observed-effect level (NOEL)

The highest concentration or amount of a substance, found by study or observation, to cause no detectable (usually adverse) alteration of morphology, functional capacity, growth, development or life span of the most sensitive test organism.

Non-active constituent (excipient)

Any ingredient, other than an active constituent, that is part of a formulated product. Non-active constituents are added at the time of manufacture for various reasons, eg to improve formulation characteristics such as stability, solubility and spreadability.

Poisons schedules

The schedules accompanying the States and Territories Poisons Acts listing the various poisons under categories which are based on the recommendations of the National Drugs and Poisons Schedule Committee (NDPSC) and published in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP, produced by the Australian Government Department of Health and Ageing). Agricultural and veterinary chemical products generally fall into one of the following categories:

Potentiation

A situation in which one substance enhances the effects of one or more other substances.

Safety directions

Statements included on the labels of agricultural chemical products which specify hazards, precautions and techniques for handling, mixing and using those products safely. Safety directions include general warnings and specific precautions and protective equipment relating to the safety of the operator. They do not include other warnings and precautions such as flammability, disposal of containers, spillage, re-entry periods and withholding periods.

Synergism

A situation in which two or more substances acting together produce an effect which is greater than would be expected from adding the effects produced when the same substances are applied separately.

Warning statements

These are listed in Appendix F of the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), and are general warning statements and precautions required for safe handling and use of specified drugs and poisons. Appendix F statements should not be added to the label if they repeat statements already included in the FAISD Handbook (Handbook of First Aid Instructions and Safety Directions for Agricultural and Veterinary Chemicals).

Withholding period

The minimum period that must elapse between the last use of a product in relation to a crop, pasture or animal, and the harvesting or cutting of, or the grazing of animals on, the crop or pasture, the shearing or slaughter of the animal, or the collection of milk or eggs from the animal for human consumption as the case may be, in order to ensure that the product’s residues fall to or below the Australian MRL.

It is part of the directions for use within the concepts of Good Agricultural Practice (GAP) in the use of agricultural and veterinary chemical products.

6.   REFERENCES

Details are provided for current editions at the time of publication. Applicants should always ensure that they obtain the most recent edition of any publication.

• Australian Government Department of Health and Ageing. Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), Commonwealth of Australia.
• Organisation for Economic Cooperation and Development. OECD Guidelines for the Testing of Chemicals, two volumes, OECD Publications Service, Paris ISBN 92 6414018 2 (Available from 2, Rue Andre-Pascal, 75775 Paris Cedex 16, France). http://new.sourceoecd.org/reference/guidelinestestingchemicals
• Therapeutic Goods Administration. ADI list (Acceptable Daily Intakes for Agricultural and Veterinary Chemicals). http://www.tga.gov.au/docs/html/adi.htm
• Therapeutic Goods Administration. FAISD Handbook (Handbook of First Aid Instructions and Safety Directions for Agricultural and Veterinary Chemicals) http://www.tga.gov.au/docs/html/faisd.htm
• Therapeutic Goods Administration. ARfD List (Acute Reference Doses for Agricultural and Veterinary Chemicals). http://www.tga.gov.au/docs/html/arfd.htm
• WHO/FAO Joint Meeting on Pesticide Residues (2004) Pesticide Residues in Food. General Considerations. Guidance on the establishment of Acute Reference Doses. Report 2004, Pages 3-9.
  http://www.fao.org/WAICENT/FAOINFO/AGRICULT/AGP/AGPP/
  Pesticid/JMPR/DOWNLOAD/2004_rep/report2004jmpr.pdf

Footnotes

1. [3.6 Acute oral toxicity] 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.
2. [Acute toxicity studies] The oral or dermal dose of a substance that produces death in 50% of a population of experimental organisms. See Glossary for further information.
3. [Acute toxicity studies] The concentration of a substance in air that produces death by inhalation in 50% of a population of experimental organisms. See Glossary for further information.

Revision history