2.IDENTITY OF THE ACTIVE SUBSTANCE (AND ITS PRECURSOR(S) IF THE ACTIVE SUBSTANCE IS GENERATED IN SITU)| For the active substance and, if applicable, its precursors, the information given in this Section shall be sufficient to enable the active substance to be identified. If it is not technically possible or if it does not appear scientifically necessary to give information on one or more of the items listed in this Section, the reasons shall be clearly stated | | |
| 2.1.Common name proposed or accepted by ISO and synonyms (usual name, trade name, abbreviation) | | |
| 2.2.Chemical name (IUPAC and CA nomenclature or other international chemical name(s)) | | |
| 2.3.Manufacturer’s development code number(s) | | |
| 2.4.CAS number plus EC, INDEX and CIPAC numbers | | |
| 2.5.Molecular and structural formula (including SMILES notation, if available and appropriate).For precursor(s) and for active substances generated in situ, information about all generated chemical substances (intended and unintended) | | In case it is not possible to exactly define the molecular structure of the precursor(s) and/or active substance, the molecular and structural formulas do not need to be provided |
| 2.6.Information on optical activity and full details of any isomeric composition (if applicable and appropriate) | | |
| 2.7.Molar mass | | |
| 2.8.Method of manufacture (syntheses pathways) of active substance including information on starting materials and solvents including suppliers, specifications and commercial availability.For active substances generated in situ, a description of the reaction schemes including all intermediate reactions and their associated chemical substances (intended and unintended) shall be provided | | |
| 2.9.Specification of purity of the active substance as manufactured in g/kg, g/l or %w/w (v/v) as appropriate, providing inclusively the upper and lower limit | | |
| 2.10.The identity of any impurities and additives including by-products of synthesis, optical isomers, degradation products (if the substance is unstable) un-reacted and end-groups etc. of polymers and un-reacted starting materials of UVC-substances | | |
| 2.11.Analytical profile of at least five representative batches (g/kg active substance) including information on content of the impurities referred to in 2.10. | | |
| 2.11.1.Analytical profile of at least five representative samples taken from the in situ generated substance(s), providing information on the content of the active substance(s) and any other constituent above 0,1 % w/w, including residues of precursor(s) | | |
| 2.12.The origin of the natural active substance or the precursor(s) of the active substance, e.g. an extract of a flower | | |
3.PHYSICAL AND CHEMICAL PROPERTIES OF THE ACTIVE SUBSTANCE3.1.Appearance| 3.1.1.Aggregate state (at 20 °C and 101,3 kPa) | | |
| 3.1.2.Physical state (i.e. viscous, crystalline, powder) (at 20 °C and 101,3 kPa) | | |
| 3.1.3.Colour (at 20 °C and 101,3 kPa) | | |
| 3.1.4.Odour (at 20 °C and 101,3 kPa) | | |
| 3.2.Melting/freezing point | | |
| 3.3.Acidity, alkalinity | | |
| 3.4.Boiling point | | |
| 3.5.Relative Density | | |
| 3.6.Absorption spectra data (UV/VIS, IR, NMR) and a mass spectrum, molar extinction coefficient at relevant wavelengths, where relevant | | |
3.7.Vapour pressure| 3.7.1.Henry’s law constant must always be stated for solids and liquids if it can be calculated | | |
| 3.8.Surface tension | | |
| 3.9.Water solubility | | |
| 3.10.Partition coefficient (n-octanol/water) and its pH dependency | | |
| 3.11.Thermal stability, identity of breakdown products | | |
| 3.12.Reactivity towards container material | | |
| 3.13.Dissociation constant | ADS | |
| 3.14.Granulometry | | |
| 3.15.Viscosity | ADS | |
| 3.16.Solubility in organic solvents, including effect of temperature on solubility | ADS | |
| 3.17.Stability in organic solvents used in biocidal products and identity of relevant breakdown products | ADS | |
6.EFFECTIVENESS AGAINST TARGET ORGANISMS| 6.1.Function, e.g. fungicide, rodenticide, insecticide, bactericide and mode of control e.g. attracting, killing, inhibiting | | |
| 6.2.Representative organism(s) to be controlled and products, organisms or objects to be protected | | |
| 6.3.Effects on representative target organism(s) | | |
| 6.4.Likely concentration at which the active substance will be used in products and, where appropriate, in treated articles | | |
| 6.5.Mode of action (including time delay) | | |
6.6.Efficacy data to support:- the innate activity of the active substance for the intended use(s), and
- any claims made on treated articles regarding the biocidal properties conferred to the article.
Efficacy data shall include any available standard protocols, laboratory tests or field trials and performance standards where appropriate, or data similar to those available for suitable reference products | | |
6.7.Any known limitations on efficacy| 6.7.1.Information on the occurrence or possible occurrence of the development of resistance and appropriate management strategies | | |
| 6.7.2.Observations on undesirable or unintended side effects on non-target organisms or on objects and material to be protected | | |
8.TOXICOLOGICAL PROFILE FOR HUMAN AND ANIMAL INCLUDING METABOLISM8.1.Skin corrosion or irritationThe assessment shall comprise the following tiers:- (a)assessment of the available human, animal and non-animal data;
- (b)skin corrosion, in vitro testing;
- (c)skin irritation, in vitro testing;
- (d)skin corrosion or irritation, in vivo testing
| | The study/ies in column 1 do(es) not need to be conducted if:- the available information indicates that the substance meets the criteria for classification for skin corrosion or irritation,
- the substance is a strong acid (pH≤ 2,0) or base (pH≥ 11,5),
- the substance is spontaneously flammable in air or in contact with water or moisture at room temperature,
- the substance meets the classification criteria for acute toxicity (Category 1) by the dermal route, or
- an acute toxicity study by the dermal route provides conclusive evidence on skin corrosion or irritation adequate for classification.
If results from one of the two studies listed in point (b) or point (c) in column 1 of this row already allow conclusive decision on the classification of a substance or on the absence of skin irritation potential, the second study does not need to be conductedAn in vivo study for skin corrosion or irritation shall be considered only if the in vitro studies listed in points (b) and (c) in column 1 of this row are not applicable, or the results of these studies are not adequate for classification and risk assessmentIn vivo studies for skin corrosion or irritation that were carried out or initiated before 15 April 2022 shall be considered appropriate to address this information requirement |
8.2.Serious eye damage or eye irritationThe assessment shall comprise the following tiers:- (a)assessment of the available human, animal and non-animal data;
- (b)serious eye damage or eye irritation, in vitro testing;
- (c)serious eye damage or eye irritation, in vivo testing
| | The study/ies in column 1 do(es) not need to be conducted if:- the available information indicates that the substance meets the criteria for classification for eye irritation or causing serious damage to eyes,
- the substance is a strong acid (pH≤ 2,0) or base (pH≥ 11,5),
- the substance is spontaneously flammable in air or in contact with water or moisture at room temperature, or
- the substance meets the classification criteria for skin corrosion leading to classification of the substance as "serious eye damage" (category 1).
If results from a first in vitro study do not allow a conclusive decision on the classification of the substance or on the absence of eye irritation potential (an)other(s) in vitro study(ies) for this endpoint shall be considered.An in vivo study for serious eye damage or eye irritation shall be considered only if the in vitro study(ies) listed in point (b) in column 1 of this row are not applicable, or the results obtained from these studies are not adequate for classification and risk assessmentIn vivo studies for serious eye damage or eye irritation that were carried out or initiated before 15 April 2022 shall be considered appropriate to address this information requirement |
8.3.Skin sensitisationThe information shall allow to conclude whether the substance is a skin sensitiser and whether it can be presumed to have the potential to produce significant sensitisation in humans (Category 1A). The information should be sufficient to perform a risk assessment where requiredThe assessment shall comprise the following tiers:- (a)assessment of the available human, animal and non-animal data;
- (b)skin sensitisation, in vitro testing. Information from in vitro or in chemico test method(s) referred to in point 5 of the introductory part of this Annex and addressing each of the following key events of skin sensitisation:
- (i)molecular interaction with skin proteins;
- (ii)inflammatory response in keratinocytes;
- (iii)activation of dendritic cells;
- (c)skin sensitisation in vivo testing. The Murine Local Lymph Node Assay (LLNA) is the first-choice method for in vivo testing. Another skin sensitisation test may only be used in exceptional cases. If another skin sensitisation test is used, justification shall be provided
| | The study/ies in column 1 do(es) not need to be conducted if:- the available information indicates that the substance meets the criteria for classification for skin sensitisation or skin corrosion,
- the substance is a strong acid (pH≤ 2,0) or base (pH≥ 11,5), or
- the substance is spontaneously flammable in air or in contact with water or moisture at room temperature.
In vitro tests do not need to be conducted if:- an in vivo study referred to in point (c) of column 1 of this row is available, or
- the available in vitro or in chemico test methods are not applicable for the substance or the results obtained from those studies are not adequate for classification and risk assessment.
If information from test method(s) addressing one or two of the key events described under point (b) in column 1 of this row allows for classification of the substance and risk assessment, studies addressing the other key event(s) do not need to be conductedAn in vivo study for skin sensitisation shall be conducted only if in vitro or in chemico test methods described under point (b) in column 1 of this row are not applicable, or the results obtained from those studies are not adequate for classification and risk assessmentIn vivo skin sensitisation studies that were carried out or initiated before 15 April 2022 shall be considered appropriate to address this information requirement |
| 8.4.Respiratory sensitisation | ADS | |
8.5.MutagenicityThe assessment of this endpoint shall comprise the following consecutive steps:- an assessment of the available in vivo genotoxicity data
- an in vitro test for gene mutations in bacteria, an in vitro cytogenicity test in mammalian cells and an in vitro gene mutation test in mammalian cells are required
- appropriate in vivo genotoxicity studies shall be considered in case of a positive result in any of the in vitro genotoxicity studies
| | |
| 8.5.1.In vitro gene mutation study in bacteria | | |
| 8.5.2.In vitro cytogenicity study in mammalian cells | | |
| 8.5.3.In vitro gene mutation study in mammalian cells | | |
8.6.In vivo genotoxicity studyThe assessment shall comprise the following tiers:- (a)If there is a positive result in any of the in vitro genotoxicity studies as listed in 8.5 and there are no reliable results available from an appropriate in vivo somatic cell genotoxicity study, an appropriate in vivo somatic cell genotoxicity study shall be conducted;
- (b)A second in vivo somatic cell genotoxicity study may be necessary depending on the in vitro and in vivo results, type of effects, quality and relevance of all available data;
- (c)If there is a positive result from an in vivo somatic cell genotoxicity study available, the potential for germ cell mutagenicity should be considered based on all available data, including toxicokinetic evidence to demonstrate whether the substance has the capacity to reach germ cells. If no clear conclusions about germ cell mutagenicity can be made, additional investigations shall be considered
| ADS | The study/ies in column 1 do(es) not need to be conducted if:- the results are negative for the three in vitro tests listed in 8.5 and no other concern has been identified (e.g. metabolites of concern formed in mammals), or
- the substance meets the criteria to be classified as a germ cell mutagen category 1A or 1B.
The germ cell genotoxicity test does not need to be conducted if the substance meets the criteria to be classified as a carcinogen, category 1A or 1B and a germ cell mutagen category 2 |
8.7.Acute toxicityIn addition to the oral route of administration (8.7.1), for substances other than gases, the information mentioned under 8.7.2 to 8.7.3 shall be provided for at least one other route of administration- The choice for the second route will depend on the nature of the substance and the likely route of human exposure
- Gases and volatile liquids should be administered by the inhalation route
- If the only route of exposure is the oral route, then information for only that route need be provided. If either the dermal or inhalation route is the only route of exposure to humans then an oral test may be considered. Before a new dermal acute toxicity study is carried out, an in vitro dermal penetration study (OECD 428) should be conducted to assess the likely magnitude and rate of dermal bioavailability
- There may be exceptional circumstances where all routes of administration are deemed necessary
| | The study/ies do(es) not generally need to be conducted if:- the substance is classified as corrosive to the skin
|
| 8.7.1.By oral routeThe Acute Toxic Class Method is the preferred method for the determination of this endpoint | | The study need not be conducted if:- the substance is a gas or a highly volatile substance
|
8.7.2.By inhalationTesting by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account:- the vapour pressure of the substance (a volatile substance has vapour pressure > 1 × 10–2 Pa at 20 °C) and/or
- the active substance is a powder containing a significant proportion (e.g. 1 % on a weight basis) of particles with particle size MMAD < 50 micrometers or
- the active substance is included in products that are powders or are applied in a manner that generates exposure to aerosols, particles or droplets of an inhalable size (MMAD < 50 micrometers)
- the Acute Toxic Class Method is the preferred method for the determination of this endpoint
| | |
8.7.3.By dermal routeTesting by the dermal route is necessary only if:- inhalation of the substance is unlikely, or
- skin contact in production and/or use is likely, and either
- the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin, or
- the results of an in vitro dermal penetration study (OECD 428) demonstrate high dermal absorption and bioavailability
| | |
8.8.Toxicokinetics and metabolism studies in mammals| The toxicokinetics and metabolism studies should provide basic data about the rate and extent of absorption, the tissue distribution and the relevant metabolic pathway including the degree of metabolism, the routes and rate of excretion and the relevant metabolites | | |
8.8.1.Further toxicokinetic and metabolism studies in mammalsAdditional studies might be required based on the outcome of the toxicokinetic and metabolism study conducted in rat. These further studies shall be required if:- there is evidence that metabolism in the rat is not relevant for human exposure
- route-to-route extrapolation from oral to dermal/inhalation exposure is not feasible
Where it is considered appropriate to obtain information on dermal absorption, the assessment of this endpoint shall proceed using a tiered approach for assessment of dermal absorption | ADS | |
8.9.Repeated dose toxicityIn general, only one route of administration is necessary and the oral route is the preferred route. However, in some cases it may be necessary to evaluate more than one route of exposure.For the evaluation of the safety of consumers in relation to active substances that may end up in food or feed, it is necessary to conduct toxicity studies by the oral routeTesting by the dermal route shall be considered if:- skin contact in production and/or use is likely, and
- inhalation of the substance is unlikely, and
- one of the following conditions is met:
- (i)toxicity is observed in an acute dermal toxicity test at lower doses than in the oral toxicity test, or
- (ii)information or test data indicate dermal absorption is comparable or higher than oral absorption, or
- (iii)dermal toxicity is recognised for structurally related substances and for example is observed at lower doses than in the oral toxicity test or dermal absorption is comparable or higher than oral absorption
Testing by the inhalation route shall be considered if:- exposure of humans via inhalation is likely taking into account the vapour pressure of the substance (volatile substances and gases have vapour pressure > 1 × 10–2 Pa at 20 °C), and/or
- there is the possibility of exposure to aerosols, particles or droplets of an inhalable size (MMAD < 50 micrometers)
| | The repeated dose toxicity study (28 or 90 days) does not need to be conducted if:- a substance undergoes immediate disintegration and there are sufficient data on the cleavage products for systemic and local effects and no synergistic effects are expected, or
- relevant human exposure can be excluded in accordance with Section 3 of Annex IV
In order to reduce testing carried out on vertebrates and in particular the need for free-standing single-endpoint studies, the design of the repeated dose toxicity studies shall take account of the possibility to explore several endpoints within the framework of one study |
| 8.9.1.Short-term repeated dose toxicity study (28 days), preferred species is rat | | The short-term toxicity study (28 days) does not need to be conducted if:- (i)a reliable sub-chronic (90 day) study is available, provided that the most appropriate species, dosage, solvent and route of administration were used,
- (ii)the frequency and duration of human exposure indicates that a longer term study is appropriate and one of the following conditions is met:
- other available data indicate that the substance may have a dangerous property that cannot be detected in a short-term toxicity study, or
- appropriately designed toxicokinetic studies reveal accumulation of the substance or its metabolites in certain tissues or organs which would possibly remain undetected in a short term toxicity study but which are liable to result in adverse effects after prolonged exposure
|
| 8.9.2.Sub-chronic repeated dose toxicity study (90 days), preferred species is rat | | The sub-chronic toxicity study (90 days) does not need to be conducted if:- a reliable short-term toxicity study (28 days) is available showing severe toxicity effects according to the criteria for classifying the substance as H372 and H373 (Regulation (EC) No 1272/2008), for which the observed NOAEL-28 days, with the application of an appropriate uncertainty factor allows the extrapolation towards the NOAEL-90 days for the same route of exposure, and
- a reliable chronic toxicity study is available, provided that an appropriate species and route of administration were used, or
- the substance is unreactive, insoluble, not bioaccumulative and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28-day "limit test", particularly if such a pattern is coupled with limited human exposure
|
| 8.9.3.Long-term repeated dose toxicity (≥ 12 months) | | The long-term toxicity study (≥ 12 months) does not need to be conducted if:- Long-term exposure can be excluded and no effects have been seen at the limit dose in the 90-day study or
- a combined long-term repeated dose/carcinogenicity study (8.11.1) is undertaken
|
8.9.4.Further repeat dose studiesFurther repeat dose studies including testing on a second species (non-rodent), studies of longer duration or through a different route of administration shall be undertaken in case of:- no other information on toxicity for a second non-rodent species is provided for, or
- failure to identify a no observed adverse effect level (NOAEL) in the 28- or the 90-day study, unless the reason is that no effects have been observed at the limit dose, or
- substances bearing positive structural alerts for effects for which the rat or mouse is an inappropriate or insensitive model, or
- toxicity of particular concern (e.g. serious/severe effects), or
- indications of an effect for which the available data is inadequate for toxicological and/or risk characterisation. In such cases it may also be more appropriate to perform specific toxicological studies that are designed to investigate these effects (e.g. immunotoxicity, neurotoxicity, hormonal activity), or
- concern regarding local effects for which a risk characterisation cannot be performed by route-to route extrapolation, or
- particular concern regarding exposure (e.g. use in biocidal products leading to exposure levels which are close to the toxicologically relevant dose levels), or
- effects shown in substances with a clear relationship in molecular structure with the substance being studied were not detected in the 28- or the 90-day study, or
- the route of administration used in the initial repeated dose study was inappropriate in relation to the expected route of human exposure and route-to-route extrapolation cannot be made.
| ADS | |
| 8.10.Reproductive toxicityFor evaluation of consumer safety of active substances that may end up in food or feed, it is necessary to conduct toxicity studies by the oral route | | The studies do not need to be conducted if:- the substance meets the criteria to be classified as a genotoxic carcinogen (classified both as germ cell mutagen category 2, 1A or 1B and carcinogenic category 1A or 1B), and appropriate risk management measures are implemented including measures related to reproductive toxicity,
- the substance meets the criteria to be classified as a germ cell mutagen category 1A or 1B and appropriate risk management measures are implemented including measures related to reproductive toxicity,
- the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available provided that the dataset is sufficiently comprehensive and informative), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma or blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and the pattern of use indicates that there is no or negligible human or animal exposure,
- the substance meets the criteria to be classified as reproductive toxicity category 1A or 1B: May damage fertility (H360F), and the available data are adequate to support a robust risk assessment, then no further testing for sexual function and fertility will be necessary. A full justification must be provided and documented if investigations for developmental toxicity are not conducted, or
- the substance is known to cause developmental toxicity, meeting the criteria for classification as reproductive toxicity category 1A or 1B: May damage the unborn child (H360D), and the available data are adequate to support a robust risk assessment, then no further testing for developmental toxicity will be necessary. A full justification must be provided and documented if investigations for sexual function and fertility is not conducted.
Notwithstanding the provisions of this column of this row, studies on reproductive toxicity may need to be conducted to obtain information on endocrine disrupting properties as laid down in 8.13.3.1. |
| 8.10.1.Pre-natal development toxicity study (OECD TG 414) on two species, preferred first species is rabbit (non-rodent) and preferred second species is rat (rodent); oral route of administration is the preferred route | | The study on the second species shall not be conducted if the study performed on the first species or other available data indicate that the substance causes developmental toxicity meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage the unborn child (H360D), and the available data are adequate to support a robust risk assessment |
| 8.10.2.Extended One-Generation Reproductive Toxicity Study (OECD TG 443), with cohorts 1A and 1B and extension of cohort 1B to include the F2 generation with the aim to produce 20 litters per dose group, F2 pups must be followed to weaning and investigated similarly as F1 pups. Rat is the preferred species and oral route of administration is the preferred route.The highest dose level should be based on toxicity and selected with the aim to induce reproductive and/or other systemic toxicity | | A two-generation reproductive toxicity study conducted in accordance with OECD TG 416 (adopted 2001 or later) or equivalent information shall be considered appropriate to address this information requirement, if the study is available and was initiated before 15 April 2022. |
| 8.10.3.Developmental neurotoxicityDevelopmental Neurotoxicity Study in accordance with OECD TG 426, or any relevant study (set) providing equivalent information, or cohorts 2A and 2B of an Extended One-Generation Reproductive Toxicity study (OECD TG 443) with additional investigation for cognitive functions | | The study shall not be conducted if the available data:- indicate that the substance causes developmental toxicity and meets the criteria to be classified as toxic for reproduction category 1A or 1B: May damage the unborn child (H360D), and
- are adequate to support a robust risk assessment
|
| 8.10.4.Further studiesA decision on the need to perform additional studies including those informing on the mechanisms should be based on the outcomes of the studies listed in 8.10.1, 8.10.2 and 8.10.3 and all other relevant available data | ADS | |
| 8.11.CarcinogenicitySee 8.11.1 for new study requirements | | A carcinogenicity study does not need to be conducted if:- the substance is classified as mutagen category 1A or 1B. The default presumption would be that a genotoxic mechanism for carcinogenicity is likely. In these cases, a carcinogenicity test will normally not be required
|
| 8.11.1.Combined carcinogenicity study and long-term repeated dose toxicityRat, oral route of administration is the preferred route. If an alternative route is proposed a justification must be provided.For evaluation of consumer safety of active substances that may end up in food or feed, it is necessary to conduct toxicity studies by the oral route | | |
8.11.2.Carcinogenicity testing in a second species- (a)A second carcinogenicity study should be conducted using the mouse as test species;
- (b)For evaluation of consumer safety of active substances that may end up in food or feed, it is necessary to conduct toxicity studies by the oral route
| | The second carcinogenicity study does not need to be conducted if the applicant can justify on the basis of scientific grounds that it is not necessary |
8.12.Relevant health data, observations and treatments| Justification should be provided if data is not available | | |
| 8.12.1.Information on signs of poisoning, clinical tests, first aid measures, antidotes, medical treatment and prognosis following poisoning | | |
| 8.12.2.Epidemiological studies | | |
| 8.12.3.Medical surveillance data, health records and case reports | | |
| 8.13.Additional studiesAdditional data which may be required depending on the characteristics and intended use of the active substanceOther available data: Available data from emerging methods and models, including toxicity pathway-based risk assessment, in vitro and "omic" (genomic, proteomic, metabolomic, etc.) studies, systems biology, computational toxicology, bioinformatics, and high-throughput screening shall be submitted in parallel | ADS | |
| 8.13.1.Phototoxicity | ADS | |
| 8.13.2.NeurotoxicityIf the active substance is an organophosphorus compound or if there is an indication, knowledge of the mechanism of action or knowledge from acute or repeated dose studies that the active substance may have neurotoxic properties, additional information or specific studies (such as OECD TG 424 or OECD TG 418 or 419 or equivalent) will be requiredIf anticholinesterase activity is detected a test for response to reactivating agents should be consideredFor evaluation of consumer safety of active substances that may end up in food or feed, it is necessary to conduct toxicity studies by the oral route | ADS | |
8.13.3.Endocrine disruptionThe assessment of endocrine disruption shall comprise the following tiers:- (a)An assessment of the available information from the following studies and any other relevant information, including in vitro and in silico methods:
- (i)8.9.1 A 28-day oral toxicity study in rodents (OECD TG 407);
- (ii)8.9.2 A 90-day oral toxicity study in rodents (OECD TG 408);
- (iii)8.9.4 A repeated dose oral toxicity study in non-rodents (OECD TG 409);
- (iv)8.10.1 A prenatal developmental toxicity study (OECD TG 414);
- (v)8.10.2 An extended one-generation reproductive toxicity study (OECD TG 443) or two-generation reproductive toxicity study (OECD TG 416);
- (vi)8.10.3 A developmental neurotoxicity study (OECD TG 426);
- (vii)8.11.1 A combined carcinogenicity study and long-term repeated dose toxicity study (OECD TG 451-3);
- (viii)A systematic review of the literature including studies on mammals and non-mammalian organisms;
- (b)If there is any information suggesting that the active substance may have endocrine disrupting properties, or if there is incomplete information on key parameters relevant for concluding on endocrine disruption, then additional information or specific studies shall be required to elucidate:
- (1)the mode or the mechanism of action; and/or
- (2)potentially relevant adverse effects in humans or animals
For evaluation of consumer safety of active substances that may end up in food or feed, it is necessary to consider the oral route and conduct animal studies by the oral route | | Where sufficient weight of evidence to conclude on the presence or absence of a particular endocrine disrupting mode of action is available:- further testing on vertebrate animals for that effect shall be omitted for that mode of action,
- further testing not involving vertebrate animals may be omitted for that mode of action.
In all cases, adequate and reliable documentation shall be provided |
8.13.3.1.Specific additional studies to investigate potential endocrine disrupting properties may include, but are not limited to the following:- (a)the mammalian toxicity studies listed in 8.13.3(a);
- (b)the in vitro assays:
- (i)Estrogen receptor transactivation assay (OECD TG 455);
- (ii)Androgen receptor transactivation assay, (OECD TG 458);
- (iii)H295R steroidogenesis assay (OECD TG 456);
- (iv)the Aromatase assay (human recombinant) OPPTS 890.1200;
- (c)Uterotrophic bioassay in rodents (OECD TG 440) and Hershberger bioassay in rats (OECD TG 441);
- (d)Pubertal development and Thyroid Function in Intact Juvenile or Peripubertal Male Rats (OPPTS 890.1500).
The decision to carry out studies in mammals shall be taken based on all available information, including a systematic review of the literature (including information on endocrine disrupting effects in non-target organisms) and the availability of suitable in silico or in vitro methods | ADS | |
8.13.4.Immunotoxicity and developmental immunotoxicityIf there is any evidence from repeat dose or reproductive toxicity studies that the active substance may have immunotoxic properties, then additional information or specific studies shall be required to elucidate:- (1)the mode or the mechanism of action; and/or
- (2)potentially relevant adverse effects in humans or animals.
For evaluation of consumer safety of active substances that may end up in food or feed, it is necessary to consider the oral route and conduct animal studies by the oral route | ADS | |
| 8.13.5.Further mechanistic studiesA decision on the need to perform additional studies should be based on all relevant data | ADS | |
| 8.14.Studies related to the exposure of humans to the active substance | ADS | |
| 8.15.Toxic effects on livestock and pets | ADS | |
| 8.16.Food and feeding stuffs studies including for food-producing animals and their products (milk, eggs and honey)Additional information related to the exposure of humans to the active substance contained in biocidal products | ADS | |
| 8.16.1.Proposed acceptable residue levels i.e. maximum residue limits (MRL) and the justification of their acceptability | ADS | |
| 8.16.2.Behaviour of the residue of the active substance on the treated or contaminated food or feeding stuffs including the kinetics of disappearanceResidue definitions should be provided where relevant. It is also important to compare residues found in toxicity studies with residues formed in food-producing animals and their products, as well as food and feed | ADS | |
| 8.16.3.Overall material balance for the active substanceSufficient residue data from supervised trials on food- producing animals and their products, as well as food and feed, to demonstrate that residues likely to arise from the proposed use would not be of concern for human or animal health | ADS | |
| 8.16.4.Estimation of potential or actual exposure of humans to the active substance and residues through diet and other means | ADS | |
| 8.16.5.If residues of the active substance occur in or on feeding stuffs for a significant period of time or are found in food of animal origin after treatment on or around food-producing animals (e.g. direct treatment on animals or indirect treatment of animal houses or surroundings) then feeding and metabolism studies in livestock shall be required to permit evaluation of residues in food of animal origin | ADS | |
| 8.16.6.Effects of industrial processing and/or domestic preparation on the nature and magnitude of residues of the active substance | ADS | |
| 8.16.7.Any other available information that is relevantIt may be appropriate to include information on migration into food, especially in the case of treatment of food contact materials | ADS | |
| 8.16.8.Summary and evaluation of data submitted under 8.16.1 to 8.16.8It is important to establish whether the metabolites found in food (from animals or plants) are the same as those tested in toxicity studies. Otherwise values for risk assessment (e.g. ADI) are not valid for the residues found | ADS | |
| 8.17.If the active substance is to be used in products for action against plants including algae then tests shall be required to assess toxic effects of metabolites from treated plants, if any, where different from those identified in animals | ADS | |
| 8.18.Summary of mammalian toxicologyProvide overall evaluation and conclusion with regard to all toxicological data and any other information concerning the active substances including NOAEL | | |
9.ECOTOXICOLOGICAL STUDIES9.1.Toxicity to Aquatic Organisms| 9.1.1.Short-term toxicity testing on fishWhen short-term fish toxicity data is required, the threshold approach (tiered strategy) should be applied.A long-term toxicity testing on fish in accordance with point 9.1.6.1 shall be considered if the substance is poorly water soluble, i.e. below 1 mg/L | | The study does not need to be conducted if:- a valid long-term aquatic toxicity study on fish is available,
- sufficient weight of evidence including the use of other data such as the Fish Embryo Acute Toxicity (FET, OECD TG 236) and/or results obtained from non-animal methods is available for this data requirement
|
9.1.2.Short-term toxicity testing on aquatic invertebrates| 9.1.2.1.Daphnia magna | | |
| 9.1.2.2.Other species | ADS | |
9.1.3.Growth inhibition study on algae| 9.1.3.1.Effects on growth rate of green algae | | |
| 9.1.3.2.Effects on growth rate of cyanobacteria or diatoms | | |
| 9.1.4.Bioconcentration | | The experimental determination may not need to be carried out if:- it can be demonstrated on the basis of physico-chemical properties (e.g. log Kow < 3) or other evidence that the substance has a low potential for bioconcentration
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| 9.1.4.1.Estimation methods |
| 9.1.4.2.Experimental determination |
| 9.1.5.Inhibition of microbial activityThe study may be replaced by a nitrification inhibition test if available data show that the substance is likely to be an inhibitor of microbial growth or function, in particular nitrifying bacteria | | |
| 9.1.6.Further Toxicity Studies on Aquatic OrganismsIf the results of the ecotoxicological studies, studies on fate and behaviour and/or the intended use(s) of the active substance indicate a risk for the aquatic environment, or if long-term exposure is expected, then one or more of the tests described in this Section shall be conducted | ADS | |
| 9.1.6.1.Long term toxicity testing on fishThe information shall be provided from long-term toxicity testing on fish in which early life-stages (eggs, larvae or juveniles) are exposed | ADS | |
9.1.6.2.Long term toxicity testing on invertebrates- (a)Daphnia growth and reproduction study
- (b)Other species reproduction and growth (e.g. Mysid)
- (c)Other species development and emergence (e.g. Chironomus)
| ADS | |
| 9.1.7.Bioaccumulation in an appropriate aquatic species | ADS | |
| 9.1.8.Effects on any other specific, non-target organisms (flora and fauna) believed to be at risk | ADS | |
| 9.1.9.Studies on sediment- dwelling organisms | ADS | |
| 9.1.10.Effects on aquatic macrophytes | ADS | |
| 9.2.Terrestrial toxicity, initial tests | ADS | |
| 9.2.1.Effects on soil micro-organisms |
| 9.2.2.Effects on earthworms or other soil- dwelling non-target invertebrates |
| 9.2.3.Acute toxicity to plants |
| 9.3.Terrestrial tests, long term | ADS | |
| 9.3.1.Reproduction study with earthworms or other soil-dwelling non-target invertebrates |
| 9.4.Effects on birds | ADS | For endpoint 9.4.3 the study does not need to be conducted if:- the dietary toxicity study shows that the LC50 is above 2000 mg/kg
|
| 9.4.1.Acute oral toxicity |
| 9.4.2.Short-term toxicity — eight-day dietary study in at least one species (other than chickens, ducks and geese) |
| 9.4.3.Effects on reproduction |
| 9.5.Effects on arthropods | ADS | |
| 9.5.1.Effects on honeybees |
| 9.5.2.Other non-target terrestrial arthropods, e.g. predators |
| 9.6.Bioconcentration, terrestrial | ADS | |
| 9.7.Bioaccumulation, terrestrial | ADS | |
| 9.8.Effects on other non-target, non-aquatic organisms | ADS | |
| 9.9.Effects on mammals | ADS | Data are derived from the mammalian toxicological assessment. The most sensitive relevant mammalian long-term toxicological endpoint (NOAEL) expressed as mg test compound/kg bw/day shall be reported |
| 9.9.1.Acute oral toxicity |
| 9.9.2.Short term toxicity |
| 9.9.3.Long term toxicity |
| 9.9.4.Effects on reproduction |
9.10.Endocrine disruptionThe assessment of endocrine disruption properties shall comprise the following tiers:- (a)An assessment of the mammalian data set in accordance with 8.13.3 to assess whether the substance has endocrine disrupting properties based on data in relation to mammals;
- (b)If it cannot be concluded based on the mammalian data in accordance with 8.13.3 or 9.1.6.1 that the substance has endocrine disrupting properties, then studies set out in 9.10.1 or 9.10.2 shall be considered taking account of any other available relevant information, including a systematic review of the literature
| | |
9.10.1.Endocrine disruption in fishSpecific studies to investigate potential endocrine disrupting properties may include, but are not limited to the following data requirements:- (a)Medaka extended one-generation test (MEOGRT, OECD TG 240);
- (b)Fish life cycle toxicity test (FLCTT, OPPTS 850.1500) covering all the "estrogen-, androgen- and steroidogenic-mediated" (EAS) parameters foreseen to be measured in the MEOGRT study
| | The study does not need to be carried out if:- there is no indication for endocrine activity or endocrine related effects from a sufficient mammalian data set in accordance with 8.13.3 or from any other relevant information (e.g. literature), and
- valid in vivo data is available, with no information suggesting that the active substance may elicit endocrine activity or effects potentially related to endocrine activity in either the Fish short term reproduction assay (FSTRA; OECD TG 229), or the 21-days fish assay (OECD TG 230) or Fish sexual developmental test (FSDT, OECD TG 234).
If other data are available covering the estrogenic, androgenic and steroidogenic, (EAS) related modalities or parameters investigated in OECD TG 229 or OECD TG 230 or OECD TG 234, then those data can be used instead |
| 9.10.2.Endocrine disruption in amphibiansSpecific additional studies to investigate potential endocrine disrupting properties may include, but are not limited to Larval amphibian growth and development assay (LAGDA; OECD TG 241) | | The study does not need to be carried out if:- there is no indication for endocrine activity or endocrine related effects from a sufficient mammalian data set in accordance with 8.13.3 or from any other relevant information (e.g. literature), and
- valid in vivo data is available, with no information suggesting that the active substance may have endocrine disrupting properties in an Amphibian metamorphosis assay (AMA; OECD 231)
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9.10.3.If there is information suggesting that the active substance may have endocrine disrupting properties, or if there is incomplete information on key parameters relevant for concluding on endocrine disruption, additional information or specific studies, as necessary, shall be required to elucidate:- (a)the mode or the mechanism of action; and/or
- (b)potentially relevant adverse effects in humans or animals.
| ADS | |
11.MEASURES NECESSARY TO PROTECT HUMANS, ANIMALS AND THE ENVIRONMENT| 11.1.Recommended methods and precautions concerning handling, use, storage, transport or fire | | |
| 11.2.In case of fire, nature of reaction products, combustion gases etc. | | |
| 11.3.Emergency measures in case of accident | | |
11.4.Possibility of destruction or decontamination following release in or on the following:- (a)air
- (b)water, including drinking water
- (c)soil
| | |
| 11.5.Procedures for waste management of the active substance for industry or professional users | | |
| 11.6.Possibility of reuse or recycling | | |
| 11.7.Possibility of neutralisation of effects | | |
| 11.8.Conditions for controlled discharge including leachate qualities on disposal | | |
| 11.9.Conditions for controlled incineration | | |
| 11.10.Identification of any substances falling within the scope of List I or List II of the Annex to Council Directive 80/68/EEC of 17 December 1979 on the protection of groundwater against pollution caused by certain dangerous substances, of Annexes I and II to Directive 2006/118/EC of the European Parliament and of the Council of 12 December 2006 on the protection of groundwater against pollution and deterioration, of Annex I to Directive 2008/105/EC of the European Parliament and of the Council of 16 December 2008 on environmental quality standards in the field of water policy, of Part B of Annex I to Directive 98/83/EC or Annexes VIII and X to Directive 2000/60/EC | | |