Optimized Strategies for Risk Assessment
of Industrial Chemicals through Integration
of Non-Test and Test Information

REACH: Information to be submitted in the technical dossier depending on tonnage

Toxicological Information

≥1 t/a ≥10 t/a ≥100 t/a ≥1000 t/a
Toxicological information
8.1 Skin irritation or skin corrosion
The assessment of this endpoint shall comprise the following consecutive steps:
(1) an assessment of the available human and animal data,

(2) an assessment of the acid or alkaline reserve,

(3) in vitro study for skin corrosion,

(4) in vitro study for skin irritation.

Specific Rules: Steps 3 and 4 do not need to be conducted if:
— the available information indicates that the criteria are met for classification as corrosive to the skin or irritating to eyes, or

— the substance is classified as very toxic in contact with skin, or

— an acute toxicity study by the dermal route does not indicate skin irritation up to the limit dose level (2 000 mg/kg body weight).

X X X X
8.1.1 In vivo skin irritation

Specific Rules: The study does not need to be conducted if:
— the substance is classified as corrosive to the skin or as a skin irritant, or

— the substance is a strong acid (pH ≤ 2,0) or base (pH ≥ 11,5), or

— the substance is classified as very toxic in contact with skin, or

— an acute toxicity study by the dermal route does not indicate skin irritation up to the limit dose level (2 000 mg/kg body weight).

X X X
8.2 Eye irritation
The assessment of this endpoint shall comprise the following consecutive steps:
(1) an assessment of the available human and animal data,

(2) an assessment of the acid or alkaline reserve,

(3) in vitro study for eye irritation.

Specific Rule: Step 3 does not need to be conducted if:
— the available information indicates that the criteria are met for classification as corrosive to the skin or irritating to eyes.

X X X X
8.2.2 In vivo eye irritation

Specific Rules: The study does not need to be conducted if:
— the substance is classified as irritating to eyes with risk of serious damage to eyes, or

— the substance is classified as corrosive to the skin and provided that the registrant classified the substance as eye irritant, or

— the substance is a strong acid (pH ≤ 2,0) or base (pH ≥ 11,5)

X X X
8.3 Skin sensitisation
The assessment of this endpoint shall comprise the following consecutive steps:
(1) an assessment of the available human, animal and alternative data,

(2) In vivo testing.

Specific Rules: Step 2 does not need to be conducted if:
— the available information indicates that the substance should be classified for skin sensitisation or corrosivity, or

— the substance is a strong acid (pH ≤ 2,0) or base (pH ≥ 11,5)

The Murine Local Lymph Node Assay (LLNA) is the first-choice method for in vivo testing. Only in exceptional circumstances should another test be used. Justification for the use of another test shall be provided.

X X X X
8.4. Mutagenicity
8.4.1 In vitro gene mutation study in bacteria

Specific Rule: Further mutagenicity studies shall be considered in case of a positive result.

X X X X
8.4.2 In vitro cytogenicity study in mammalian cells or in vitro micronucleus study

Specific Rules: The study does not usually need to be conducted
— if adequate data from an in vivo cytogenicity test are available, or

— the substance is known to be carcinogenic category 1 or 2 or mutagenic category 1, 2 or 3.

X X X
8.4.3 In vitro gene mutation study in mammalian cells,
if a negative result in Annex VII, Section 8.4.1. and Annex VIII, Section 8.4.2.

Specific Rule: The study does not usually need to be conducted if adequate data from a reliable in vivo mammalian gene mutation test are available.

X X X
Specific Rule: Appropriate in vivo mutagenicity studies shall be considered in case of a positive result in any of the genotoxicity studies in Annex VII or VIII. X X X
Specific Rules:
If there is a positive result in any of the in vitro genotoxicity studies in Annex VII or VIII and there are no results available from an in vivo study already, an appropriate in vivo somatic cell genotoxicity study shall be proposed by the registrant.

If there is a positive result from an in vivo somatic cell study available, the potential for germ cell mutagenicity should be considered on the basis of all available data, including toxicokinetic evidence. If no clear conclusions about germ cell mutagenicity can be made, additional investigations shall be considered.
X X
Specific Rules: If there is a positive result in any of the in vitro genotoxicity studies in Annexes VII or VIII, a second in vivo somatic cell test may be necessary, depending on the quality and relevance of all the available data.
If there is a positive result from an in vivo somatic cell study available, the potential for germ cell mutagenicity should be considered on the basis of all available data, including toxicokinetic evidence. If no clear conclusions about germ cell mutagenicity can be made, additional investigations shall be considered.
X
8.5 Acute toxicity
Specific Rule: The study/ies do(es) not generally need to be conducted if:
— the substance is classified as corrosive to the skin.
8.5.1 By oral route

Specific Rule: The study need not be conducted if a study on acute toxicity by the inhalation route (8.5.2) is available.

X X X X
Specific Rule: In addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route need be provided. X X X
8.5.2. By inhalation

Specific Rule: Testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

X X X
8.5.3. By dermal route

Specific Rule:Testing by the dermal route is appropriate if:
(1) inhalation of the substance is unlikely; and

(2) skin contact in production and/or use is likely; and

(3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin.

X X X
8.6. Repeated dose toxicity
8.6.1. Short-term repeated dose toxicity study (28 days), one species, male and female, most appropriate route of administration, having regard to the likely route of human exposure

Specific Rules: The short-term toxicity study (28 days) does not need to be conducted if:
— a reliable sub-chronic (90 days) or chronic toxicity study is available, provided that an appropriate species, dosage, solvent and route of administration were used, or

— where a substance undergoes immediate disintegration and there are sufficient data on the cleavage products, or

— relevant human exposure can be excluded in accordance with Annex XI Section 3.

The appropriate route shall be chosen on the following basis:

Testing by the dermal route is appropriate if:
(1) inhalation of the substance is unlikely; and

(2) skin contact in production and/or use is likely; and

(3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin.

Testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

The sub-chronic toxicity study (90 days) (Annex IX, Section 8.6.2) shall be proposed by the registrant if:
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.

Further studies shall be proposed by the registrant or may be required by the Agency in accordance with Article 40 or 41 in case of:

— failure to identify a NOAEL in the 28 or the 90 days study, unless the reason for the failure to identify a NOAEL is absence of adverse toxic effects, or

— toxicity of particular concern (e.g. serious/severe effects), or

— indications of an effect for which the available evidence 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), or

— the route of exposure 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, or

— particular concern regarding exposure (e.g. use in consumer products leading to exposure levels which are close to the dose levels at which toxicity to humans may be expected), 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 days study.

X X X
Unless already provided as part of Annex VIII requirements or if tests according to Section 8.6.2 of Annex IX is proposed. In this case, Section 3 of Annex XI shall not apply.
X X
8.6.2. Sub-chronic toxicity study (90-day),
one species, rodent, male and female, most appropriate route of administration, having regard to the likely route of human exposure.

Specific Rules: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 R48, 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, or

— a reliable chronic toxicity study is available, provided that an appropriate species and route of administration were used, or

— a substance undergoes immediate disintegration and there are sufficient data on the cleavage products (both for systemic effects and effects at the site of uptake), or

— the substance is unreactive, insoluble 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.

The appropriate route shall

The appropriate route shall be chosen on the following basis:

Testing by the dermal route is appropriate if:
(1) skin contact in production and/or use is likely; and

(2) the physicochemical properties suggest a significant rate of absorption through the skin; and

(3) one of the following conditions is met:

— toxicity is observed in the acute dermal toxicity test at lower doses than in the oral toxicity test, or

— systemic effects or other evidence of absorption is observed in skin and/or eye irritation studies, or

— in vitro tests indicate significant dermal absorption, or

— significant dermal toxicity or dermal penetration is recognised for structurally-related substances.

Testing by the inhalation route is appropriate if:
— exposure of humans via inhalation is likely taking into account the vapour pressure of the substance

and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

Further studies shall be proposed by the registrant or may be required by the Agency in accordance with Articles 40 or 41 in case of:
— failure to identify a NOAEL in the 90 days study unless the reason for the failure to identify a NOAEL is absence of adverse toxic effects, or

— toxicity of particular concern (e.g. serious/severe effects), or

— indications of an effect for which the available evidence 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), or

— particular concern regarding exposure (e.g. use in consumer products leading to exposure levels which are close to the dose levels at which toxicity to humans may be expected).

X X
8.6.3. Long-term repeated toxicity study (≥ 12 months)

Specific Rules: A long-term repeated toxicity study (≥ 12 months) may be proposed by the registrant or required by the Agency in accordance with Articles 40 or 41 if the frequency and duration of human exposure indicates that a longer term study is appropriate and one of the following conditions is met:
— serious or severe toxicity effects of particular concern were observed in the 28-day or 90-day study for which the available evidence is inadequate for toxicological evaluation or risk characterisation, or

— effects shown in substances with a clear relationship in molecular structure with the substance being studied were not detected in the 28-day or 90-day study, or

— the substance may have a dangerous property that cannot be detected in a 90-day study.

X
8.6.4. Further repeated dose toxicity studies

Specific Rules: Further studies shall be proposed by the registrant or may be required by the Agency in accordance with Articles 40 or 41 in case of:
— toxicity of particular concern (e.g. serious/severe effects), or

— indications of an effect for which the available evidence is inadequate for toxicological evaluation 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), or

— particular concern regarding exposure (e.g. use in consumer products leading to exposure levels which are close to the dose levels at which toxicity is observed).

X
8.7. Reproductive toxicity
8.7.1. Screening for reproductive/ developmental toxicity, one species (OECD 421 or 422),
if there is no evidence from available information on structurally related substances, from (Q)SAR estimates or from in vitro methods that the substance may be a developmental toxicant

Specific Rules:This study does not need to be conducted if:
— the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented, or

— the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, or

— relevant human exposure can be excluded in accordance with Annex XI section 3, or

— a pre-natal developmental toxicity study (Annex IX, 8.7.2) or a two-generation reproductive toxicity study (Annex IX, Section 8.7.3) is available.

If a substance is known to have an adverse effect on fertility, meeting the criteria for classification as Repr Cat 1 or 2: R60, and the available data are adequate to support a robust risk assessment, then no further testing for fertility will be necessary. However, testing for development toxicity must be considered.

If a substance is known to cause developmental toxicity, meeting the criteria for classification as Repr Cat 1 or 2: R61, and the available data are adequate to support a robust risk assessment, then no further testing for developmental toxicity will be necessary. However, testing for effects on fertility must be considered.

In cases where there are serious concerns about the potential for adverse effects on fertility or development, either a pre-natal developmental toxicity study (Annex IX, Section 8.7.2) or a two-generation reproductive toxicity study (Annex IX, Section 8.7.3) may be proposed by the registrant instead of the screening study.

X X X
Specific Rules:The studies do not need to be conducted if:
— the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented, or

— the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, or

— the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/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 there is no or no significant human exposure.

If a substance is known to have an adverse effect on fertility, meeting the criteria for classification as Repr Cat 1 or 2: R60, and the available data are adequate to support a robust risk assessment, then no further testing for fertility will be necessary. However, testing for development toxicity must be considered.
If a substance is known to cause developmental toxicity, meeting the criteria for classification as Repr Cat 1 or 2: R61, and the available data are adequate to support a robust risk assessment, then no further testing for developmental toxicity will be necessary. However, testing for effects on fertility must be considered.

X X
8.7.2. Pre-natal developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure (B.31 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 414)

Specific Rule:The study shall be initially performed on one species. A decision on the need to perform a study at this tonnage level or the next on a second species should be based on the outcome of the first test and all other relevant available data.

X X
8.7.2. Developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure (OECD 414) X
8.7.3. Two-generation reproductive toxicity study, one species, male and female, most appropriate route of administration, having regard to the likely route of human exposure,
if the 28-day or 90-day study indicates adverse effects on reproductive organs or tissues

Specific Rule:The study shall be initially performed on one species. A decision on the need to perform a study at this tonnage level or the next on a second species should be based on the outcome of the first test and all other relevant available date.

X X
Unless already provided as part of Annex IX requirements X
8.8. Toxicokinetics
8.8.1. Assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information X X X
8.9. Carcenogenicity
8.9.1. Carcinogenicity study

Specific Rules:A carcinogenicity study may be proposed by the registrant or may be required by the Agency in accordance with Articles 40 or 41 if:
— the substance has a widespread dispersive use or there is evidence of frequent or long-term human exposure, and

— the substance is classified as mutagen category 3 or there is evidence from the repeated dose study(ies) that the substance is able to induce hyperplasia and/or pre-neoplastic lesions.

If the substance is classified as mutagen category 1 or 2, the default presumption would be that a genotoxic mechanism for carcinogenicity is likely. In these cases, a carcinogenicity test will normally not be required.

X

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