xmlns:atom="http://www.w3.org/2005/Atom" xmlns:atom="http://www.w3.org/2005/Atom"

[X1ANNEX IX U.K. STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 100 TONNES OR MORE (1)

Editorial Information

At the level of this Annex, the registrant must submit a proposal and a time schedule for fulfilling the information requirements of this Annex in accordance with Article 12(1)(d).

Column 1 of this Annex establishes the standard information required for all substances manufactured or imported in quantities of 100 tonnes or more in accordance with Article 12(1)(d). Accordingly, the information required in column 1 of this Annex is additional to that required in column 1 of Annexes VII and VIII. Any other relevant physicochemical, toxicological and ecotoxicological information that is available shall be provided. Column 2 of this Annex lists specific rules according to which the registrant may propose to omit the required standard information, replace it by other information, provide it at a later stage or adapt it in another way. If the conditions are met under which column 2 of this Annex allows an adaptation to be proposed, the registrant shall clearly state this fact and the reasons for proposing each adaptation under the appropriate headings in the registration dossier.

[F1Without prejudice to the information submitted for other forms, any relevant physicochemical, toxicological and ecotoxicological information shall include characterisation of the nanoform tested and test conditions. A justification shall be provided where QSARs are used or evidence is obtained by means other than testing, as well as a description of the range of the characteristics/properties of the nanoforms to which the evidence can be applied.]

Textual Amendments

In addition to these specific rules, a registrant may propose to adapt the required standard information set out in column 1 of this Annex according to the general rules contained in Annex XI. In this case as well, he shall clearly state the reasons for any decision to propose adaptations to the standard information under the appropriate headings in the registration dossier referring to the appropriate specific rule(s) in column 2 or in Annex XI (2) .

Before new tests are carried out to determine the properties listed in this Annex, all available in vitro data, in vivo data, historical human data, data from valid (Q)SARs and data from structurally related substances (read-across approach) shall be assessed first. In vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided. Prior to testing, further guidance on testing strategies should be consulted in addition to this Annex.

When, for certain endpoints, it is proposed not to provide information for other reasons than those mentioned in column 2 of this Annex or in Annex XI, this fact and the reasons shall also be clearly stated.

7. INFORMATION ON THE PHYSICOCHEMICAL PROPERTIES OF THE SUBSTANCE U.K.

COLUMN 1 STANDARD INFORMATION REQUIRED COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1
7.15. Stability in organic solvents and identity of relevant degradation products

Only required if stability of the substance is considered to be critical.

7.15. The study does not need to be conducted if the substance is inorganic.
7.16. Dissociation constant
7.16. The study does not need to be conducted if:

  • the substance is hydrolytically unstable (half-life less than 12 hours) or is readily oxidisable in water, or

  • it is scientifically not possible to perform the test for instance if the analytical method is not sensitive enough.

7.17. Viscosity

8. TOXICOLOGICAL INFORMATION U.K.

COLUMN 1 STANDARD INFORMATION REQUIRED COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1
8.4. 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.

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, unless already provided as part of Annex VIII requirements or if tests according to Section 8.6.2 of this Annex is proposed. In this case, Section 3 of Annex XI shall not apply.
[F28.6.2. 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.
8.6.2. 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 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.

For nanoforms toxicokinetics shall be considered including recovery period and, where relevant, lung clearance.

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, and in particular for nanoforms indirect genotoxicity), 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).]

8.7. Reproductive toxicity
8.7. 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.

[F3If a substance is known to have an adverse effect on fertility, meeting the criteria for classification as toxic for reproduction 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 fertility will be necessary. However, testing for developmental toxicity must be considered.

If a substance is known to cause 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, then no further testing for developmental toxicity will be necessary. However, testing for effects on fertility must be considered.]

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 [F4made under] Article 13(3) or OECD 414).
8.7.2. 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.
[F58.7.3. Extended One-Generation Reproductive Toxicity Study (B.56 of the Commission Regulation on test methods [F6made under] Article 13(3) or OECD 443), basic test design (cohorts 1A and 1B without extension to include a F2 generation), one species, most appropriate route of administration, having regard to the likely route of human exposure, if the available repeated dose toxicity studies (e.g. 28-day or 90-day studies, OECD 421 or 422 screening studies) indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity.
8.7.3. An Extended One-Generation Reproductive Toxicity Study with the extension of cohort 1B to include the F2 generation shall be proposed by the registrant or may be required by the Agency in accordance with Article 40 or 41, if:
(a)

the substance has uses leading to significant exposure of consumers or professionals, taking into account, inter alia, consumer exposure from articles, and

(b)

any of the following conditions are met:

  • the substance displays genotoxic effects in somatic cell mutagenicity tests in vivo which could lead to classifying it as Mutagen Category 2, or

  • there are indications that the internal dose for the substance and/or any of its metabolites will reach a steady state in the test animals only after an extended exposure, or

  • there are indications of one or more relevant modes of action related to endocrine disruption from available in vivo studies or non-animal approaches.

An Extended One-Generation Reproductive Toxicity Study including cohorts 2A/2B (developmental neurotoxicity) and/or cohort 3 (developmental immunotoxicity) shall be proposed by the registrant or may be required by the Agency in accordance with Article 40 or 41, in case of particular concerns on (developmental) neurotoxicity or (developmental) immunotoxicity justified by any of the following:

  • existing information on the substance itself derived from relevant available in vivo or non-animal approaches (e.g. abnormalities of the CNS, evidence of adverse effects on the nervous or immune system in studies on adult animals or animals exposed prenatally), or

  • specific mechanisms/modes of action of the substance with an association to (developmental) neurotoxicity and/or (developmental) immunotoxicity (e.g. cholinesterase inhibition or relevant changes in thyroidal hormone levels associated to adverse effects), or

  • existing information on effects caused by substances structurally analogous to the substance being studied, suggesting such effects or mechanisms/modes of action.

Other studies on developmental neurotoxicity and/or developmental immunotoxicity instead of cohorts 2A/2B (developmental neurotoxicity) and/or cohort 3 (developmental immunotoxicity) of the Extended One-Generation Reproductive Toxicity Study may be proposed by the registrant in order to clarify the concern on developmental toxicity.

Two-generation reproductive toxicity studies (B.35, OECD TG 416) that were initiated before 13 March 2015 shall be considered appropriate to address this standard information requirement.

The study shall be performed on one species. The need to perform a study at this tonnage level or the next on a second strain or a second species may be considered and a decision should be based on the outcome of the first test and all other relevant available data.]

9. ECOTOXICOLOGICAL INFORMATION U.K.

COLUMN 1 STANDARD INFORMATION REQUIRED COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1
9.1. Aquatic toxicity
9.1. Long-term toxicity testing shall be proposed by the registrant if the chemical safety assessment according to Annex I indicates the need to investigate further the effects on aquatic organisms. The choice of the appropriate test(s) depends on the results of the chemical safety assessment.
9.1.5. Long-term toxicity testing on invertebrates (preferred species Daphnia ), (unless already provided as part of Annex VII requirements)
9.1.6. Long-term toxicity testing on fish, (unless already provided as part of Annex VIII requirements)

The information shall be provided for one of the Sections 9.1.6.1, 9.1.6.2 or 9.1.6.3.

9.1.6.1. Fish early-life stage (FELS) toxicity test
9.1.6.2. Fish short-term toxicity test on embryo and sac-fry stages
9.1.6.3. Fish, juvenile growth test
9.2. Degradation
9.2. Further biotic degradation testing shall be proposed by the registrant if the chemical safety assessment according to Annex I indicates the need to investigate further the degradation of the substance and its degradation products. The choice of the appropriate test(s) depends on the results of the chemical safety assessment and may include simulation testing in appropriate media (e.g. water, sediment or soil).
9.2.1. Biotic
[F29.2.1.2. Simulation testing on ultimate degradation in surface water
9.2.1.2. The study need not be conducted if:

  • the substances is highly insoluble in water, or

  • the substance is readily biodegradable.

For nanoforms, the study may not be waived on the basis of high insolubility in water alone.]

9.2.1.3. Soil simulation testing (for substances with a high potential for adsorption to soil)
9.2.1.3. The study need not be conducted:

  • if the substance is readily biodegradable, or

  • if direct and indirect exposure of soil is unlikely.

9.2.1.4. Sediment simulation testing (for substances with a high potential for adsorption to sediment)
9.2.1.4. The study need not be conducted:

  • if the substance is readily biodegradable, or

  • if direct and indirect exposure of sediment is unlikely.

9.2.3. Identification of degradation products
9.2.3. Unless the substance is readily biodegradable
[F29.3. Fate and behaviour in the environment
9.3.2. Bioaccumulation in aquatic species, preferably fish
9.3.2. The study need not be conducted if:

  • the substance has a low potential for bioaccumulation (for instance a log Kow ≤ 3) and/or a low potential to cross biological membranes, or

  • direct and indirect exposure of the aquatic compartment is unlikely.

For nanoforms, use of any physicochemical property (e.g. octanol water partition coefficient, dissolution rate, dispersion stability) as a reason for waiving the study shall include adequate justification of its relevance to low potential for bioaccumulation or unlikely direct and indirect exposure of the aquatic compartment.

9.3.3. Further information on adsorption/desorption depending on the results of the study required in Annex VIII
9.3.3. The study need not be conducted if:

  • based on the physicochemical properties, the substance can be expected to have a low potential for adsorption (e.g. the substance has a low octanol water partition coefficient), or

  • the substance and its degradation products decompose rapidly.

For nanoforms, use of any physicochemical property (e.g. octanol water partition coefficient, dissolution rate, dispersion stability) as a reason for waiving the study shall include adequate justification of its relevance to low potential for adsorption.]

[F29.4. Effects on terrestrial organisms
9.4. These studies do not need to be conducted if direct and indirect exposure of the soil compartment is unlikely.

In the absence of toxicity data for soil organisms, the equilibrium partitioning method may be applied to assess the hazard to soil organisms. Where the equilibrium partitioning method is applied to nanoforms, this shall be scientifically justified.

The choice of the appropriate tests depends on the outcome of the chemical safety assessment.

In particular for substances that have a high potential to adsorb to soil or that are very persistent, the registrant shall consider long-term toxicity testing instead of short-term.]

9.4.1. Short-term toxicity to invertebrates
9.4.2. Effects on soil micro-organisms
9.4.3. Short-term toxicity to plants

10. METHODS OF DETECTION AND ANALYSIS U.K.

Description of the analytical methods shall be provided on request, for the relevant compartments for which studies were performed using the analytical method concerned. If the analytical methods are not available this shall be justified.]

(1)

[X1This Annex shall apply to producers of articles that are required to register in accordance with Article 7 and to other downstream users that are required to carry out tests under this Regulation adapted as necessary.]

(2)

[X1Note: conditions for not requiring a specific test that are set out in [regulations under] Article 13(3) that are not repeated in column 2, also apply.]

Editorial Information