Human health hazard band C hazard characteristics

Reproductive toxicity

Reproductive toxicity means that any of the following apply to the industrial chemical: 

• the chemical is known, presumed or suspected to produce adverse effects on sexual function and fertility, as described in chapter 3.7 of the GHS, with the chemical classified as toxic to reproduction (category 1 or 2), or 
• the chemical is on the list of chemicals with high hazards for categorisation based on its reproductive toxicity, or 
• the chemical is an ester or salt of specified chemicals in the table below, which are on the list of chemicals with high hazards for categorisation based on reproductive toxicity, unless an exception as identified in the table below is met for that chemical, or 
• an in vivo study on the chemical conducted following an acceptable test guideline for reproductive toxicity, carcinogenicity, chronic toxicity, subchronic oral toxicity, subchronic dermal toxicity or subchronic inhalation toxicity results in adverse effects on sexual function and fertility, as described in chapter 3.7 of the GHS.

Information required to demonstrate the absence of the hazard characteristic, reproductive toxicity  

• If the chemical is a polyhalogenated organic chemical and the human health exposure band for the introduction is 4 - 
  • an in vivo test result on the chemical or suitable read across information conducted following an acceptable test guideline for reproductive toxicity, which results in none of the adverse effects on sexual function or fertility described in chapter 3.7 of the GHS;
• Otherwise – 
  • confirmation that the chemical is not on the list of chemicals with high hazards for categorisation, based on its reproductive toxicity
  • confirmation that the chemical is not an ester or salt of the specified chemicals shown in the below table, which are on the list of chemicals with high hazards for categorisation based on reproductive toxicity.

Reproductive toxicity - exception criteria

Check the following table - an ester or salt of the chemical has the reproductive toxicity hazard characteristic, unless one or more of the following exception criteria apply. 
 

Note – Low levels of low molecular weight species (in relation to a polymer) means less than 10% (by mass) of molecules with a molecular weight that is less than 500 g/mol and less than 25% (by mass) of molecules with a molecular weight that is less than 1,000 g/mol.

Developmental toxicity

Developmental toxicity means that any of the following apply to the industrial chemical:

• the chemical is known, presumed or suspected to produce adverse effects on the development of the offspring or effects on the offspring via lactation, as described in chapter 3.7 of the GHS, with the chemical classified as follows: 
  • toxic to reproduction (category 1 or 2), or 
  • effects on or via lactation, or 
• the chemical is on the list of chemicals with high hazards for categorisation based on its developmental toxicity, or
• the chemical is an ester or salt of specified chemicals in the table below, which are on the list of chemicals with high hazards for categorisation based on developmental toxicity, unless an exception as identified in the table below is met for that chemical, or 
• an in vivo study on the chemical conducted following an acceptable test guideline for developmental toxicity or reproductive toxicity results in adverse effects on the development of the offspring or effects on the offspring via lactation, as described in chapter 3.7 of the GHS.
   

Information required to demonstrate the absence of the hazard characteristic, developmental toxicity

• If the chemical is a polyhalogenated organic chemical and the human health exposure band for the introduction is 4 – 
  • an in vivo test result on the chemical or suitable read across information conducted following an acceptable test guideline for developmental toxicity or reproductive toxicity which results in none of the adverse effects on the development of the offspring or effects on the offspring via lactation, as described in chapter 3.7 of the GHS
• Otherwise – 
  • confirmation that the chemical is not on the list of chemicals with high hazards for categorisation, based on its developmental toxicity and
  • confirmation that the chemical is not an ester or salt of the specified chemicals shown in the below table, which are on the list of chemicals with high hazards for categorisation, based on developmental toxicity.

Developmental toxicity - exception criteria

Check the following table - an ester or salt of the chemical has the development toxicity hazard characteristic, unless one or more of the following exception criteria apply. 

Note – Low levels of low molecular weight species (in relation to a polymer) means less than 10% (by mass) of molecules with a molecular weight that is less than 500 g/mol and less than 25% (by mass) of molecules with a molecular weight that is less than 1,000 g/mol
  

Adverse effects mediated by an endocrine mode of action

Adverse effects of mediated by an endocrine mode of action means that any of the following apply to the industrial chemical: 

• the chemical meets all of the following: 
  • it shows an adverse effect in an intact organism or its progeny, which is a change in the morphology, physiology, growth, development, reproduction or lifespan of an organism, system or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in the susceptibility to other influences, and 
  • it has an endocrine activity, which is the capacity to alter the function(s) of the endocrine system, and 
  • the adverse effect is a consequence of the endocrine activity

or

• the chemical is on the list of chemicals with high hazards for categorisation, based on its adverse effects mediated by an endocrine mode of action or 
• the chemical is an ester or salt of specified chemicals in the table below, which are on the list of chemicals with high hazards for categorisation based on adverse effects mediated by an endocrine mode of action unless an exception, as identified in the table below, is met for that chemical, or 
• the chemical meets all of the following: 
  • information is available that is relevant to determining whether the chemical has the hazard characteristic, adverse effects mediated by an endocrine mode of action, and 
  • the information has been considered in a weight of evidence analysis based on the following guidance documents: 
    • the EU guidance for identifying endocrine disruptors*, and 
    • the guidance provided in OECD GD 150**; and 
  • the weight of evidence analysis concludes that the chemical has the hazard characteristic, adverse effects mediated by an endocrine mode of action. 

Information required to demonstrate the absence of the hazard characteristic, adverse effects mediated by an endocrine mode of action

• If the chemical has existing information relevant to determining whether it has the hazard characteristic, adverse effects mediated by an endocrine mode of action, information is required to demonstrate that the chemical does not have this hazard characteristic: 
  • this must involve a documented weight of evidence analysis based on the EU guidance for identifying endocrine disruptors* and the guidance in OECD GD 150**, and 
  • the analysis must conclude that the chemical does not have the hazard characteristic, adverse effects mediated by an endocrine mode of action.
• Otherwise– 
  • confirmation that the chemical is not on the list of chemicals with high hazards for categorisation, based on its adverse effects mediated by an endocrine mode of action and
  • confirmation that the chemical is not an ester or salt of the specified chemicals shown in the below table, which are on the list of chemicals with high hazards for categorisation, based on adverse effects mediated by an endocrine mode of action. 

Adverse effects mediated by an endocrine mode of action - exception criteria

Check the following table - an ester or salt of the chemical has the adverse effects mediated by an endocrine mode of action hazard characteristic, unless one or more of the following exception criteria apply. 

Note – Low levels of low molecular weight species (in relation to a polymer) means less than 10% (by mass) of molecules with a molecular weight that is less than 500 g/mol and less than 25% (by mass) of molecules with a molecular weight that is less than 1,000 g/mol.

*Guidance for the identification of endocrine disruptors in the context of 39 Regulations (EU) No 528/2012 and (EC) No 1107/2009, 2018 

**‘OECD Series on Testing and Assessment, No. 150 - Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption.’  OECD, OECD Series on Testing and Assessment, No. 150, 2018
 

Genetic toxicity

Genetic toxicity means that any of the following apply to the industrial chemical: 

• the chemical is known to induce or may induce mutations in the germ cells of humans, as described in chapter 3.5 of the GHS, with the chemical classified as germ cell mutagenicity (category 1 or 2), or 
• the chemical is on the list of chemicals with high hazards for categorisation, based on its genetic toxicity, or 
• the chemical is an ester or salt of specified chemicals in the table below, which are on the list of chemicals with high hazards for categorisation based on genetic toxicity unless an exception, as identified in the table below, is met for that chemical, or 
• an in vitro study on the chemical:
  • conducted following an acceptable test guideline for gene mutation or chromosomal abnormalities results in the prediction of mutagenic or genotoxic effects, as described in chapter 3.5 of the GHS, and 
  • the results of the study have not been negated by in vivo studies conducted on the chemical for gene mutation, chromosomal abnormalities or heritable germ cell mutagenicity, or 
• an in vivo study on the chemical conducted following an acceptable test guideline for gene mutation, chromosomal abnormalities or heritable germ cell mutagenicity results in mutagenic or genotoxic effects, as described by chapter 3.5 of the GHS.

Information required to demonstrate the absence of the hazard characteristic, genetic toxicity

The information required to demonstrate that a chemical does not have the hazard characteristic, genetic toxicity, is: 

• if the human health exposure band for the introduction is 4 - at least one of the following: 
  • information to demonstrate that the chemical is included on the Select Committee on GRAS Substances (SCOGS) Database as a Type 1 conclusion, and that the human health exposure expected from the industrial use of the chemical is no higher than the human health exposure expected from food use, or 
  • information to demonstrate that the chemical has been notified to the US FDA GRAS notification program and FDA had no questions about the notifier’s conclusion of GRAS status, and that the human health exposure expected from the industrial use of the chemical is no higher than the human health exposure expected from food use, or 
  • information that demonstrates that the chemical is a substance covered by Entry 9 of Annex V of the REACH Regulation, or 
  • information to demonstrate that the chemical is a high molecular weight polymer, and if you are seeking to demonstrate that the introduction meets the criteria for very low risk and is not one of the 'special cases' mentioned in step 4.5 - test results from an in vitro study on the polymer or from suitable read across information conducted following an acceptable test guideline for gene mutation, which demonstrates the absence of mutagenic effects, or 
  • test results that demonstrate the absence of mutagenic or genotoxic effects from both: 
    • study on the chemical or from suitable read across information conducted following an acceptable test guideline for gene mutation, and 
    • study on the chemical or from suitable read across information conducted following an acceptable test guideline for chromosomal abnormalities. 
• if the human health exposure band for the introduction is 3, and you are seeking to demonstrate that the introduction meets the criteria for very low risk and is not one of the 'special cases' mentioned in step 4.5 - at least one of the following: 
  • inclusion of the chemical in the Select Committee on GRAS Substances (SCOGS) Database as a Type 1 conclusion, as long as the human health exposure expected from the industrial use of the chemical is no higher than the human health exposure expected from food use, or 
  • the chemical has been notified to the US FDA GRAS notification program and FDA had no questions about the notifier’s conclusion of GRAS status, as long as the human health exposure expected from the industrial use of the chemical is no higher than the human health exposure expected from food use, or 
  • information that demonstrates that the chemical is a substance covered by Entry 9 of Annex V of the REACH Regulation, or
  • if the polymer is a high molecular weight polymer, test results from an in vitro study on the polymer or from suitable read across information conducted following an acceptable test guideline for gene mutations, which demonstrates the absence of mutagenic effects, or 
  • information that demonstrates the absence of mutagenic or genotoxic effects from both: 
    • information on the chemical or from suitable read across information that addresses gene mutations - this could be: 
      • a suitable in silico prediction, both with and without metabolic activation, or 
      • test results from a study conducted following an acceptable test guideline for gene mutations; and
    • test results from a study on the chemical or from suitable read across information conducted following an acceptable test guideline for chromosomal abnormalities.
• Otherwise– 
  • confirmation that the chemical is not on the list of chemicals with high hazards for categorisation, based on its genetic toxicity and
  • confirmation that the chemical is not an ester or salt of the specified chemicals shown in the below table, which are on the list of chemicals with high hazards for categorisation, based on genetic toxicity.

Note – Low levels of low molecular weight species (in relation to a polymer) means less than 10% (by mass) of molecules with a molecular weight that is less than 500 g/mol and less than 25% (by mass) of molecules with a molecular weight that is less than 1,000 g/mol. 

Genetic toxicity - exception criteria

Check the following table - an ester or salt of the chemical has the genetic toxicty hazard characteristic, unless one or more of the following exception criteria apply. 

• in addition, if the human health exposure band for the introduction is 4 and the chemical is a UV filter, information is required to justify why the chemical would not cause genetic toxicity mediated by UV light. This may include one or more of the following: 
  • the chemical has a molar extinction coefficient/absorption coefficient of less than 1,000 Lmol^-1cm^-1 at wavelengths between 290 and 700 nm (based on the results of a study following OECD test guideline 101), or 
  • results from in vitro phototoxicity studies, or 
  • results from in vitro or in vivo genetic toxicity studies where the methods have been modified to include photoactivation.

More information: Categorisation of UV filters

Example 1 – chemical is a salt of a specified chemical which is on the list of chemicals with high hazards for categorisation, based on carcinogenicity 

Peter wants to introduce the chemical glycine, N,N-bis[2-[bis(carboxymethyl)amino]ethyl]-, sodium salt (1:?) (CAS: 7578-43-0), which is a salt of Glycine, N,N-bis(carboxymethyl)- (CAS: 139-13-9) that is in the table of specified chemicals for carcinogenicity. The proposed introduction has a molecular weight of 415.33 g/mol and therefore does not meet the exception criterion “the salt/ester is a high molecular weight polymer, with low levels of low molecular weight species” nor the exception criterion “the molecular weight of the salt/ester is greater than or equal to 1,000 g/mol”. Thus, Glycine, N,N-bis(2-(bis(carboxymethyl)amino)ethyl)-, sodium salt (CAS: 7578-43-0) is considered to have the human health hazard characteristic carcinogenicity.

Peter’s introduction's human health hazard band is C so he should move on to the next step – step 4.5 Work out your human health risk for categorisation.

Example 2 – chemical is an ester of a specified chemical which is on the list of chemicals with high hazards for categorisation, based on carcinogenicity and genetic toxicity 

Rose wants to introduce an ester of [1,1’-Biphenyl]-2-ol, which has a molecular weight ≥1,000 g/mol. The ester itself is not on the List, but her chemical is an ester of [1,1’-Biphenyl]-2-ol, which is in the tables of specified chemicals for carcinogenicity and genetic toxicity. So she needs to consider whether an exception applies to this chemical. If an exception does not apply, the ester would be considered to have the same high hazard characteristics as [1,1’-Biphenyl]-2-ol (carcinogenicity and genetic toxicity). But because Rose’s chemical has a molecular weight greater than or equal to1,000 g/mol, it meets the exception criteria. 

Rose’s ester is not considered to have the human health hazard characteristics of carcinogenicity and genetic toxicity. 

Rose continues through step 4.4 of the categorisation process and next needs to follow our guidance on checking human health hazard band B hazard characteristics.

Example 3 – polymer is an ester of a specified chemical which is on the list of chemicals with high hazards for categorisation, based on genetic toxicity

Paul wants to introduce a branched polymer containing phenol, 2-amino- bound to side chains via ester linkages. 
The polymer itself is not on the List, but it contains phenol, 2-amino-, which is in the table of specified chemicals for genetic toxicity. So he needs to consider whether an exception applies to this chemical. If an exception does not apply, the polymer would be considered to have the same high hazard characteristics as phenol, 2-amino- (genetic toxicity). 

The number average molecular weight (NAMW) of Paul’s polymer is 4,500 g/mol with 17% by mass having a molecular weight less than 1,000 g/mol and 8% by mass having a molecular weight less than 500 g/mol. The exception criteria for polymers states that there must be low levels of low molecular weight species which means less than 10% (by mass) of molecules with a molecular weight that is less than 500 g/mol and less than 25% (by mass) of molecules with a molecular weight that is less than 1,000 g/mol. Therefore, the polymer meets the exception criteria and is not considered to have the genetic toxicity hazard characteristic. 

Paul continues through step 4.4 of the categorisation process and next needs to follow our guidance on checking human health hazard band B hazard characteristics.