Endocrine disrupting substances (EDs) are implicated in declining sperm counts, and rising rates of genital malformation, certain cancers, obesity and diabetes.

This post informs you of proposed EU Regulation of endocrine disrupting chemicals as two new Hazard Classes within the CLP Regulation.

If you wish to find out more about our services for hazard classification, see our services page or contact us. For help with the jargon, check our glossary.

Introduction

The European Commission has published a draft Regulation [1] that incorporates endocrine disrupting effects as new Hazard Classes into the CLP Regulation [2]. The draft Regulation is open for comments until 18 October 2022.

The Regulation introduces the following new Hazard Classes :

• endocrine disruptor for human health
• endocrine disruptor for the environment
• persistent, bioaccumulative and toxic (PBT)
• very persistent and very bioaccumulative (vPvB)
• persistent, mobile and toxic (PMT)
• very persistent and very mobile (vPvM)

The Regulation is expected to be finalised at the end of 2022, but the changes to classification and labelling will have a long transition period so that industry can make changes gradually:

• substances have to be classified in the new Hazard Classes 18 months after the Regulation’s ‘entry into force’ (EIF)
• substance already classified before the EIF date and placed on the market have 42 months before re-classification required
• mixtures have to be classified in the new Hazard Classes 36 months after the Regulation’s EIF
• mixtures already classified before the EIF date and placed on the market have 60 months before re-classification required

This post relates to endocrine disrupting chemicals for human health and the environment. It describes the proposed hazard classification and labelling for substances and mixtures, and the overlap with current Hazard Classes.

The other Hazard Classes concerning persistent chemicals will be described in a later post.

What is endocrine disruption?

An earlier post discussed the hazards of chemicals that cause adverse effects in the endocrine system. The endocrine system comprises glands and hormones that regulate many aspects of development and behaviour in macro-organisms (eg mammals, birds, fish), particularly foetal development, puberty, and sexual behaviour.

In humans, these endocrine disrupting substances (EDs) are implicated in declining sperm counts, genital malformations in newborns, and rising rates of certain cancers. There is also possible impairment in neural development, sexual behaviour, obesity and diabetes. Such disorders are increasing in both children and adults.

The most widely studied endocrine effects in humans relate to only three hormone types: estrogens (in female sexual development and reproduction), androgens (particularly testosterone in male development), and thyroxine (in control of reproduction and metabolic rate). Dozens of other hormones have not been assessed as targets for EDs.

In wildlife, EDs can cause hermaphroditism – a condition known as intersex. Fish and frogs are particularly sensitive to EDs in rivers and lakes. Many other species have not been studied in terms of the effects of EDs.

An internationally accepted definition of EDs is give by the World Health Organisation (WHO/IPCS):

‘an endocrine disrupter is an exogenous substance or mixture that alters functions(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations.’

Thus an endocrine disruptor works through the glands, hormones, and receptors to cause harms (not merely alterations) in whole organisms (not only in cells or tissues). The definition does not mention doses, so a substance may be classified as an ED even if it exerts this effect only at unrealistically high concentrations.

REACH Article 57 mentions EDs as being of equal concern as carcinogens, mutagens and reproductive toxicants (CMRs), and are therefore identified as ‘substances of very high concern’ (SVHCs; see earlier post) and are subject to Authorisation and forced withdrawal from the market.

Several common chemicals have been identified as EDs, including some phthalates, perfluoroalkyl substances (PFASs), and bisphenol A; substances historically found in many food and drink applications.

Testing for endocrine disruptors

Some standard tests for REACH Registration can detect EDs, particularly long-term mammalian tests (eg repeated-dose toxicity, and reproductive and developmental toxicity).

If a chemical is suspected of being an ED, then there are an increasing number of specialised tests to investigate endocrine disrupting effects in mammals or wildlife. The assessor needs to choose tests based on available information, and concerns for particular endocrine effects. Some of these tests are not internationally validated, so their use in regulatory decision making is limited.

It is likely that future changes to the REACH Regulation, which prescribes the testing strategy for chemicals, will include a battery of tests – from in vitro receptor binding to long-term animal tests – similar to that currently required for genotoxicity.

Other evidence may come from structure–activity relationships, ie using data from a different substance that has a similar chemical structure.

Current classification of endocrine disruptors

Hazard classification is the categorization of chemical harms (see our Compendium of chemical hazards) into easily identifiable, standard descriptions, such as flammable liquid, skin irritation, or specific target organ toxicity.

Hazard classification in the EU and UK is performed according to the CLP Regulation. This gives the criteria for each Hazard Class, and its subdivisions (ie Hazard Categories).

The CLP Regulation is based on the United Nation’s (UN) Globally Harmonized System of Classification and Labelling of Chemicals (GHS) [3]. Versions of the GHS are implemented in all industrialized nations, and provides an ‘off-the-peg’ chemical control policy for developing countries. See our earlier post for more details of the GHS.

The new Hazard Categories are not part of the GHS, and will not be recognised beyond the EU. In the interest of speed, the EU preferred to press ahead with the new Hazard Classes. However, the EU have applied to the UN to have them incorporated into the GHS in the future.

A detailed description of the classification process for substances is given in an earlier post.

Some EDs will fall into Hazard Classes already part of the CLP hazard classification system, particularly: toxic to reproduction, specific target organ toxicity, and carcinogenicity. The test methods, criteria, and labelling requirements are already established in the GHS and Annex I of the CLP Regulation.

Endocrine effects are not specifically mentioned in the Hazard Classes for the environment, but may be included as a general ‘adverse effect’ in long-term testing in aquatic species, especially fish.

The endocrine disruption Hazard Classes are unusual because they focus on the mechanism that causes the adverse effect (ie via the endocrine system), and not on the type of effect (eg foetal development, cancer, or target organ toxicity).

Proposal for classification and labelling of endocrine disruptors

The new draft Regulation creates a new Hazard Class under the CLP Regulation specifically for endocrine disruptors (EDs).

There are separate Hazard Classes for human health and the environment.

New Hazard Classes for are also proposed for substances that are persistent, bioaccumulative and toxic (PBT) and persistent, mobile and toxic (PMT). EDs qualify for the toxic (T) part in the definition of these substances, and could lead to classification in both Hazard Classes.

Endocrine disruptor for human health

Human health Hazard Class for EDs is divided into two Hazard Categories based on the strength of evidence for the effects, in a similar way to carcinogens, mutagens, and reproductive toxicants.

• Category 1: known or presumed ED effect in humans, based on human or animal data.
• Category 2: suspected ED effect in humans, based on human or animal data, but insufficient evidence for classification in Category 1 (eg where the link between endocrine activity and adverse effect is less established).

Similarly to reproductive toxicants, the ED classification is not required where the adverse effects are the result of general toxicity and not a specific ED effect.

Mixtures containing ED ingredients are classified using concentration thresholds. Mixture classification is described in a previous post. Generic concentration thresholds for EDs in mixtures are:

• mixture classified as Category 1 if Category 1 ingredient present at ≥ 0.1%
• mixture classified as Category 2 if Category 2 ingredient present at ≥ 1%

The label elements for substances and mixtures classified as ‘endocrine disruptor for human health’ are given in Table 1 below:

	Category 1	Category 2
Abbreviated classification	ED HH 1	ED HH 2
Pictogram	to be determined	to be determined
Signal word	Danger	Warning
Hazard Statement	EUH380: May cause endocrine disruption in humans	EUH381: Suspected of causing endocrine disruption in humans
Precautionary Statements	P201: Obtain special instructions before use; P202: Do not handle until all safety precautions have been read and understood; P263: Avoid contact during pregnancy and while nursing; P280: Wear protective gloves/protective clothing/eye protection/face protection; P308 + P313: IF exposed or concerned: Get medical advice/attention; P405: Store locked up; P501: Dispose of contents/container to …	P201: Obtain special instructions before use; P202: Do not handle until all safety precautions have been read and understood; P263: Avoid contact during pregnancy and while nursing; P280: Wear protective gloves/protective clothing/eye protection/face protection; P308 + P313: IF exposed or concerned: Get medical advice/attention; P405: Store locked up; P501: Dispose of contents/container to …

Endocrine disruptor for the environment

The environmental Hazard Class for EDs is similarly divided into two Hazard Categories based on the strength of evidence for the effects.

• Category 1: known or presumed ED effect for the environment, based on animal data.
• Category 2: suspected ED effect for the environment, based on animal data, but insufficient evidence for classification in Category 1 (eg where the link between endocrine activity and adverse effect is less established).

The ED classification is not required where the effects are the result of general toxicity and not a specific ED effect.

Mixtures containing ED ingredients are classified using concentration thresholds. Mixture classification is described in a previous post. Generic concentration thresholds for EDs in mixtures are:

• mixture classified as Category 1 if Category 1 ingredient present at ≥ 0.1%
• mixture classified as Category 2 if Category 2 ingredient present at ≥ 1%

The label elements for substances and mixtures classified as ‘endocrine disruptor for the environment’ are given in Table 2 below:

	Category 1	Category 2
Abbreviated classification	ED ENV 1	ED ENV 2
Pictogram	to be determined	to be determined
Signal word	Danger	Warning
Hazard Statement	EUH430: May cause endocrine disruption in the environment	EUH431: Suspected of causing endocrine disruption in the environment
Precautionary Statements	P201: Obtain special instructions before use; P202: Do not handle until all safety precautions have been read and understood; P273: Avoid release to the environment; P391: Collect spillage; P405: Store locked up; P501: Dispose of contents/container to …	P201: Obtain special instructions before use; P202: Do not handle until all safety precautions have been read and understood; P273: Avoid release to the environment; P391: Collect spillage; P405: Store locked up; P501: Dispose of contents/container to …

References

[back to Introduction] [back to Current Regulation of EDs]

[1] Commission delegated regulation (EU) amending Regulation (EC) No 1272/2008 as regards hazard classes and criteria for the classification, labelling and packaging of substances and mixtures; available at the European Commission website: https://ec.europa.eu/info/index_en.

[2] Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures (as amended).

[3] Globally Harmonized System of Classification and Labelling (GHS); Eighth Revised Edition; United Nations; 2019.