Identification of Substances of Very High Concern (SVHC) under the 'equivalent level of concern' route (REACH Article 57(f)) : neurotoxicants and immunotoxicants as examples.
Date: 2015-08-20
Institutions: Institute for Health and Consumer Protection
Subjects: European Chemicals Agency, chemical industry, chemical product, dangerous substance, database, environmental risk prevention, industrial research, public health, regulation (EU), report, research and development, research method, toxic substance

Identification of Substances of Very High Concern 
(SVHC) under the 'equivalent level of concern' route 
(REACH Article 57(f)) – neurotoxicants and 
immunotoxicants as examples 

Laia Quiros Pesudo and Karin Aschberger 

2015 

Report  EUR 27383 
EN

European Commission 

Joint Research Centre 

Institute for Health and Consumer Protection 

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JRC96572 

EUR 27383 EN 

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ISSN 1831-9424 (online) 

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Abstract 
This report analyses whether substances classified for specific target organ toxicity (STOT) according Regulation (EC) No 1272/2008 on 
Classification, Labelling and Packaging, in particular those causing immunotoxic or neurotoxic effects, would be eligible to be identified 
as substances of very high concern (SVHC) under the 'equivalent level of concern' route set out in Article 57(f) of REACH Regulation (EC) 
No  1907/2006  (Registration,  Evaluation,  Authorisation  and  Restriction  of  Chemicals).  This  document  attempts  to  identify,  characterise 
and  compare  the  'level  of  concern'  that  exists  for  immunotoxic  and  neurotoxic  substances  with  that  of  CMRs  (carcinogens,  mutagens 
and/or  reproductive  toxicants).  The  comparison  considers  the  seriousness,  irreversibility  and  delay  of  hazardous  effects,  together  with 
other factors, such as the quality of life affected, consequences for society and the possibility to derive a safe concentration.  

Identification of Substances of Very High Concern 
(SVHC) under the 'equivalent level of concern' route 

(REACH Article 57(f)) – 
neurotoxicants and immunotoxicants as examples 

Authors 
Laia Quiros Pesudo and Karin Aschberger 

August 2015 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 

 
 
Table of contents 

Preface .................................................................................................................................................... 7 

Executive summary ................................................................................................................................. 9 

1.  Background ................................................................................................................................... 11 

2.  General identification and assessment of SVHC ........................................................................... 12 

3. 

Identification of STOT-SE/RE classified substances as SVHC ........................................................ 13 

3.1. 

STOT classification ................................................................................................................. 13 

3.1.1. 

Identification of hazard information for STOT-SE/RE substances .................................... 15 

3.1.2. 

Identification of hazard information for neurotoxicants .................................................. 15 

3.1.3. 

Identification of hazard information for immunotoxicants .............................................. 16 

4. 

'Level of Concern' comparison ...................................................................................................... 18 

4.1. 

Health Effects ........................................................................................................................ 21 

4.1.1. 

Type of possible health effects ..................................................................................... 21 

4.1.2. 

Irreversibility of health effects ...................................................................................... 22 

4.1.3. 

Delay of health effects .................................................................................................. 24 

4.2.  Other considerations ............................................................................................................ 26 

4.2.1. 

Quality of life affected .................................................................................................. 26 

4.2.2. 

Societal concern ............................................................................................................ 27 

4.2.3. 

Is derivation of a ‘safe concentration’ possible? .......................................................... 28 

5. 

Specific considerations ................................................................................................................. 30 

5.1. 

Potency ................................................................................................................................. 30 

5.2.  Groups at risk to immunotoxicant and neurotoxicant exposure .......................................... 30 

5.2.1. 

Age ................................................................................................................................ 30 

5.2.2. 

Developmental immune and neurotoxicity .................................................................. 31 

5.2.3. 

Immunodeficiency ........................................................................................................ 32 

5.2.4. 

Genetic susceptibility and gender ................................................................................. 32 

6.  Conclusions ................................................................................................................................... 33 

Abbreviations ........................................................................................................................................ 35 

Annex I: STOT classification in CLP and Criteria for STOT classification ............................................... 36 

Annex II: Adverse health effects caused by immunotoxicants and neurotoxicants ............................. 39 

A.2.1. 

Adverse immune system effects ....................................................................................... 39 

A.2.2. 

Adverse effects of neurotoxicants .................................................................................... 41 

Annex III: Examples for chemicals with potential neurotoxic effects ................................................... 43 

A.3.1.  Metals ............................................................................................................................... 43 

5 

A.3.2. 

Pesticides .......................................................................................................................... 44 

A.3.3. 

Organic solvents ................................................................................................................ 44 

6 

 
 
 
Preface 

This  report  has  been  prepared  in  the  frame  of  an  Administrative  Arrangement  between  the 
Directorate-General Environment (DG ENV) and the Joint Research Centre (JRC), Institute for Health 
and  Consumer  Protection  (IHCP)  on  'Scientific  and  technical  support  to  safety  assessment  of 
chemicals'.  It  analyses  whether  substances  classified  for  specific  target  organ  toxicity  (STOT) 
according  Regulation  (EC)  No  1272/2008  on  Classification,  Labelling  and  Packaging,  in  particular 
those causing immunotoxic or neurotoxic effects, would be eligible to be identified as substances of 
very  high  concern  under  the  ‘equivalent  level  of  concern’  route  set  out  in  Article  57(f)  of  REACH 
Regulation (EC) No 1907/2006 (Registration, Evaluation, Authorisation and Restriction of Chemicals). 
After  an  internal  review  by  JRC-IHCP  and  DG  ENV,  a  draft  version  of  this  report  was  circulated  to 
participants of the 'Sensitiser and other equivalent level of concern substances (ELoC) Coordination 
Group (SCG)' organised by ECHA. Comments received from the SCG were taken into consideration in 
this final version. 

We would like to thank the SCG experts and the colleagues from DG ENV, ECHA and JRC, especially 
from the Systems Toxicology and Chemical Assessment and Testing Units, for their useful comments. 

7 

 
 
8 

 
 
Executive summary 

Article  57  of  REACH  Regulation  (EC)  No  1907/2006  (Registration,  Evaluation,  Authorisation  and 
Restriction of Chemicals) specifies the criteria for substances to be included in Annex XIV, the 'List of 
Substances Subject to Authorisation' under REACH, also known as Substances of Very High Concern 
(SVHC).  According  to  Article  57  (a-e)  carcinogens,  mutagens,  and  chemicals  toxic  for  reproduction 
(CMR) as well as substances which are persistent, bioaccumulative and toxic (PBT), or very persistent 
and  very  bioaccumulative  (vPvB)  may  be  considered  SVHC.  In  addition  endocrine  disruptors  and 
other chemicals which give rise to an equivalent level of concern (ELoC) (equivalent to CMRs, PBT or 
vPvB),  and  for  which  there  is  scientific  evidence  of  probable  serious  effects  to  human  health  or 
environment  can  be  identified  as  SVHC  on  a  case-by-case  basis,  as  stated  in  Article  57(f)  of  this 
regulation. There is currently no specific guidance or established criteria available and therefore case 
studies for specific toxicity endpoints are being prepared to facilitate this ELoC comparison. 

This paper aims at analysing whether substances classified in the Regulation (EC) No 1272/2008 on 
Classification, Labelling and Packaging (CLP) as Specific Target Organ Toxicity (STOT) Category 1 and 
Category  2  (single  or  repeated  exposure  (STOT-SE  or  STOT-RE)),  particularly  immunotoxicants and 
neurotoxicants, fulfil the proposed criteria to support the identification of these compounds as SVHC 
according to  Art. 57(f). It attempts  to identify, characterise and  compare the level of concern that 
exists for immunotoxicants and neurotoxicants with that of CMRs. This assessment is based on the 
it  may  be  demonstrated  that  the  impacts  caused  by 
consideration  that  in  certain  cases 
immunotoxicants and neurotoxicants on the health of the affected individuals and on the society as 
a whole, can be comparable to those elicited by CMRs. To determine an equivalent level of concern 
to CMRs, the comparison assessment focuses on the seriousness, irreversibility and delay of health 
effects  but  considers  also  other  factors  such  as  effects  on  quality  of  life,  societal  concerns  or  the 
possibility to derive a 'safe concentration'.  

The  assessment  suggests  that  some  substances  showing  immunotoxic  or  neurotoxic  effects  could 
present an 'equivalent level of concern' to CMRs and potentially be identified as SVHC according to 
the  Art.  57(f)  route  in  REACH.  For  both,  neurotoxic  and  immunotoxic  substances  a  case-by-case 
justification  considering  the  hazard  assessment  and  evidence  of  an  equivalent  level  of  concern  is 
necessary. Societal concern and impairment of quality of life can be a consequence of exposure to 
neurotoxicants  or  immunotoxicants  particularly  for  a  vulnerable  part  of  the  population,  including 
children  and  elderly  as  well  as  people  with  a  challenged  immune  system,  which  may  be  more 
sensitive  to  lower  concentrations.  A  particular  challenge  is  that  for  both,  immunotoxic  and 
neurotoxic  effects,  the  relationship  between  chemical  exposure  and  effect  may  not  always  be 
obvious. In general, identification of SVHC that exert immunotoxic effects is more complex than of 
substances with neurotoxic effects, due to the lack of EU methods or OECD test guidelines.  

Neurotoxicity or immunotoxicity effects occurring at dose ranges that are critical for the respective 
STOT-SE/RE classification (category 1 and 2) should be primarily considered for SVHC identification. 
This paper underlines the importance of a harmonised classification as a STOT-SE/RE substance for 
these  specific  effects  before  starting  any  SVHC  identification.  However  for  the  'equivalent  level  of 
concern' evaluation and justification also other factors need to be taken into account on a case-by-
case basis.  

9 

10 

 
 
1. 

Background 

The  European  Commission  is  committed  to  have  all  relevant  currently  known  Substances  of  Very 
High Concern (SVHC) included in the Candidate list (Annex XIV o REACH) by 20201. The objective is to 
determine the relevance of the substances already recognised as SVHC and to identify potential new 
ones.  To  achieve  this  target,  the  Commission  and  ECHA  with  the  support  of  Member  States 
Competent Authorities for REACH drafted a Roadmap in which screening of dossiers and evaluation 
of  Risk  Management  Options  (RMO)  strategies  are  fundamental  steps  in  the  identification  of 
relevant SVHC that later on may be subject to an authorisation process. 

According to Article 57 of the REACH Regulation (EC) No 1907/2006, substances of very high concern 
are substances that meet the criteria for classification as carcinogens, mutagens, and chemicals toxic 
for reproduction (CMR) as well as substances which are persistent, bioaccumulative and toxic (PBT), 
or very persistent and very bioaccumulative (vPvB) (Art.57 (a-e)). Article 57 (f) applies to endocrine 
disruptors and other chemicals which give rise to an equivalent level of concern to CMRs or PBTs or 
vPvBs,  for  which  there  is  scientific  evidence  of  probable  serious  effects  to  human  health  or 
environment […] and which are identified on a case-by-case basis. Such substances may be identified 
as SVHCs in accordance with the procedure set out in Article 59.  

This paper aims at analysing whether substances classified for specific target organ oxicity (STOT), in 
particular  those  causing  immunotoxic  or  neurotoxic  effects,  are  eligible  to  be  identified  as 
substances  of  very  high  concern.  This  document  is  thus  in  line  with  the objective  of  the  Roadmap 
2020 drafted by the EC to define a process or methodology […] on how to assess the different groups 
of potential SVHCs, in particular with the purpose to identify relevant SVHCs falling under Article 57 
(f) of REACH.  

This document introduces the steps for the general identification of SVHC and the proposed factors 
to assess an equivalent level of concern to CMRs. Thereafter it presents the criteria for STOT-SE/RE 
classification  and  indicates  a  list  of  methods  and  technical  challenges  found  in  the  hazard 
identification process for neurotoxicants and immunotoxicants. The main part of the document is a 
systematic  assessment  of  the  proposed  ELoC  factors  to  evaluate  their  applicability  in  the 
identification  of  neurotoxicants  and  immunotoxicants  as  SVHC.  Annex  I  includes  an  extended 
description of criteria for STOT-SE/RE classification according CLP; Annex II describes adverse health 
effects  caused  by  immunotoxicants  and  neurotoxicants.  Finally,  examples  for  chemicals  with 
potential neurotoxic effects are presented in Annex III. 

1 Council of the European Union: Roadmap for SVHCs identification and implementation of REACH Risk Management measures from now 
to 2020 http://register.consilium.europa.eu/pdf/en/13/st05/st05867.en13.pdf 

11 

 
 
                                                            
2. 

General identification and assessment of SVHC 

The  process  of  identification  of  SVHC  is,  in  general,  based  on  intrinsic  hazard  properties  of 
substances.  Thus,  when  possible,  the  consultation  of  the  harmonised  classification  and  criteria 
provided in Annex I of CLP (Regulation (EC) No 1272/2008 on classification, labelling and packaging 
of substances and mixtures) is useful as a starting point.  

For substances under Art. 57(a-e), hazard identification and characterisation in accordance with CLP 
regulation  is  the  first  step  in  the  process  of  SVHC  identification.  In  the  case  of  the  substances 
following  the  route  Art.  57(f),  it  would,  however,  not  be  a  straightforward  task.  Along  with  the 
hazard identification, a substance may be identified as SVHC if it is demonstrated, on a case-by-case 
basis, that it shows adverse effects on human health of equivalent level of concern (ELoC) compared 
to CMR effects2. Art. 57 (f) was envisaged as a safety net to control other potential risks than those 
covered by Art. 57(a-e), and little guidance is provided to determine the level of concern and assist 
the regulators in the identification of SVHC substances based on equivalent concern. 

With the purpose to provide support in this task, a workshop was organised in March 2012 by the 
German  institutions,  BfR  (Federal  Institute  for  Risk  Assessment)  and  BAuA  (Federal  Institute  for 
Occupational  Safety  and  Health) 3.  In  this  meeting,  some  considerations  and  principles  were 
discussed  in  the  context  of  establishing  a  harmonised  and  general  concept  for  SVHC  identification 
according to the mentioned Art. 57 (f) route4. Factors identified as relevant for the identification of a 
substance  as  a  SVHC  and  for  comparison  of  the  ELoC  with  CMR  substances  were:  seriousness  of 
effect  (e.g.  partly  or  non-reversible  effects,  delayed  time  lag  following  exposure  or  postnatal 
developmental toxicity), strength of evidence, relevance for humans and potency. 

The  first  group  of  substances  discussed  for  identification  as  SVHC  via  Art.  57  (f)  route  (excluding 
endocrine  disruptors)  were  chemicals  with  respiratory  and  skin  sensitising  properties.  ECHA 
prepared a discussion paper in which they discussed sensitisers, as a potential group to be identified 
as  SVHC  and  concluded  that  the  relevant  factors  mentioned  in  the  BfR/BAuA  workshop  could  be 
used  to  demonstrate  an  'equivalent  level  of  concern'  to  CMRs5.  The  document  also  advocated 
getting  a  harmonised  classification  and  labelling  under  CLP  before  suggesting  identification  of  the 
substance concerned as SVHC, and in case a harmonised and general concept cannot be followed, a 
case-by-case  justification  for  each  individual  substance  to  be  identified  as  SVHC  was  suggested  by 
different partners during the discussions. 

2 In this document ELoC is only considered in relation to human health concerns. 
3 BfR and BAuA workshop on 'REACH Article 57 (f): Non-Endocrine Disrupting Human Health Hazards Leading to SVHC Identification'. 
(http://www.bfr.bund.de/cm/343/reach-article-57-buchstabe-f-non-endocrine-disrupting-human-health-hazards-leading-to-svhc-
identification.pdf) 
4 http://www.baua.de/en/Topics-from-A-to-Z/Hazardous-Substances/Workshops/REACH-2012.html  
5 Identification of substances as SVHCs due to equivalent level of concern to CMRs (Article 57(f)) – sensitisers as an example; 
http://echa.europa.eu/documents/10162/19126370/dp_sensitisers_final_en.pdf 

12 

 
 
                                                            
3. 

Identification of STOT-SE/RE classified substances as SVHC 

The current document focuses on substances classified as  specific target organ toxicity (STOT) and 
the  objective  is  to  analyse  whether  such  compounds  present  hazard  characteristics  that  may  give 
rise to an ELoC to CMRs. This is based on the assumption, that any severe, delayed and/or persistent 
damage  to  organs  or  organ systems  falling  under  the STOT-SE/RE  criteria  may  give rise  to  ELoC  to 
CMRs. This document focuses specifically on immunotoxic and neurotoxic properties as these effects 
are considered of specific concern. 

3.1.  STOT classification  

Specific target organ toxicity, according to the CLP Regulation (Annex I: section 3.8.1.1 and 3.9.1.1), 
is defined as specific, [non-lethal]6 target organ toxicity arising from a single [or repeated] exposure 
to a substance or mixture7. All significant health effects that can impair function, both reversible and 
irreversible, immediate and/or delayed and not specifically addressed by [other hazard categories]. 

Specific target organ toxicity can occur by any route that is relevant for humans and encompasses 
several  adverse  effects  that  may  be  severe,  delayed  and/or  irreversible  such  as  haemotoxicity, 
hepatotoxicity, nephrotoxicity, neurotoxicity and immunotoxicity, but also transient effects such as 
respiratory tract irritation and narcotic effects. Effects falling under another hazard category such as 
acute  toxicity,  skin  corrosion/irritation,  serious  eye  damage/eye  irritation,  respiratory  or  skin 
sensitisation, germ cell mutagenicity, carcinogenicity, reproductive toxicity or aspiration toxicity are 
covered by other classification criteria and, therefore they should not be classified as STOT.  

Substances  presenting  STOT  effects  are  classified  differently  depending  on  whether  these  adverse 
effects are detected after single or repeated exposure and consequently would be classified as STOT-
single  exposure  (STOT-SE)  or  STOT-repeated  exposure  (STOT-RE),  respectively  (Table  1).  In  some 
cases, toxic effects classified as STOT-SE could be mistaken as acute toxicity effects and care should 
be taken to avoid 'double classification'. The main criterion to differentiate these two classifications 
is  lethality;  classification  for  acute  toxicity  is  assigned  to  lethal  effects,  while  non-lethal  severe 
effects  in  a  single  organ  or  biological  system  but  also  generalised  changes  of  a  less  severe  nature 
involving several organs, delayed and/or irreversible toxic effects after single exposure are classified 
as STOT-SE. 

6 This criterion only applies for STOT-SE (single exposure). 
7 http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02008R1272-20131201&from=EN 

13 

 
 
                                                            
Table 1  Classification and labelling for specific target organ toxicity after single and repeated exposure 

Hazard class 

Hazard 
category 

Abbreviation  GHS pictogram 

Signal 
word 

Hazard 
code 

Hazard statement 

Specific target 
organ toxicity 
Single  
exposure 

Specific target 
organ toxicity 
Repeated 
exposure 

Category 1 

STOT SE 1 

Danger 

H370 

Category 2 

STOT SE 2 

Warning 

H371 

Category 3 

STOT SE 3 

Warning 

H335 

Causes damage to organs (or 
state all organs affected, if 
known) (state route of 
exposure if it is conclusively 
proven that no other routes of 
exposure cause the hazard) 

May cause damage to organs 
(or state all organs affected, if 
known) (state route of 
exposure if it is conclusively 
proven that no other routes of 
exposure cause the hazard) 

May cause respiratory 
irritation 

H336 

May cause drowsiness or 
dizziness 

Category 1 

STOT RE 1 

Danger 

H372 

Category 2 

STOT RE 2 

Warning 

H373 

Causes damage to organs 
(state all organs affected, if 
known) through prolonged or 
repeated exposure (state 
route of exposure if it is 
conclusively proven that no 
other routes of exposure 
cause the hazard) 

May cause damage to organs 
(state all organs affected, if 
known) through prolonged or 
repeated exposure (state 
route of exposure if it is 
conclusively proven that no 
other routes of exposure 
cause the hazard) 

As the range of possible STOT effects is broad, this document will be centred on the evaluation of 
substances  with  neurotoxic  (including  effects  on  special  senses  and  effects  on  the  peripheral 
nervous system) or immunotoxic effects as potential candidates to be identified as SVHC (Annex II: 
Adverse health effects caused by immunotoxicants and neurotoxicants). This is motivated by the fact 
that  these  effects,  besides  inducing  direct  toxic  effects,  may  lead  to  cognitive  and  behavioural 
impairment  or  increased  sensibility  sensitivity  to  infectious  or  other  diseases,  which  may  have 
considerable consequences on the quality of life and create societal cost in terms of the  profound 
health compromise.  

This document focuses on substances classified as  STOT-SE/RE  1 and 2, which  cause or  may cause 
serious damage to organs through single or repeated exposure. Substances showing reversible and 
less  serious  effects  such  as  respiratory  irritation  and  drowsiness  or  dizziness  effects,  classified  as 
STOT-SE 3, are not considered for SVHC identification. 

14 

  
 
 
 
 
 
3.1.1.  Identification of hazard information for STOT-SE/RE substances 

The identification of human health hazard generally comes from animal  studies or where available 
from  human  experience/incidents.  Information  may  also  be  obtained  using  read-across  from 
structurally-related substances and from appropriate in vitro or in silico models, if applicable. Animal 
tests  involve  single  or  repeated  exposure  via  any  relevant  route  of  exposure8.  According  to  CLP 
guidance, acute toxicity studies in animals may provide hazard information about toxic effects of a 
substance  on  target  tissues/organs  that  reach  the  classification  as  STOT-SE.  Furthermore,  STOT-RE 
effects  can  be  determined  using  repeated  dose  animal  studies  treated  during  28  day,  90  day  or 
lifetime studies (up to 2 years), together with the information provided by other long-term studies 
(carcinogenicity,  neurotoxicity  or  reproductive  toxicity).  During  the  assessment  of  potential  STOT 
substances, adverse effects in more than one organ should be considered, and due to the difficulties 
to interpret some results, in most cases expert judgement is required to follow a weight-of-evidence 
approach considering all the data available. 

Standard  oral  (but  not  standard  dermal  or  inhalation)  28-day  and  90-day  toxicity  studies  include 
endpoints capable of detecting evidence of neurotoxic and immunotoxic effects. In addition, in 2011 
OECD  adopted  as  a  Test  Guideline  the  'Extended  One  Generation  Reproductive  Toxicity  study 
(EOGRTS)'  (OECD  TG  443).  This  study  is  designed  not  only  to  provide  information  on  reproductive 
toxicity  but  also  includes  other  endpoints  such  as  developmental  neurotoxicity,  developmental 
immunotoxicity,  and  endocrine-mediated  toxicity.  Immunotoxic  and  neurotoxic  effects  identified 
using  OECD  TG  443,  TG  426  (Developmental  Neurotoxicity  Study)  or  other  developmental  studies 
capable  of  identifying  these  effects  as  described  below,  would  however  be  considered  as 
developmental effects leading to a hazard classification under the category of reproductive toxicants 
in CLP regulation and would thus already be considered as SVHC according to Art 57 (c). Therefore, 
for  the  identification  of  neurotoxic  and  immunotoxic  hazard  other  studies  may  be  necessary  to 
further investigate the same effects9. In this regard, international guidance documents are available 
to  assist  in  the  evaluation  of  available  data  and  to  recommend  tests  to  determine  STOT  specific 
effects such as neurotoxicity and immunotoxicity10,11,12,13.  

3.1.2. Identification of hazard information for neurotoxicants 

Indicators  of  neurotoxicity  include  clinical  observations,  a  functional  observational  battery,  motor 
activity assessment and histopathological examination of the spinal cord and the sciatic nerve.  

The identification of chemicals with potential to cause damage on the developing brain is performed 
following  OECD  TG  426  (Developmental  Neurotoxicity  Study,  mostly  in  rats)  and  on  the  matured 
nervous  system  according  to  TG  424  (Neurotoxicity  Study  in  rodents).  The  delayed  neurotoxicity 

8 ECHA guidance to Regulation (EC) No 1272/2008 (CLP Regulation) http://echa.europa.eu/documents/10162/13562/clp_labelling_en.pdf 
9 ECHA Guidance on information requirements and Chemical Safety Assessment 
(http://echa.europa.eu/documents/10162/13632/information_requirements_r7a_en.pdf) 
10 Harmonization Project Document No. 10: Guidance for immunotoxicity risk assessment for chemicals (WHO/IPCS) 
11 OECD series on testing and assessment: Number 20, Guidance Document for Neurotoxicity Testing (2004) 
12 EPA Risk Assessment Forum: Guidelines for Neurotoxicity Risk Assessment (1998) 
13 Environmental Health Criteria 223. Neurotoxicity risk assessment for human health: principles and approaches, 2001 
(http://www.inchem.org/documents/ehc/ehc/ehc223.htm#_223241000) 

15 

                                                            
study in hens (OECD TG 419) is specifically designed to be used in the assessment and evaluation of 
the neurotoxic effects of organophosphorus substances.  

To  obtain  information  on  potential  neurotoxic  effects  of  chemicals,  the  OECD  Guidance  document 
for  neurotoxicity  testing  (2004)14 suggested  other  OECD  Test  Guidelines  including  those  for  single 
dose toxicity (e.g. OECD TG 40215, TG 40316, TG 42017, TG 42318 and TG 42519), repeated dose toxicity 
(e.g. OECD TG 40720 and TG 40821), as well as Test Guidelines specifically developed for the study of 
neurotoxicity in adult and young laboratory animals [OECD Test Guidelines (TG 418 and TG 419) for 
Delayed  Neurotoxicity  of  Organophosphorus  Substances  and  OECD  Test  Guideline 
for 
Developmental Neurotoxicity (TG 426), OECD Test Guideline for Combined Repeated Dose Toxicity 
Study with Reproduction/Developmental Toxicity Screening Test (TG 422)] 22. The Biocidal Products 
Regulation  (BPR)  (EU)  No  528/201223 also  gives  recommendations  on  the  toxicological  information 
required  to  support  the  approval  of  an  active  substance.  In  the  case  of  the  evaluation  of 
neurotoxicity,  the  legal  text  mentions  the  preferred  test  species  (rat,  except  for  delayed 
neurotoxicity where adult hens are suggested) or specific tests such as cholinesterase activity test24. 

It is important to indicate that neurotoxicity not only includes effects on the central nervous system 
but  also  serious  damage  (morphological  or  functional  or  both)  of  the  eye  (retina,  eye  nerve),  ear 
(hearing), and effects affecting the sense of smell and the peripheral nervous system. Examinations 
in the standard OECD test guideline are often not sufficient for the hazard characterisation or even 
identification of these effects. 

3.1.3. Identification of hazard information for immunotoxicants 

Indicators of immunotoxicity include changes of haematological parameters, serum globulin levels, 
organ  weights  alterations  and/or  histopathological  changes  in  immune  organs  such  as  spleen, 
thymus, lymph nodes and bone marrow.  

In  the  case  of  immunotoxicants,  no  specific  OECD  TG  guidelines  or  EU  methods  are  available  to 
characterise  immunotoxic  properties  and  information  on  immunosuppression,  immunostimulation 
or  autoimmune  diseases  may  not  always  be  derived  from  available  standard  test  guidelines.  The 
information  requirements  in  the  BPR  (EU)  (EU)  No  528/2012  regarding  immunotoxicity  mention 
direct observation (e.g. clinical cases) to assess  any pathogenicity and infectiveness to humans and 

14 http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?doclanguage=en&cote=env/jm/mono(2004)25 
15 OECD (1987),Test No. 402: Acute Dermal Toxicity, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing. 
16 OECD (2009),Test No. 403: Acute Inhalation Toxicity, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing. 
17 OECD (2002),Test No. 420: Acute Oral Toxicity - Fixed Dose Procedure, OECD Guidelines for the Testing of Chemicals, Section 4, OECD 
Publishing. 
18 OECD (2002),Test No. 423: Acute Oral toxicity - Acute Toxic Class Method, OECD Guidelines for the Testing of Chemicals, Section 4, OECD 
Publishing. 
19 OECD (2008),Test No. 425: Acute Oral Toxicity: Up-and-Down Procedure, OECD Guidelines for the Testing of Chemicals, Section 4, OECD 
Publishing. 
20 OECD (2008),Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents, OECD Guidelines for the Testing of Chemicals, Section 
4, OECD Publishing. 
21 OECD (1998),Test No. 408: Repeated Dose 90-Day Oral Toxicity Study in Rodents, OECD Guidelines for the Testing of Chemicals, Section 
4, OECD Publishing. 
22 OECD series on testing and assessments (Number 20): Guidance Document for neurotoxicity testing. ENV7JM7MONO(2004)25. 
23 http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02012R0528-20140425&from=EN 
24 Biocidal Product Regulation (BPR, Regulation (EU) No 528/2012). 

16 

                                                            
other  mammals  under  conditions  of  immunosuppression.  Information  from  immunosuppression 
tests included in other international guidance documents (e.g. EMA (ICH Topic 8 from 2006)25, EPA 
(OPPTS 870.7800 from 1998)26) may also be considered. 

Due  to  the  lack  of  EU/OECD  methods,  a  better  identification  and  distinction  of  effects  associated 
with  the  immune  system  (e.g.  immunosuppression  and  immunostimulation)  may  only  be  derived 
from  enhanced  examinations  included  in  repeated  dose  toxicity  studies 27.  Also,  as  for  the 
neurotoxicants,  the  outcome  of  the  assessment  of  developmental  immunotoxicity  in  EOGRTS  may 
be informative on potential effects of immunotoxicants in adults. 

For  specific  immunological  effects  such  as  respiratory  and  skin  sensitisation,  partly  validated  tests 
are available. These have, however, a separate classification, and will therefore not be addressed in 
this document; the criteria to identify these substances as SVHC have been previously examined in 
the above-mentioned ECHA discussion paper.  

Specific effects and their potency, supporting the classification for Category 1 and 2 of STOT-SE/RE in 
CLP  guidance,  together  with  specific  adverse  effects  of  immunotoxicants  and  neurotoxicants  are 
discussed in more detail in classification in this document.  

25 ICH Topic S 8 Immunotoxicity Studies for Human Pharmaceuticals. CHMP/167235/2004. 
26 Health Effects Test Guidelines: OPPTS 870.7800 Immunotoxicity [EPA 712–C–98–351]: 
http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0156-0049 
27 Schulte, Agnes et.al. "Two Immunotoxicity Ring Studies According to OECD TG 407—Comparison of Data on Cyclosporin A and 
Hexachlorobenzene." Regulatory Toxicology and Pharmacology 36, 12–21 (2002). 

17 

 
 
                                                            
4. 

'Level of Concern' comparison 

The  first  step  in  the  identification  of  a  chemical  as  SVHC  under  Art.  57(f)  is  the  hazard 
characterization, i.e. in the current case the identification as an  immunotoxicant or  neurotoxicant. 
This  should  enable  a  decision  on  a  classification  of  the  substance, 
if  required.  Hazard 
characterisation  and  classification  per  se  however  are  not  sufficient  and  an  'equivalent  level  of 
concern'  compared  to  carcinogenic,  mutagenic  or  reproductive  toxic  substances  needs  to  be  also 
demonstrated.  

The  level  of  concern  thus  takes  into  account  other  factors  in  addition  to  hazardous  properties,  as 
stated in the ECHA discussion paper on the Identification of substances as SVHCs due to equivalent 
level  of  concern  to  CMRs  (Article  57(f))  –  sensitisers  as  an  example  are:  […]  the  seriousness  of  the 
effects, the often irreversible nature of the effects, the consequences for society and the difficulty in 
performing  concentration-based  risk  assessments  (except  for  reproductive  effects)28.  Furthermore, 
the OECD Guidance document for neurotoxicity testing (2004) suggests that  the level of concern of 
the neurotoxic effects should be based on type, severity, number and either full or partial reversibility 
of the effects. Chemicals which produce a clear and consistent pattern of neurotoxicity at lower dose 
levels than other organ/system toxicity are generally of higher concern than chemicals which produce 
only a few unrelated effects. 

To compare the level of concern of immune- and neurotoxicants with CMRs, this document builds on 
ECHA's  discussion  paper,  in  which  the  factors  considered  suitable  to  identify  as  to  whether  a 
substance  with  respiratory  or  skin  sensitising  properties  may  be  identified  as  a  SVHC  have  been 
evaluated. The same factors are discussed here to evaluate the level of concern for adverse effects 
elicited  by  exposure  to  immunotoxicants  and  neurotoxicants.  The  evaluation  of  these  factors  for 
CMRs  presented  in  ECHA's  paper  (see  text  in  italics)  is  included  also  in  this  document  for 
comparative purposes. Furthermore, for clarity, the same outline as in ECHA's discussion paper has 
been followed: 

  Health effects (Section 4.1) 

Type of possible health effects 
Irreversibility of health effects 

- 
- 
-  Delay of health effects 

  Other factors (Section 4.2) 

-  Quality of life affected 
- 
Societal concern 
- 
Is derivation of a 'safe concentration' possible? 

Table 2 summarises the comparison based on these relevant factors among CMRs, immunotoxicants 
and neurotoxicants. This table also includes results from the previous analysis of ELoC on respiratory 
sensitisers, presented in ECHA’s document. 

28Identification of substances as SVHCs due to equivalent level of concern to CMRs (Article 57(f)) – sensitisers as an example 
(http://echa.europa.eu/documents/10162/13657/svhc_art_57f_sensitisers_en.pdf) 

18 

 
                                                            
Table 2. ‘Level of Concern’ comparison between CMRs, Respiratory Sensitisation, Immunotoxicity and Neurotoxicity29  

C & M 

R 

Respiratory Sensitisation 

Immunotoxicity 

Neurotoxicity 

Possible  serious  health 
effects? 

YES –  
  Serious & 

permanent organ 
dysfunction 
 
Inheritable defects 
  Could lead to death 

YES –  
  Serious & permanent 
organ dysfunction 
  Malformations or death 
in (unborn) children 

YES –  
  Serious & permanent 
organ dysfunction 
  Permanent impairment 

of lung functions 
  Could lead to death 

Irreversibility  of  health 
effects30? 

YES –  
 

Irreversible effects 

YES –  
 

Irreversible effects 

1
9

YES –  
 

Induction phase of 
sensitisation 

  Elicitation phase of 

sensitisation -can lead 
to irreversible lung 
dysfunction 

YES –  
  Potential for serious & 

permanent organ dysfunction 
  Morphological abnormalities 

YES –  
  Potential for serious & 

permanent organ dysfunction 

  Permanent 

indicative for 
impairment/functional changes 
of immune system; increase of 
neoplastic diseases, and 
infections. Induction and 
increase of autoimmune 
diseases and allergic processes 

  Could lead to death  
YES –  
  Effects can be irreversible 

impairment/functional changes 
of central or peripheral nervous 
system, other organs/organ 
systems including CNS 
depression and effects on 
special senses (motor, sight, 
hearing, sense of smell) as well 
as learning and memory. 

YES –  
  Effects can be irreversible, 

depending on dose and time of 
exposure (especially during 
susceptible life stages: 
postnatal development and 
aging) and/or half-life in body 

Delay of health effects? 

YES –  
  Long delay until 
effects manifest 

YES –  
  Medium delay until 
effects manifest 

YES –  
  Long/medium delay 

between induction and 
elicitation phases 

YES –  
  Delay (medium to long) until 
effects manifest possible 

YES –  
  Delay (medium to long) until 
effects manifest possible 
(depending on half-
life/accumulation in body) 

29 This table is a modification from Table 1 in ECHA’s paper on sensitisers (see the reference in footnote 28). 
30 Based on discussion if only irreversible effects classify as serious it was concluded that also some CR effects could be reversible (BfR and BAuA workshop on 'REACH Article 57 (f): Non-Endocrine Disrupting Human 
Health Hazards Leading to SVHC Identification'). 

 
 
 
 
 
 
 
                                                            
C & M 

R 

Respiratory Sensitisation 

Immunotoxicity 

Neurotoxicity 

YES –  
  Children with 

YES –  
  Long-term illness 

YES –  
  Long-term illness limiting 

Quality of life impaired? 

Societal concern? 

YES –  
  Long-term illness 
limiting possibility 
of living a normal 
working and private 
life 

  Possible mental/ 
psychological 
impacts 

YES –  
  Widespread 

concern about 
cancer 

developmental effects 
may need life-long 
medication/ support in 
their daily life 
  Life of parents also 
affected (emotional 
investment, care, 
financial costs) 

YES –  
  Widespread concern 

about adverse effects in 
children 

  Cost implications 

for society in terms 
of healthcare 

  Cost implications for 
society in terms of 
healthcare 

  Disability 

2
0

Is  derivation  of  a  ‘safe 
concentration’ possible? 

NORMALLY NO - 
 

‘Zero risk’ only 
possible where no 
exposure 

NORMALLY YES -  
  Possible to determine a 
safe concentration 

limiting the possibility 
of living a normal 
working and private 
life 

  Require long-term 

medication 

  Re-training of affected 

staff 

YES –  
  Cost implications for 
society in terms of 
healthcare and 
retraining 
  Associated with 

disability 

possibility of living a normal 
working and private life 

  Possible mental/ psychological 
impacts (due to related effects 
such as reduced defense, 
cancer or autoimmune 
diseases) 

YES –  
  Widespread concern about 

increase of infections or other 
related diseases 

  Cost implications for society in 
terms of healthcare (increase 
morbidity/premature mortality) 

  Disability 

NO –  
  Difficult to establish 

the threshold dose for 
induction and 
elicitation 

  Derivation of safe 

concentration is not 
routinely possible 

Potentially YES –  
  Possible to determine a safe 
concentration for certain 
substances 

  Difficult to establish a safe 

concentration for certain end-
points (U-shaped dose-response 
relationships) for certain 
substances 

YES- 
  Long-term illness and reduced 
productivity limiting possibility 
of living a normal working and 
private life 

  Possible mental/ psychological 
impacts (due to effects on 
peripheral or central NS and 
special senses) 

YES –  
  Widespread concern about 
effects on the adult nervous 
system 

  Cost implications for society in 
terms of healthcare (increased 
risk of antisocial behavior as 
well as morbidity/premature 
mortality) 
  Disability 

Potentially YES -  
  Possible to determine a safe 
concentration for certain 
substances for adult 
neurotoxicity  

  Difficult to establish a safe 

concentration for certain end-
points (U-shaped dose-response 
relationships) for certain 
substances 

 
 
 
 
 
 
 
 
 
 
 
4.1. 

 Health Effects 

4.1.1.  Type of possible health effects  

The initial point to identify a substance as SVHC is to evaluate whether the adverse effects exerted 
by  the  exposure  to  that  substance  are  serious  and  relevant  to  humans.  Classification  under  CLP 
regulation  may  provide  information  on  the  hazardous  properties  of  substances  and  guidance  to 
evaluate whether these effects may have a serious impact on human health and could be considered 
as equivalent level of concern to CMR substances (Cat. 1A/B). 

 

 

 

In the case of carcinogens and mutagens, exposure to these substances has the potential to 
cause  serious  adverse  health  effects  in  a  proportion  of  the  population  i.e.  serious  and 
permanent organ dysfunction, inheritable defects and/or death. 

In  the  case  of  reproductive  toxicants  (development),  exposure  has  the  potential  to  cause 
serious adverse health  effects in a proportion of  the population  i.e. serious and permanent 
organ dysfunction, defects and/or death. 

In the case of immunotoxicants, exposure has the potential to cause serious adverse health 
effects  in  (a  proportion  of)  the  population.  In  principle,  immunotoxicants  can  cause 
immunosuppression,  immunostimulation  or  an  abnormal  immune  response  (such  as 
autoimmunisation)  (see  Annex  II:  Adverse  health  effects  caused  by  immunotoxicants  and 
neurotoxicants). Immunosuppression effects can be linked to an increase of susceptibility to 
infectious  diseases  as  well  as  to  a  decrease  of  the  response  to  immunisation,  potentially 
leading to an increased number of infections cases in the general population. In this regard, 
increases in the incidence of colds or influenza in occupational settings, as in the case of lead 
were reported31. Furthermore, exposure to certain immunotoxicants has been related to an 
increased  incidence  of  neoplastic  diseases  or  the  development  of  certain  autoimmune 
diseases; i.e. several studies have associated the occupational exposure to  crystalline silica 
to  rheumatoid  arthritis,  scleroderma,  or  systemic  lupus  erythematosus 32,33.  Exposure  to 
some organic solvents has been also described as a risk factor for developing autoimmune 
diseases  such  as  scleroderma-like  syndrome34,35.  However,  the  findings  from  different 
studies  on  chemical-induced autoimmunity  are  not  always  consistent  and  further research 
may be needed to make definitive conclusions on these effects, at this point of time. Also it 
is extremely difficult to link the development of autoimmune diseases to a specific chemical, 
i.e.  genetic  disposition  and 
due  to  the  complex  nature  of  autoimmune  diseases, 

31 Horiguchi, S., et al. "Frequency of cold infections in workers at a lead refinery." Osaka city medical journal 38.1 (1992): 79. 
32 Environmental health criteria 236. Principles and methods for assessing autoimmunity associated with exposure to chemicals (WHO, 
2006). 
33 Cooper, Glinda S., Frederick W. Miller, and Dori R. Germolec. "Occupational exposures and autoimmune diseases." International 
immunopharmacology 2.2 (2002): 303-313. 
34 Cooper, Glinda S., et al. "Evidence of autoimmune-related effects of trichloroethylene exposure from studies in mice and humans." 
Environ Health Perspect 117.5 (2009): 696-702. 
35 Barragán-Martínez, Carolina, et al. "Organic solvents as risk factor for autoimmune diseases: a systematic review and meta-analysis." 
PloS one 7.12 (2012): e51506. 

21 

 
 
                                                            
environmental factors. Besides, there may be long lag time before the disease is manifested, 
hence the link to the potential causal agent may be impossible to make. Cases of chemical 
exposure  and  immunostimulation  effects  have  been  also  reported  in  the  literature.  For 
example, repeated dose 28-day oral toxicity studies in rats treated with hexachlorobenzene 
showed histomorphologic alterations, an increased lymphocyte migration activity, indicative 
of immunostimulation36. 

 

In the case of neurotoxicants, exposure of humans may lead to changes in sensory function, 
motor  function,  and  changes  in  the  performance  of  learned  behaviour,  memory  and 
cognitive impairment. The exposure to some neurotoxicants has also been  discussed to be 
related to the development of progressive neurodegenerative diseases, e.g. Alzheimer's and 
Parkinson-like  diseases;  however,  further  research  has  been  suggested  to  confirm  this 
association since data on this topic is very scarce. In fact, some of the observed neurological 
disorders  may  actually  originate  from  exposure  during  development.  Although  the 
development of the nervous system continues postnatally, developmental neurotoxicity for 
the  purposes  of  hazard  classification  and  the  CLP  regulation  would  fall  in  the  category  of 
reproductive toxicants and thus already be considered as SVHC according to Art 57 (c). 

4.1.2.  Irreversibility of health effects 

In  the  ECHA  discussion  paper  on  sensitisers,  the  irreversibility  of  effects  is  listed  as  a  supportive 
criterion  to  identify  a  substance  as  SVHC,  based  on  the  fact  that  changes  in  the  structure  and/or 
function  of  the  organ  could  be  permanent.  Irreversibility  is  estimated  by  the  absence  of  a  full 
recovery or by an incomplete recovery within the foreseen recovery periods of the respective test 
guidelines. 

 

 

 

In the case of carcinogens and mutagens, adverse health effects e.g. development of cancer 
may lead to death or irreversible ill health. 

In the case of reproductive toxicants (development), adverse health effect may be present in 
the form of irreversible malformations in children. 

In the case of some immunotoxicants, reversibility of adverse effects has been observed and 
once the exposure to the substances ceases, the immune system is able to return to its prior 
status37. However, one of the concerns of immunosuppression effects is its association with 
an  increased  risk  of  cancer  due  to  the  failure  of  the  immune  system  or  to  a  higher  risk  of 
developing  virus-induced  neoplasias38.  Even  though  there  is  evidence  of  a  link  between 
certain chemicals and immunosuppressive effects, it is important to note that some authors 
have  reported  that  the  data  to  support  a  causal  relationship  between  the  association  of 

36 Schulte, Agnes, et al. "Two immunotoxicity ring studies according to OECD TG 407—comparison of data on cyclosporin A and 
hexachlorobenzene." Regulatory Toxicology and Pharmacology 36.1 (2002): 12-21. 
37 Guidance for immunotoxicity risk assessment for chemicals (IPCS harmonization project document; no. 10). 
38 Luster, Michael I., et al. "Relationships between chemical-induced immunotoxicity and carcinogenesis." Drug information journal 30.1 
(1996): 281-286. 

22 

 
 
                                                            
certain cancers and chemicals with immunotoxic potential is insufficient, especially following 
exposure of adults39. Occupational exposure to chemicals such as certain solvents, crystalline 
silica or certain pesticides may influence the development of systemic autoimmune disease 
in 
leading  to 
epidemiological or animal studies and are not always strong and clear. 

irreversible  effects 40 .  These  associations  have  been  reported  only 

 

limited  and  depends  on 

the 
internal  dose 

In the case of neurotoxicants, adverse effects may be reversible or irreversible. The nervous 
system  is  known  for  having  a  functional  reserve  capacity.  Its  ability  to  return  to  the  state 
prior  to  exposure,  as  well  as  its  ability  to  compensate  and  adapt  for  neurotoxic  insults  is 
targeted  cells,  subcellular  structures  or 
however 
Its  capacity  of 
leading  to  neurotoxicity. 
neurotransmitters  and  the 
regeneration following neuronal cell degeneration/death is absent or very limited and even 
though  effects  after  single  exposure  to  certain  neurotoxicants  may  disappear  when  the 
exposure  ceases,  as  in  the  case  of  certain  organic  solvents,  this  fact  may  not  discard  the 
presence of injuries or cell death. Also, in some cases exposure to neurotoxicants has been 
associated  with  chronic  and  irreversible  diseases,  e.g.  long-term  occupational  exposure  to 
certain  organic  solvent  may  induce  encephalopathy,  an  irreversible  damage  to  the  central 
nervous  system  (mild  to  severe  cognitive  impairment  that  affects  memory,  attention,  and 
psychomotor  functions).  Also  chronic  exposure  to  neurotoxicants  may  be  linked  with  the 
development of neurodegenerative diseases41, which entail the irreversible loss of neuronal 
structure  and  functions,  also  defined  as  neurodegeneration 42 .  For  example,  certain 
neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease have been 
discussed to be associated with exposure to metals or pesticides. Occupational exposure to 
heavy  metals,  e.g.  manganese,  iron,  copper,  mercury,  zinc,  and  lead  has  been  associated 
with neurological symptoms with similarities to Parkinson's disease such as weakness, bent 
posture,  whispering  speech,  limb  tremor,  and  salivation43,44.  Furthermore,  drinking  water 
and  occupational  exposure  to  aluminium45,46 and  other  metals  such  as  mercury  and  lead 
have  been  suggested  to  be  a  risk  factor  in  Alzheimer's  disease  or  the  development  of 
neuropathological  (neurofibrillary  tangles  and  senile  plaques)  and  clinical  symptoms 
(presenile dementia, reduced mental test scores) similar to those of  Alzheimer's disease 47. 

39 Veraldi, Angela, et al. "Immunotoxic effects of chemicals: A matrix for occupational and environmental epidemiological studies." 
American journal of industrial medicine 49.12 (2006): 1046-1055. 
40 Cooper, Glinda S., Frederick W. Miller, and Dori R. Germolec. "Occupational exposures and autoimmune diseases." International 
immunopharmacology 2.2 (2002): 303-313. 
41 HPA CHaPD 001: Review of Environmental Chemicals and Neurotoxicity: Focus on Neurological Diseases (HPA, UK, 2007)  
42 Cannon, Jason R., and J. Timothy Greenamyre. "The role of environmental exposures in neurodegeneration and neurodegenerative 
diseases." Toxicological Sciences 124.2 (2011): 225-250. 
43 Gorell, J. M., et al. "Occupational exposures to metals as risk factors for Parkinson's disease." Neurology 48.3 (1997): 650-658. 
44 Olanow, C. W. "Manganese-induced parkinsonism and Parkinson's disease." Annals of the New York Academy of Sciences 1012.1 (2004): 
209-223. 
45 Flaten, Trond Peder. "Aluminium as a risk factor in Alzheimer’s disease, with emphasis on drinking water." Brain research bulletin 55.2 
(2001): 187-196. 
46 Graves, Amy B., et al. "Occupational exposures to solvents and aluminium and estimated risk of Alzheimer's disease." Occupational and 
environmental medicine 55.9 (1998): 627-633. 
47 Liu, Guijian, et al. "Metal exposure and Alzheimer’s pathogenesis." Journal of structural biology 155.1 (2006): 45-51. 

23 

 
 
                                                            
Aluminium  has  been  also  described  as  a  potent  neurotoxicant  and  the  causal  agent  of 
encephalopathy in patients that receive dialysis due to chronic renal failure48,49. 

During the BfR/BAuA workshop, some stakeholders commented that although some adverse effects 
may be reversible over time, the potential damage and social impact as a result of these temporary 
effects  cannot  be  excluded  (e.g.  prolonged  periods  of  illness,  lower  performance  or  accidents  at 
work).  

In certain exposure scenarios it could be relevant to take also into account the impact that reversible 
effects  may  have  on  human  health  and  on  the  determination  of  the  level  of  concern.  Reversible 
effects such as headache, dizziness, decrease of concentration, movement disorders in occupational 
settings in which operating dangerous machinery is required may raise a higher level of concern for 
their fatal consequences. These effects are normally a response to exposure concentrations eliciting 
acute  effects.  However,  in  some  cases  the  reversibility  of  such  effects  may  be  so  slow  that  these 
effects may raise a level of concern similar to irreversible effects. In general, a complicating issue is 
that  the  permanence  (irreversibility)  of  effects  (especially  for  immunotoxicity)  may  often  not  be 
demonstrated in standard guideline studies, and possibly be derived only from epidemiological data 
and generic medicinal knowledge on these aethiopathologies. 

4.1.3.  Delay of health effects 

Toxic  effects  of  some  substances  may  be  only  detected  after  a  long  period  of  time  between  the 
exposure and manifestation of the adverse effects. In this case, risk management measures may be 
not  taken  in  time,  and  individuals  might  be  exposed  for  a  long  period  to  chemicals  for  which 
potential  health  effects  and  risks  are  unknown.  Delay  of  effects,  although  not  a  specific  relevant 
factor  for  the  identification  of  SVHCs,  could  be  an  important  aspect  to  establish  higher  levels  of 
concern. 

In addition, delay of effects of chemicals could be an important feature during early postnatal stages 
of life, in which systems affected are immature and effects can be expressed or observed only after a 
long period of time. In this case, it is often difficult to relate this effect to a chemical exposure and 
therefore  it  won't  be  recognise  to  be  of  concern.  Toxicity  testing  may  help  in  the  identification  of 
delayed  effects,  and  taking  appropriate  risk  management  measures  on  time  could  avoid  the 
potential risk posed by these chemicals. 

 

In the case of carcinogens and mutagens, there are usually long delays before adverse effects 
manifest themselves.  

48 Alfrey, Allen C., Gary R. LeGendre, and William D. Kaehny. "The dialysis encephalopathy syndrome: possible aluminum intoxication." 
New England Journal of Medicine 294.4 (1976): 184-188. 
49 Wills, MichaelR, and John Savory. "Aluminium poisoning: dialysis encephalopathy, osteomalacia, and anaemia." The Lancet 322.8340 
(1983): 29-34. 

24 

 
 
                                                            
 

 

 

In the case of reproductive toxicants (development) there can be some delay before adverse 
effects manifest themselves.  

In the case of immunotoxicants, depending on the mode of action and the time of exposure, 
both immediate and long delayed adverse effects could be expected. Depending on the dose 
and  the  observed  effects,  the  immune  system  may  have  a  capacity  to  return  to  normal 
status  after  exposure  to  immunotoxicants;  however,  immune  dysfunction  due  to  early 
postnatal exposure or during immune system maturation, may increase the later-life risk to 
certain  autoimmune  diseases  and  other  health  effects50 or  immune  dysfunction  (e.g.  by 
decreased  defense  against  infections)  may  become  obvious  much  later  than  the  primary 
immunosuppressive effect. As mentioned previously, an increased risk of cancer might also 
be a potential delayed effect of exposure to immunosuppressant chemicals or a co-morbid 
effect of substances with chemical-induced autoimmunity effects51. 

In  the  case  of  neurotoxicants,  exposure  of  children  to  certain  chemicals  with  neurotoxic 
effects may lead to delayed and permanent effects such as learning disabilities, sensory and 
memory deficits, and cognitive developmental delays. Also long-term low-level exposure has 
been related to a decrease in performance in  neuropsychological functions; an increase of 
persistent developmental disorders, delays in cognitive development and attention deficit/ 
hyperactivity  disorder52. In  adults,  short-term  exposure to  some organic  solvents  has  been 
linked to transient symptoms that generally disappear when the exposure ceases; however, 
long-term exposure may result in the delayed effects (observed for organic solvents or when 
the  neurotoxicants  accumulates  in  the  nervous  tissues).  A  well-known  example  of  delayed 
effects  of  neurotoxicants  are  the  symptoms  after  exposure  to  some  organophosphates 
which 
induced  delayed  polyneuropathy',  a  rare 
neurodegenerative  disease  that  is  characterised  by  the  central  and  peripheral  nervous 
system degeneration, followed by symptoms as ataxia and paralysis that may appear after 3 
weeks after exposure. Other toxic effects associated with exposure to organophosphates are 
the cholinergic syndrome (sweating, lacrimation, salivation, respiratory difficulties, tremors, 
ataxia),  and  the  intermediate  syndrome  (respiratory  difficulties  due  to  malfunctions  of 
respiratory  muscles)  that  appear  not  delayed  after  exposure.  Depression  symptoms  have 
been  also  reported  after  long-term  occupational  exposure  to  certain  chemicals,  such  as 
certain pesticides 53 or carbon disulphide54,55. 

'organophosphate 

is  also  called 

50 These effects would be considered as developmental effects and therefore be considered as SVHC.  
51 Dietert, Rodney R. "Role of developmental immunotoxicity and immune dysfunction in chronic disease and cancer." Reproductive 
Toxicology 31.3 (2011): 319-326. 
52 Grandjean, Philippe, and Philip J. Landrigan. "Developmental neurotoxicity of industrial chemicals." The Lancet 368.9553 (2006): 2167-
2178. 
53 Bazylewicz-Walczak, B., W. Majczakowa, and M. Szymczak. "Behavioral effects of occupational exposure to organophosphorous 
pesticides in female greenhouse planting workers." Neurotoxicology 20.5 (1999): 819-826. 
54 Vigliani, Enrico C. "Carbon disulphide poisoning in viscose rayon factories." British journal of industrial medicine 11.4 (1954): 235. 
55 Aaserud, Olaf, et al. "Carbon disulfide exposure and neurotoxic sequelae among viscose rayon workers." American journal of industrial 
medicine 18.1 (1990): 25-37. 

25 

 
 
                                                            
4.2.  Other considerations 

According  to  the  ECHA  discussion  paper  on  sensitisers,  other  factors  of  concern  to  consider  the 
identification of a substance under Art. 57 (f) are the impairment of quality of life, consequences for 
society  and  the  difficulty  to  establish  dose-response  relationships  for  the  risk  assessment  of  these 
substances. 

The  social  impact  of  exposure  to  a  substance  may  be  determined  at  individual  level  (how  the 
exposure  and  effects  of  this  substance  impacts  on  the  regular  life  of  an  affected  individual)  or  at 
societal level, regarding which are the social and economic implications for the population. 

In addition, the possibility to derive safe levels of exposure could be informative to decide the 'level 
of  concern'  of  a  substance  and  may  be  taken  into  consideration  on  a  case-by-case  basis  for 
prioritisation. Exposure to chemicals for which safe levels can be derived may be controlled by risk 
management measures and lead to a lower level of concern. 

4.2.1.  Quality of life affected 

 

 

 

 

In the case of carcinogens and mutagens, possible side-effects such as organ dysfunction can 
result in the person having to live with a long-term illness, limiting the possibility of living a 
normal  working  and  private  life.  Regardless  of  the  prognosis,  the  negative  health  effects 
caused by exposure to carcinogens and mutagens are generally considered to be a ‘serious’ 
consequence, as it always has the potential to be fatal. 

In  the  case  of  developmental  toxicants,  depending  on  the  effect  manifested,  the  long-term 
consequences  for  the  infants/person  may  be  very  severe  and  impair  the  quality  of  life. 
Children having developmental effects may need life-long medication and/or support during 
their daily life. There is also an indirect effect on the quality of life of such children’s parents 
in terms of emotional investment, care and financial resources needed. 

In  the  case  of  immunotoxicants,  long-term  adverse  health  effects  may  appear  after 
exposure, i.e. an increase risk to severe infections and/or cancer or irreversible autoimmune 
diseases.  In  these  cases,  the  possibilities  for  affected  individuals  to  live  a  normal  life  are 
limited and quality of life could be impaired for long periods. 

In  the  case  of  neurotoxicants,  exposure  may  lead  to  chronic  diseases  that  need  life-long 
treatment56,57. Also, at the workplace, exposure to neurotoxicants has been associated with 
a  slow-down  of  the  performance  on  reaction-time  tasks  or  changes  in  vision58,59.  For 

56 Alavanja, Michael CR, Jane A. Hoppin, and Freya Kamel. "Health Effects of Chronic Pesticide Exposure: Cancer and Neurotoxicity* 3." 
Annu. Rev. Public Health 25 (2004): 155-197. 
57 Kamel, Freya, and Jane A. Hoppin. "Association of pesticide exposure with neurologic dysfunction and disease." Environmental Health 
Perspectives 112.9 (2004): 950. 
58 Viaene, M. K., et al. "Neurobehavioural effects of occupational exposure to cadmium: a cross sectional epidemiological study." 
Occupational and environmental medicine 57.1 (2000): 19-27. 

26 

 
 
                                                            
example,  long-term  exposure  to  white  spirit  (longer  than  10  years)  may  lead  to  the 
impairment  of  brain  function  and  can  therefore  be  associated  with  a  high  risk  for  the 
development of a chronic toxic encephalopathy60. 

It  is  important  to  note,  that  certain  immunotoxic  or  neurotoxic  effects  if  detected  time  after 
exposure,  e.g.  during  childhood  and  adolescence,  may  originate  from  exposure  during  in  utero 
development  and  should  therefore  be  classified  as  neurodevelopmental  toxicants  (i.e.  toxic  for 
reproduction,  R).  Some substances  may  be immunotoxic and/or  neurotoxic  in  adults  and  progeny, 
possibly at different dose levels. It has been suggested that immunotoxicity and neurotoxicity could 
occur at lower doses in postnatal developing organisms than in adults (see also 5.2). These effects 
are not examined in the test guidance used to reach the developmental toxicity classification. Each 
effect needs proper consideration with regard to the population group and hazard class.  

4.2.2.  Societal concern 

Societal concern is not considered a determining factor for the identification of substances as SVHC 
but  it  could  provide  relevant  information  about  the  level  of  concern  of  a  substance,  in  particular 
about its effects at social and economic levels in society. 

 

 

 

In the case of carcinogens and mutagens, there is widespread concern in society, due to the 
high  prevalence  of  cancer  in  the  worldwide  population  and  the  uncertainty  surrounding 
future effects that may be persistent, e.g. development of cancer and potential death. There 
can be a high cost of treating affected individuals in society. 

In the case of developmental toxicants, the potential adverse health effects on children e.g. 
severe  malformations  or  restrained  intellectual  capabilities  are  of  high  concern  for  the 
society. There can also be a high cost of treating affected individuals in society. 

In  the  case  of  immunotoxicants,  substances  with  immunosuppressive  mechanisms,  which 
may result in an increased risk of incidence of neoplasms (due to immunosuppression), may 
give rise to a similar level of concern as carcinogens. Also a decrease in host resistance and 
an improper response to vaccination are primary effects of concern because of public health 
implications:  the  spread  and  increase  of  infectious  diseases  such  as  cold  and  influenza 
generate  costs  related  to  increased  sick leave  or  absences  from  work,  costs  in health  care 
goods  and  services,  and  loss  of  productivity  at  the  workplace.  Furthermore,  autoimmune 
chemical-related diseases are in general chronic; thereby it may imply a lifetime cost for the 
health system61. 

59 Costa, Thiago Leiros, et al. "Long-Term Occupational Exposure to Organic Solvents Affects Color Vision, Contrast Sensitivity and Visual 
Fields." PloS one 7.8 (2012): e42961. 
60 Nielsen, Gunnar Damgård, Søren Peter Lund, and Ole Ladefoged. "Neurological Effects of White Spirit: Contribution of Animal Studies 
during a 30‐Year Period*." Basic & clinical pharmacology & toxicology 98.2 (2006): 115-123. 
61 Blanciforti, Laura A., and Michael I. Luster. "Considerations in estimating social and economic impacts of immunotoxic agents." Human 
and Ecological Risk Assessment 12.5 (2006): 888-903. 

27 

 
 
                                                                                                                                                                                         
 

In the case of neurotoxicants, the levels of concern to chemical exposure are based on the 
magnitude of effect, duration of the exposure and reversibility of some neurotoxic effects. 
Of particular concern is the fact that few chemicals have been evaluated for neurotoxicity as 
well as the lack of research on the relationship between adverse effects and exposure to low 
concentrations  of  neurotoxicants  and  its  potential  impact  on  the  society62.  As  mentioned, 
neurotoxic effects at the workplace may be very serious and may lead to significant financial 
losses resulting from health problems63. 

4.2.3.  Is derivation of a ‘safe concentration’ possible? 

The possibility to derive safe concentrations is not a decisive factor during the process to identify a 
chemical as SVHC, as the identification of SVHC is based on hazard; however, this information could 
be  relevant  and  may  be  taken  into  consideration  on  a  case-by-case  basis.  Exposure  to  chemicals 
whose safety levels can be derived may be controlled by later risk management measures. 

 

 

 

In the case of non-threshold carcinogens and mutagens, it is only possible to conclude ‘zero 
risk’ if there is no exposure.  In  certain  cases,  even very small doses of such substances  can 
cause  adverse  effects,  which  may  only  manifest  after  several  years  of  exposure. 
Consequently, derivation of a safe concentration is normally not possible, except in few cases 
of non-genotoxic carcinogens. 

In  the  case  of  developmental  toxicants,  it  is  normally  possible  to  determine  a  toxicological 
threshold and consequently a safe concentration. 

In  the  case  of  immunotoxicants,  it  is  normally  possible  to  derive  a  dose-response 
relationship  for  immunosuppression;  however,  the  calculation  of  this  dose-relationship 
depends on the mode of action of the chemical and the considered endpoint. In this regard, 
and  bearing  in  mind  the  lack  of  scientific  consensus  in  this  topic,  some  researches  have 
suggested that certain immunotoxic end-points may follow a non-monotonic dose-response 
curve, in which effects produced at low doses are opposite to those exerted  by high doses 
(also  called  'hormesis  effect').  An  example  for  this  is  the  effect  of  methylmercury  in  the 
response of peripheral blood lymphocytes to phytohaemagglutinin, where in rats high-doses 
produce  suppression  and  low-doses  produce  stimulation  of  this  parameter64.  Therefore, 
'safe concentrations' may vary not only depending on the substance but also on the immune 
parameter considered which might be important information in particular cases. 

 

In the case of neurotoxicants, it is possible to establish safe levels of exposure in most of the 
cases, but the same issues with potential hormesis effects as described above can be found 

62 Bellinger, David C. "Effect modification in epidemiologic studies of low-level neurotoxicant exposures and health outcomes." 
Neurotoxicology and teratology 22.1 (2000): 133-140. 
63 Callender, T. J., et al. "Social and economic impact of neurotoxicity in hazardous waste workers in Lenoir, North Carolina." 
Environmental research 73.1 (1997): 166-174. 
64 Omara, Felix Olima, et al. "Immunotoxicity of environmentally relevant mixtures of polychlorinated aromatic hydrocarbons with methyl 
mercury on rat lymphocytes in vitro." Environmental toxicology and chemistry 16.3 (1997): 576-581. 

28 

 
 
                                                            
in  the  literature  for  some  chemicals  showing  neurotoxic  effects  including  polychlorinated 
biphenyls or heavy metals such as mercury or aluminium 65,66. Although a safe concentration 
may exist theoretically, some neurotoxicants (such as lead)67 are hazardous at extremely low 
concentrations that are already exceeded by environmental exposure. 

65 Kuriyama, Sergio Noboru, and Ibrahim Chahoud. "In utero exposure to low-dose 2, 3′, 4, 4′, 5-pentachlorobiphenyl (PCB 118) impairs 
male fertility and alters neurobehavior in rat offspring." Toxicology 202.3 (2004): 185-197. 
66 Calabrese, Edward J., and Linda A. Baldwin. "Inorganics and hormesis." CRC Critical Reviews in Toxicology 33.3-4 (2003): 215-304. 
67 http://www.efsa.europa.eu/de/efsajournal/doc/1570.pdf 

29 

 
 
 
 
                                                            
5. 

Specific considerations 

5.1.  Potency 

In  the  previous  ECHA  discussion  paper,  potency  was  discussed  as  a  potential  supporting  factor, 
specific for sensitisers, when evaluating the level of concern during the process of identification of 
SVHC.  Potency  may  be  a  factor  to  be  considered  since  potent  immunotoxicants  or  neurotoxicants 
may evoke adverse effects at lower exposure levels. Similarly to sensitisers, potent immunotoxicants 
or  neurotoxicants  are  suggested  to  be  prioritised  over  less  potent  toxicants,  since  less  potent 
toxicant will  give rise  to  a  lower  concern  than  toxicants  with  high potency.  Toxicity  of  substances, 
and as consequence potency, is based on a description of the dose-effect relationship values which 
could be used as a measurement of toxic potential and to set exposure limits68. However, in contrast 
with  the  case  of  sensitisers  (e.g.  EC3  derivation  from  murine  local  lymph  node  assay  test  (LLNA) 
values)  69,  there  are  no  established  values  or  tests  for  potency  evaluation  of  immune  and 
neurotoxicants. The guidance values as defined in the CLP criteria70 for STOT-SE/RE category 1and 2 
(see  classification  could  be  used  for  hazard  identification  and  classification  but  also  as  potency 
indication. 

5.2.  Groups at risk to immunotoxicant and neurotoxicant exposure 

In order to evaluate the social impact of some chemicals, it is important to take into consideration 
the  group  of  the  population  at  higher  health  risk  due  to  exposure  to  these  substances.  In  certain 
cases,  some  individuals  of  the  population  such  as  children  and  pregnant  women  are  usually 
considered  groups  at  risk71. In  other  cases,  determinant  characteristics  of  a  group  of  people  could 
lead  to  a  higher  risk  for  particular  chemicals.  Age,  an  immunocompromised  state  or  genetic 
susceptibility are some of these characteristics. 

5.2.1. Age 

Age-related difference to exposure to chemicals could be linked not only to differences in exposure 
and  accumulation  over  time  but  also  differences  in  susceptibility  to  substances.  In  the  elderly 
population,  immunosenescence,  an  age-related  dysfunction  of  the  immune  system,  together  with 
other factors such as malnutrition and age-associated physiological changes have been related to an 
in  the  response  to 
increase  of  the  susceptibility  to 
vaccination72,73,74. Also, it has been suggested that the elderly could be more susceptible to chemical 

infectious  diseases,  and  a  decrease 

68 Environmental Health Criteria 223. Neurotoxicity risk assessment for human health: principles and approaches (WHO, 2001).  
69 EC3 value is the concentration of a chemical required to elicit a threefold stimulation of proliferation in draining lymph nodes in the 
murine local lymph node assay. This value is intrapolated from the dose response curve. 
70 Guidance on the Application of the CLP Criteria; http://echa.europa.eu/documents/10162/13562/clp_en.pdf 
71 Effects in these groups may be classified as reprotoxicants. 
72 Wick, Georg, and Beatrix Grubeck-Loebenstein. "The aging immune system: primary and secondary alterations of immune reactivity in 
the elderly." Experimental gerontology 32.4 (1997): 401-413. 
73 Harmonization Project Document No. 10: Guidance for immunotoxicity risk assessment for chemicals (WHO/IPCS). 
74 Gavazzi, Gaëtan, and Karl-Heinz Krause. "Ageing and infection." The Lancet infectious diseases 2.11 (2002): 659-666. 

30 

 
 
                                                            
insults  and  have  a  reduced  capacity  to  respond  to  new  toxic  perturbations,  and  to  compensate 
previous exposures. Previous exposure to neurotoxicants has been related with the development of 
some neurodegenerative diseases in the aged population. 

5.2.2. Developmental immune and neurotoxicity  

The  focus  of  this  paper  is  immunotoxicity  and  neurotoxicity  in  adults;  however,  in  order  to 
understand  more  the  consequences  of  these  chemicals  it  is  necessary  to  take  into  consideration 
some  information  on  developmental  immune-  and  neurotoxicity,  even  though  these  effects  are 
specifically  covered  under  toxicity  for  reproduction.  Effects  may  be  diagnosed  a  long  period  after 
birth, and therefore it is an important factor to be discussed in this paper. 

It  is  not  explicit  if  developmental  neurotoxicity  and  immunotoxicity  occurring  solely  as  a  result  of 
exposure during childhood (and not prenatal or via lactation) is covered by developmental toxicity. 
CLP Regulation 1272/2008 (Annex I, 3.7.1.4) states that Developmental toxicity includes, in its widest 
sense, any effect which interferes with normal development of the conceptus, either before or after 
birth, and resulting from exposure of either parent prior to conception, or exposure of the developing 
offspring during prenatal development, or postnatally, to the time of sexual maturation. However, it 
is considered that classification under the heading of developmental toxicity is primarily intended to 
provide a hazard warning for pregnant women, and for men  and women of reproductive capacity. 
Therefore, for pragmatic purposes of classification, developmental toxicity essentially means adverse 
effects  induced  during  pregnancy,  or  as  a  result  of  parental  exposure.  Therefore,  the  hazard 
statement of the label covers only the unborn child. 

Similar  to  the  elderly,  the  children's  immune  and  neural  system  could  be  more  susceptible  to 
chemicals  than  that  of  adults.  Substances  exerting  these  effects  may  be  referred  to  as 
developmental immunotoxicants or neurotoxicants are considered substances toxic for reproduction 
even  though  effects  may  be  diagnosed  long  periods  after  birth,  and  therefore  it  is  an  important 
factor  to  discuss  them  in  this  section.  Toxicity  during  development  may  be  more  severe  due  to 
several factors such as the rapid organ development or/and increased absorption rates; exposure to 
higher  doses  (considering  dose  per  kg  body  weight),  and  the  possibly  reduced  capacity  of 
detoxification  for  xenobiotics.  In  some  cases,  even  low  exposure  levels  may  result  in  long-lasting 
effects that will become evident with age. 

In the case of immunotoxicants, it is generally believed that the immature immune system is more 
susceptible than the fully mature system and sequels could be more persistent. Maturation of the 
immune  system  is  a  critical  and  sensitive  process  that  may  be  affected  by  exposure  to 
immunotoxicants. Effects during maturation may lead to a lifelong dysfunctional immune system. In 
children, diseases as leukaemia, influenza, asthma, type 1 diabetes and allergic diseases have been 
associated with exposure to immunotoxicants during the developmental stage. In contrast, in adults 

31 

 
 
disturbance  of  the  immune  system  normally  requires  higher  doses  and  in  comparison  to 
developmental immunotoxicity such effects are more likely to be reversible75. 

In the case of neurotoxicants, the developing brain is more vulnerable than an adult brain. Indeed, 
exposure  during  early  foetal  development  can  cause  brain  injury  at  doses  much  lower  than  those 
affecting  adult  brain  functions.  Exposure  to  chemicals  in  the  environment  during  early  foetal 
development76 has  been  associated  with  development  of  neurodevelopmental  disorders  such  as 
motor  and  sensory  deficits,  developmental  delays,  learning  disabilities,  attention  deficit  disorder, 
mental retardation or autism77. 

5.2.3. Immunodeficiency 

Exposure  to  chemicals  that  in  a  healthy  population  would  pose  mild  or  moderate  changes  in  the 
immune system response may cause severe effects in individuals with a challenged immune system. 

5.2.4. Genetic susceptibility and gender 

Genetic  predisposition  in  the  population  may  be  a  factor  to  consider  especially  when  evaluating 
chemicals  with  immunotoxic  or  neurotoxic  effects.  Susceptibility  to  some  effects  or  disorders  may 
increase with the presence of congenital defects, and in some cases the genetic predisposition of an 
individual  could  be  a  determinant  factor,  as  in  the  case  of  some  chemically-induced  autoimmune 
disorders. 

Another  influential  factor  to  consider  is  the  gender  bias  that  some  immune  diseases  exhibit. 
Exposure to immunotoxicants during postnatal early-life stages may produce differences in response 
depending  on  the  gender.  This  fact  is  notable  in  the  case  of  predominance  of  some  autoimmune 
diseases78,  particularly  in  women;  in  fact  it  has  been  reported  that  under  certain  conditions 
(thyroiditis, scleroderma, and systemic lupus erythematous) more than 85% of patients are female79. 
The  evaluation  of  the  impact  of  certain  chemicals  on  the  immune  system  (with  exception  of 
sensitisers)  is  a  challenging  task  that  has  led  to  the  controversy  whether  small  changes  in  the 
immune function may be significant and used to assess the risk of exposure to immunotoxicants in 
human populations. In the case of neurotoxicants, the sensitivity to neurotoxicants varies across the 
general population although the reasons for this variability are still unknown80. 

75 Luebke, Robert W., et al. "The comparative immunotoxicity of five selected compounds following developmental or adult exposure." 
Journal of Toxicology and Environmental Health, Part B 9.1 (2006): 1-26. 
76 Effects associated with exposure during early foetal stage are covered by reproductive toxicity. 
77 Grandjean, Philippe, and Philip J. Landrigan. "Developmental neurotoxicity of industrial chemicals." The Lancet 368.9553 (2006): 2167-
2178. 
78 Environmental health criteria 236. Principles and methods for assessing autoimmunity associated with exposure to chemicals (WHO, 
2006). 
79 Cooper, Glinda S., Frederick W. Miller, and Dori R. Germolec. "Occupational exposures and autoimmune diseases." International 
immunopharmacology 2.2 (2002): 303-313. 
80 Vahter, Marie, et al. "Gender differences in the disposition and toxicity of metals." Environmental research 104.1 (2007): 85-95. 

32 

 
 
 
 
                                                            
6. 

Conclusions 

An  evaluation  of  relevant  factors  to  compare  an  'equivalent  level  of  concern'  to  carcinogenic, 
mutagenic  or  reprotoxic  substances  has  been  performed  for  substances  classified  as  STOT-SE/RE 
(category  1  and  2),  particularly  for  substances  showing  immunotoxic  or  neurotoxic  effects.  This 
evaluation  follows  the  criteria  proposed  by  different  stakeholders  as  considered  previously  in  the 
ECHA's  discussion  paper  on  sensitisers,  and  includes  the  following  factors:  the  type  of  possible 
health effects, the irreversibility and the delay of such effects. 

The  evaluation  suggests  that  some  substances  showing  severe  immunotoxic  or  neurotoxic  effects 
following  single  or  repeated  exposure  could  present  an  'equivalent  level  of  concern'  as  CMRs  and 
potentially be identified as SVHC according to the Art. 57(f) route in REACH. For both, neurotoxic and 
immunotoxic substances a case-by-case justification considering hazard assessment and evidence of 
an equivalent level of concern is necessary. 

Neurotoxic effects include motor and sensor activity alteration, effects on reflex action or effects on 
cognition.  After  acute  exposure,  these  effects  may  be  transient,  and  therefore,  some  substances 
causing these effects may not be considered as potential SVHC candidates according to Article 57(f); 
however,  long-term  exposure  with  slowly  reversible  effects  or  delayed  effects  may  lead  to 
irreversible damage of the nervous system resulting in serious chronic diseases, e.g. encephalopathy, 
neurodegenerative diseases, and cognitive impairment. 

Also  some  chemicals  causing  immunotoxic  effects  could  be  seen  as  potential  SVHC  candidates. 
Immunosuppression is normally reversible but long-term exposure may result in secondary effects, 
e.  g.,  increased  risk  of  infections  or  development  of  tumours.  Also,  a  number  of  autoimmune 
diseases  have been associated  with  long-term  chemical  exposure  or  suggested  to  arise  as  delayed 
effects  following  an  exposure  during  a  critical  time  window;  however,  the  identification  of  these 
chemicals may be problematic due to the very complex nature of these diseases. 

In both, immunotoxic and neurotoxic effects, the relationship between chemical exposure and effect 
may not always be obvious. In general, identification of SVHC that exert immunotoxic effects is more 
complex than of substances with neurotoxic effects. The reason is, that no specific EU methods or 
OECD  test  guidelines  are  available  to  characterise  immunotoxic  properties  and  information  on 
immunosuppression,  immunostimulation  or  autoimmune  diseases  is  mainly  retrieved  from  non-
standard tests. 

As stated in Art. 57 (f), the only  determining factor for the identification of  substances as SVHC, is 
the existence of scientific evidence of probable serious effects, which give rise to an equivalent level 
of  concern  to  CMR  substance.  However,  other  factors  as  discussed  in  the  BfR/  BAuA  workshop  on 
REACH  Article  57(f)  and  as  presented  in  the  ECHA  discussion  paper  on  sensitisers  may  provide 
relevant information about the level of concern of a substance to be taken into consideration in the 
case-by-case evaluation of these chemicals, such as the impairment of quality of life, consequences 
for society and the difficulty in performing risk assessments. 

33 

 
 
In this regard, societal concern and impairment of quality of life can be a consequence of exposure 
to  neurotoxicants  or  immunotoxicants  particularly  for  vulnerable  population.  In  addition,  in  some 
cases  the  derivation  of  safe  threshold  levels  could  be  difficult  for  both  neurotoxicants  and 
immunotoxicants; however in general it is possible and risks can be controlled under different risk 
management  options.  Potency,  age,  genetic  susceptibility  and  gender  are  considerations  that  may 
be  taken  into  account  when  evaluating  the  level  of  concern.  In  this  case,  groups  at  higher  risk  to 
immunotoxicant and  neurotoxicant  exposure  include  children and elderly  as  well  as  people with  a 
challenged immune system, which may be more sensitive to lower concentrations. 

In conclusion, neurotoxicity or immunotoxicity effects occurring at dose ranges, which are critical for 
the  respective  STOT  classification  (STOT-SE  or  STOT-RE,  category  1  and  2)  should  be  primarily 
considered for SVHC identification. In agreement with the previous discussion paper on sensitisers, 
this document underlines the importance of a harmonised classification as STOT substance for these 
specific effects before starting any SVHC identification, followed by a case-by-case 'equivalent level 
of concern' evaluation and justification. 

34 

 
 
 
 
Abbreviations 

BaUA 

BfR 

BPR 

CLP 

CMR 

ECHA 

ELoC 

EMA 

Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (German 
Federal Institute for Occupational Safety and Health) 

Bundesinstitut für Risikobewertung (German Federal Institute for 
Risk Assessment) 

Regulation (EU) No 528/2012 on Biocidal Products Regulation 

Regulation (EC) No 1272/2008 on Classification, Labelling and 
Packaging of Substances and Mixtures 

Carcinogenic, Mutagenic or Toxic for Reproduction 

European Chemicals Agency 

Equivalent Level of Concern 

European Medicines Agency 

EOGRTS 

Extended One-Generation Reproductive Toxicity Study 

EPA 

ICH 

OECD 

OECD TG 

United States Environmental Protection Agency 

International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 

Organisation for Economic Co-operation and Development 

Organisation for Economic Co-operation and Development Test 
Guidelines 

OPPTS 

US-EPA Office of Prevention, Pesticides and Toxic Substances 

35 

 
 
 
 
 
 
 
 
 
Annex I: STOT classification in CLP and Criteria for STOT classification 

STOT  classification  encompasses  several  adverse  effects  that  may  be  severe,  delayed  and/or 
and 
irreversible, 
immunotoxicity,  but  also  transient  effects  as  respiratory  tract  irritation  and  narcotic  effects.  As  a 
starting point, JRC assessed the endpoints immunotoxicity and neurotoxicity. 

including  haemotoxicity,  hepatotoxicity,  nephrotoxicity,  neurotoxicity 

In the Regulation (EC) No 1272/2008 and the Guidance to the Regulation on classification, labelling 
and packaging (CLP) of substances and mixtures, STOT classification for Category 1 and 2 depends on 
whether  the  adverse  outcomes  are  significant  or  relevant,  or  whether  they  are  severe,  thereby 
having a significant impact on human health (see summary in table below). This evidence could be 
based  on  human  studies;  e.g.  case  reports,  epidemiological  studies,  medical  surveillance  and 
reporting schemes and information from national poisons centres, and/or based on animal studies 
that  on  many  occasions  could  be  more  informative  than  human  cases,  since  animal  studies  are 
conducted under controlled conditions respecting exposure and other experimental settings. 

As  mentioned in  the  guidance,  weight-of-evidence  and  expert judgement are required  to  properly 
classify  a  substance  under  STOT  categorisations.  CLP  regulation  provides  dose/concentration 
guidance  values  to  be  used  as  part  of  a  weight-of-evidence  evaluation  and  to  assist  in  the 
classification of STOT substances in Category 1 or 2 (see Table A.1 below). In addition, STOT-SE and 
STOT-RE categories are derived from significant data on non-lethal toxic effects from acute toxicity 
testing and 28 or 90-day repeated-dose studies, respectively81. 

Other relevant evidences  from studies  in humans and/or animals to  be considered as listed in the 
CLP Regulation 1272/2008 (Annex I: 3.9.2.7.3) to support STOT classification are: 

(a) morbidity or death resulting from repeated or long-term exposure. Morbidity or death may result 
from repeated exposure, even to relatively low doses/concentrations, due to bioaccumulation of the 
substance  or  its  metabolites,  and/or  due  to  the  overwhelming  of  the  de-toxification  process  by 
repeated exposure to the substance or its metabolites. 

(b)  significant  functional  changes  in  the  central  or  peripheral  nervous  systems  or  other  organ 
systems,  including  signs  of  central  nervous  system  depression  and  effects  on  special  senses  (e.g., 
sight, hearing and sense of smell). 

(c) any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis 
parameters. 

(d)  significant  organ  damage  noted  at  necropsy  and/or  subsequently  seen  or  confirmed  at 
microscopic examination. 

81 CLP Guidance value ranges for single-dose exposures (Annex 1: 3.8.2.1.9.3) and for repeated-dose exposure (Annex 1: 3.9.2.9.6., Annex 
3.9.2.9.7). ECHA Guidance on the Application of the CLP Criteria. ECHA (2012). 

36 

 
 
                                                            
(e) multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative 
capacity. 

(f) morphological changes that are potentially reversible but provide clear evidence of marked organ 
dysfunction (e.g., severe fatty change in the liver). 

(g) evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital 
organs incapable of regeneration. 

In  the  next  section,  specific  adverse  effects  of  immunotoxicants  and  neurotoxicants  significant  for 
STOT classification are discussed. 

37 

 
 
 
Table A 1. Criteria and guidance values82 to assist in Category 1 and 2 classifications for STOT-SE and STOT-RE83 

STOT-SE Cat. 1 

STOT-SE Cat. 2 

STOT-RE Cat. 1 

STOT-RE Cat. 2 

Criteria 

Basis of evidence 

Observations  

3
8

Proposed guidance 
values  

Proposed guidance 
values, inhalation 
(gas) 
Proposed guidance 
values, inhalation 
(vapour)  
(dust/mist/fume) 

Significant toxicity in humans or 
potential to produce significant 
toxicity in humans following single 
exposure 
Human cases or epidemiological 
studies or observations in 
experimental animals with 
significant and/or severe toxic 
effect, of relevance to human 
health 
Significant non-lethal effects 
observed in acute toxicity testing 

Presumed to have the potential 
to be harmful to human health 
following single exposure 

Studies in experimental animals, 
of relevance to human health 

Significant non-lethal effects 
observed in acute toxicity testing 

C ≤ 300 (oral)  
C ≤ 1000 (dermal) 
(mg/kg bw) 
C ≤ 2500 (gas) 
(ppmV/4h) 

2000 < C ≤ 300 (oral) 
2000 < C ≤ 1000 (dermal) 
(mg/kg bw) 
20000 < C ≤ 2500 (gas) 
(ppmV/4h) 

Significant toxicity in humans or 
potential to produce significant 
toxicity in humans following 
repeated exposure 
Human cases or epidemiological 
studies or observations in 
experimental animals with 
significant and/or severe toxic 
effect, of relevance to human 
health 
Significant toxic effects observed in 
90-day repeated-dose animal 
studies, in rats (oral) or rabbits 
(dermal) 
Generally low exposure 
concentrations 
C ≤ 10 (oral) 
C ≤ 20 (dermal) 
(mg/kg bw/d) 
C ≤ 50 (gas) 
(ppmV/6h/day) 

Presumed to have the potential to 
be harmful to human health 
following repeated exposure 

Studies in experimental animals of 
relevance to human health 

Significant toxic effects observed in 
90-day repeated-dose animal 
studies, in rats (oral) or rabbits 
(dermal) 
Generally moderate exposure 
concentrations 
10 < C ≤ 100 (oral) 
20 < C ≤ 200 (dermal) 
(mg/kg bw/d) 
50 < C ≤ 250 (gas) 
(ppmV/6h/day) 

C ≤ 10 (vapour) 
C ≤ 1.0 (dust/mist/fume) 
(mg/l/4h) 

20 < C ≤ 10 (vapour) 
5.0 < C ≤ 1.0 (dust/mist/fume) 
(mg/l/4h) 

C ≤ 0.2 (vapour) 
C ≤ 0.02 (dust/mist/fume) 
(mg/l/6h/day) 

0.2 < C ≤ 1 (vapour) 
0.02 < C ≤ 0.2 (dust/mist/fume) 
(mg/l/6h/day) 

82 Guidance values and ranges for guidance purposes, as part of the weight-of-evidence approach to assist with decisions about classification.  
83 Adapted from: http://echa.europa.eu/documents/10162/13562/clp_en.pdf; and CLP Regulation 

 
 
 
 
 
 
 
 
                                                            
Annex II: Adverse health effects caused by immunotoxicants and 
neurotoxicants 

A.2.1. Adverse immune system effects 

The  immune  system  is  a  complex  system  that  provides  the  body  with  a  proper  balance  of  the 
immune  response,  including  host  defence  against  pathogens  or  neoplasias;  response  to  foreign 
compounds, and recognition and discrimination of self from non-self body components. 

the 

immune 

Immunotoxicology  investigates  how  substances  can  interact,  alter,  and  compromise  the  immune 
system function contributing to a wide range of adverse effects from mild to severe. Substances can 
affect 
including 
immunosuppression,  allergies,  hypersensitivity  reactions,  higher  risk  to  develop  autoimmune 
diseases and dysfunctional anti-inflammatory responses84. The seriousness of these effects depends 
on  the  mode  of  action,  severity  of  damage  on  immune  system  (including  all  immune  tissues)  and 
vulnerability of the population exposed as well as the time of exposure to the chemicals. 

system  evoking  a  combination  of  adverse  outcomes 

Among the adverse immunotoxic effects, immunosuppression, immunostimulation and autoimmune 
response have been taken into consideration as potential outcomes to be relevant for identification 
of  SVHC.  Immunological  effects  such  as  allergies  or  hypersensitivity  reactions  are  classified  under 
another CLP category, and have been previously discussed.  

 

Immunosuppression:  

Exposure  to  chemicals  with  immunosuppressant  effects  may  lead  to  an  increased  risk  of 
incidence  of  neoplastic  diseases,  an  increase  of  the  susceptibility  and  potential  severity  of 
infectious diseases, and/or a decrease in the response and effect of immunisation, having as 
a possible consequence also the increase in the number of incidence of infection cases in the 
general population. 

Although  an  increased  risk  to  certain  types  of  cancer  has  been  linked  to  a  decreased 
effectiveness  of  the  immune  system  in  eliminating  neoplastic  cells  or  virus-  related 
neoplastic events, cancer has also been described as a co-morbid adverse effect related with 
other chronic immune-based diseases, especially those as a consequence of developmental 
immunotoxicity.  Regarding  changes  in  host  resistance  (to  tumour  cells,  bacteria,  viruses), 
adverse  effects  may  be  mild  or  severe,  even 
lethal,  depending  on  the  exposure 
characteristics and vulnerability of the population exposed. Usually, in healthy populations, 
small  changes  in  resistance  to  infections  will  lead  to  mild  to  moderate  adverse  effects, 
whereas  they  could  be  severe  in  individuals  with  immunodeficiency  diseases  or  under 
immunosuppressive therapy. 

Cellular changes such as atrophy or decreases in population of T-cell or B-cell compartments 
can directly be seen in animal studies (detection can be improved by specific methods that 

84 Harmonization Project Document No. 10: Guidance for immunotoxicity risk assessment for chemicals (WHO/IPCS) 

39 

 
 
                                                            
are  not  standard).  The  proof  of  dysfunction  of  the  innate,  nonspecific  immune  responses 
against  infections,  is  rarely  available  in  regulatory  datasets.  Testing  on  specific  immune 
responses is even more rarely found. 

 

Immunostimulation: 

Effects due to alterations by immunostimulation are not very well understood, and usually 
difficult to evaluate; they may exacerbate allergic reactions, worsening autoimmune disease 
and induce or amplify inflammatory response causing organ damage.  

  Autoimmunity: 

Autoimmunity and autoimmune diseases result from altered immune responses against self-
molecules. The immunological effectors and mechanisms involved in autoimmune reaction 
are the same of those associated with responses to foreign antigens, including activation of 
the  innate  and  adaptive  immune  systems,  production  of  inflammatory  mediators  and 
activation of T lymphocytes or the generation of antibodies with specificity for self-antigens. 

A number of chemicals have been identified as potential triggers of autoimmunity and linked 
to  an  elevated  risk  to  some  systemic  autoimmune  diseases  (scleroderma-like  disease, 
Raynaud  phenomenon,  and  systemic  lupus  erythematosus).  However,  the  identification  of 
chemical-associated  autoimmune  effects  is  challenging  since  autoimmune  diseases  are 
complex  disorders,  not  yet  well  understood.  Studies  in  animals  exposed  to  substances 
showing  autoimmunogenic  potential  (e.g.  some  metals,  dioxins,  or  some  pesticides), 
presented  cellular,  biochemical  and  clinical  alterations  similar  to  known  autoimmune 
diseases85. 

Evaluation  and  identification  of  immunotoxic  effects  are  not  easy  tasks.  Adverse  effects  of  some 
chemicals have shown clinical features similar to several autoimmune diseases; however, chemicals 
inducing  autoimmunity  are  difficult  to  identify  due  to  the  lack  of  validated  models  and  strategies. 
Furthermore, the immune system is present in nearly each tissue of any organ and alterations may 
lead  to  other  organ  dysfunctions  that  by  default  are  not  considered  as  cause  of  a  failure  of  the 
immune system. Thus, in  most cases the application of a  weight-of-evidence  approach by  experts, 
on the available data is required. 

Currently,  the  identification  of  immunotoxicity  effects  is  carried  out  using  in  vivo,  repeated-dose 
toxicity in rats or mice, and in vitro studies, from which a broad range of parameters are measured. 
This  list  of  factors  include  haematology  changes,  lymphoid  organ  weights,  histopathology  of 
lymphoid  tissues  and  tissues  where  immune  complexes  may  deposit,  bone  marrow  cellularity, 
distribution  of  lymphocyte  subsets  and  NK-cell  activity  or  primary  antibody  response  to  T-cell 

85 Environmental Health Criteria 236. Principles and methods for assessing autoimmunity associated with exposure to chemicals. WHO 
(2006) 

40 

 
 
                                                            
dependent  antigen,  as  well  as  alterations  in  the  immune  function  or  characterisation  of  host 
resistance response 86. 

A.2.2. Adverse effects of neurotoxicants 

The  nervous  system  is  a  complex  organ  system  that  controls  several  functions  including  sensory, 
motor and cognitive function. 

The  OECD  guidance  for  "Neurotoxicity  Study  in  Rodents"  (TG  424)87 describes  neurotoxicity  as  an 
adverse change in the structure or function of the nervous system, central and peripheral that results 
from  exposure  to  a  chemical,  biological  or  physical  agent.  In  this  definition,  an  adverse  change 
should be considered any detrimental effect that affects the normal function of the nervous system 
resulting  from  single  or  repeated  exposure.  Furthermore,  a  group  of  experts  on  neurotoxicity  risk 
assessment for human health from the WHO Environmental Health Criteria Programme have divided 
neurotoxic effects in two types, structural and functional88: Structural neurotoxic effects are defined 
as neuroanatomical  changes  occurring  at any level  of nervous system organization.  These  changes 
may  be  indicated  by  changes  in  brain  morphology  or  weight,  or  histologic  changes  at  tissue  and 
cellular  level.  Functional  changes  are  defined  as  neurochemical,  neurophysiological  or  behavioural 
effects. These effects include adverse changes in somatic/autonomic, sensory, motor and cognitive 
function, and may  be traced by changes in  neurophysiological endpoints such  as changes in nerve 
conduction,  sensory  potential  or  electrocephalographic  pattern;  in  behavioural  and  neurological 
endpoints  such  as  headache,  dizziness,  unconsciousness,  seizures,  cognitive  problems,  memory 
problems, and memory loss, behavioural, alteration of motor control, changes in learning, memory 
or attention. 

In  a  report,  published  by  EFSA  in  2012,  on  Identification  of  Cumulative  Assessment  Groups  of 
Pesticides, the authors grouped the effects on the nervous system in effects concerning functional 
changes  related  to  the  motor  division  (including  movement  of  muscles,  effects  of  locomotion  and 
neuropathy), effects on reflex action, hypertrophy/ hyperplasia in the brain, cell degenerations and 
neoplasms in the brain89. 

Neurotoxicity  not  only  includes  effects  on  the  central  nervous  system  but  also  neurotoxic  effects 
(morphological or functional or both) on the eye (retina, eye nerve), ear (hearing), the sense of smell 
and the peripheral nervous system, considered serious damage of organs. A major problem is that 
examinations  in  the  standard  OECD  test  guideline  are  often  not  sufficient  for  the  hazard 
characterisation or even identification  of these effects. Moreover,  indications coming from human 
observations  remain  only  as  indicators  since  a  causal  link  between  exposure  and  effects  is  often 
difficult to establish. 

86 Dietert, Rodney R., ed. Immunotoxicity testing: methods and protocols. Humana Press, 2010. 
87 OECD (1997), Test No. 424: Neurotoxicity Study in Rodents, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing. 
88 http://www.inchem.org/documents/ehc/ehc/ehc223.htm 
89 External scientific report submitted to EFSA Identification of Cumulative Assessment Groups of Pesticides (National Food Institute, 
Technical University of Denmark-EFSA): http://www.efsa.europa.eu/en/supporting/doc/269e.pdf 

41 

 
 
                                                            
Some  effects  of  short-term  or  acute  exposure  may  be  detected  early  after  the  exposure,  whereas 
long-term  exposure  to  relatively  low-concentrations  may  result  in  impairment  of  the  functional 
capacity of the nervous system where can only be detected after a long period of after exposure. In 
the  latter  case  it  is  not  always  easy  to  establish  a  causal  link  between  exposure  and  effects,  or 
between patterns of exposure or dose. In these cases, integration of hazard characterisation, dose-
response  analysis  and  exposure  assessment  as  well  as  expert  judgment  of  the  data  available  is 
necessary. 

42 

 
 
 
 
Annex III: Examples for chemicals with potential neurotoxic effects 

A number of chemicals such as some metals, pesticides and organic solvents have been associated 
with effects on the nervous system. The severity of these effects can range from mild to severe and 
it  is  also  important  to  note  that  the  absence  or  limited  capacity  of  regeneration  of  the  nervous 
system, especially in some neuronal regions, increases the level of concern of potential changes that 
can occur in the system. Some of the effects associated with these chemicals are presented in this 
Annex: 

A.3.1. Metals  

Long-term exposure to certain metals can lead to neurotoxic effects. Welders have been associated 
with  a  higher  risk  to  suffer  some  neurological  dysfunctions  than  welders  not  exposed  to  these 
metals.  For  example,  some  occupational  studies  in  workers  in  foundries90 or  exposed  to  welding 
fumes91,92 suggested  a  link  between  the  chronic  inhalation  to  aluminium  with  pre-clinical  mild 
cognitive  disorder  which  might  prelude  Alzheimer's  disease  and  evoke  delays  in  reaction  time  of 
exposed  workers.  Also,  some  epidemiological  studies  of  drinking  water  with  high  content  of 
aluminium have suggested the exposure to high levels of this metal as an important risk factor in the 
pathogenesis of Alzheimer’s type disease93. Biochemical changes related with exposure to high levels 
of  aluminium  such  as  formation  and  accumulation  of  amyloid  beta  protein,  and  aggregation  of 
microtubullar  protein  tau  forming  neurofibrillary  tangles  may  contribute  to  the  loss  of  neurons  in 
the hippocampus (symptoms of mild impairment in verbal memory).  Aluminium pot-room workers 
have  presented  incoordination,  intention  tremor  and  cognitive  deficits.  Other  symptoms  often 
reported were loss of balance, memory loss, joint paint, dizziness, numbness and severe weakness. 
Other study showed the prevalence of neurological symptoms as incoordination and depression. 

Exposure to lead has also been associated with decline in cognitive function (after acute or longer-
term  exposure),  contribution  to  cognitive  and  behavioural  impairments94 and  to  induction  of 
neuropathy95. 

The  nervous  system  is  the  principal  target  tissue  affected  by  methylmercury  in  adults.  Chronic 
exposure to organic forms of mercury such as the lipid-soluble form of mercury has been reported 
to perturb neuromotor, behavioural and cognitive functions96. 

90 Polizzi, Salvatore, et al. "Neurotoxic effects of aluminium among foundry workers and Alzheimer’s disease." Neurotoxicology 23.6 
(2002): 761-774. 
91 Buchta, M., et al. "Longitudinal study examining the neurotoxicity of occupational exposure to aluminium-containing welding fumes." 
International archives of occupational and environmental health 76.7 (2003): 539-548. 
92 Buchtaa, Mark, et al. "Neurotoxicity of exposures to aluminium welding fumes in the truck trailer construction industry." Environmental 
Toxicology and Pharmacology 19.3 (2005): 677-685. 
93 Flaten, Trond Peder. "Aluminium as a risk factor in Alzheimer’s disease, with emphasis on drinking water." Brain research bulletin 55.2 
(2001): 187-196. 
94 Florea, Ana-Maria, and Dietrich Büsselberg. "Occurrence, use and potential toxic effects of metals and metal compounds." Biometals 
19.4 (2006): 419-427. 
95 Chuang, Hung-Yi, et al. "The influence of milk intake on the lead toxicity to the sensory nervous system in lead workers." 
Neurotoxicology 25.6 (2004): 941-949 

43 

 
 
                                                            
A.3.2. Pesticides 

some 

insecticides, 

For  example 

long-term  outcome. 

Exposure  to  certain  pesticides  has  been  associated  with  an  increased  risk  for  behavioural  and 
certain 
neurological 
including 
organophosphates,  carbamates,  pyrethroids,  or  organochlorines 
interfere  with  chemical 
neurotransmission  or  ion  channels,  and  usually  cause  reversible  neurotoxic  effects,  that  could 
nevertheless be lethal. Exposure to some of these chemicals has been associated with an increased 
risk  to  develop  Parkinson's  disease97,98.  Parkinson's  disease  is  a  progressive  degeneration  of 
dopaminergic neurons of the substantia nigra pars compacta that project to the striatum and play a 
role in controlling motor functions. Effects similar to those evoked in Parkinson's disease as rigidity, 
resting tremors, bradykinesia and postural instability as well as others such as cognitive impairment, 
sleep  disturbances,  olfactory  dysfunction  and  depression  have  been  reported  after  poisoning  or 
episodes of accidentally high exposure to these pesticides99. 

is 

It 
important  to  note  that  the  association  between  the  exposure  to  pesticides  and 
neurodegenerative diseases as Alzheimer's disease and Parkinson's disease is under scientific debate 
since  epidemiological  studies  present  some  evidence  of  these  links  but  the  data  available  are 
insufficient  to  support  a  causal  relationship  between  the  exposure  to  a  particular  pesticide  or 
mixture and these diseases. 

A.3.3. Organic solvents 

Several organic solvents  have been identified as having neurotoxic effects. Iregren and Gamberale 
(1995)  investigated  experimentally  the  potential  neurotoxicity  of  different  single  and  mixtures  of 
organic  solvents  (such  as  methyl  butyl  ketone,  styrene,  toluene,  white  spirit,  or  xylene)  and  also 
reviewed effects of solvents investigated by other labs (e.g. formaldehyde, acetone or methyl ethyl 
ketone).  The  authors  concluded  that  exposure  to  organic  solvents  were  generally  slight,  transient, 
narcotic  effects  that  resulted  in  prolonged  delayed  responses  in  behavioural  tests.  In  the  CLP 
Regulation, these effects  are covered  by STOT-SE Cat. 3 as  transient  target organ effects  (Annex I: 
Table 3.8.1) that, may range from slight dizziness to deep unconsciousness and it gives as an example 
the  organic  solvent  toluene  to  illustrate  this  category  (CLP  3.8.6.1.4  Example  4:  Toluene). 
Furthermore, these authors also noted that the effects resulting from long-term exposure to these 
chemical  in  occupational  settings  were  not  very  specific  and  mainly  diffuse  symptoms  as  fatigue, 
memory impairment or reduction in intellectual functions100.  

96 Jonnalagadda, S. B., and P. V. V. Rao. "Toxicity, bioavailability and metal speciation." Comparative Biochemistry and Physiology Part C: 
Pharmacology, Toxicology and Endocrinology 106.3 (1993): 585-595. 
97 Wang, Anthony, et al. "The association between ambient exposure to organophosphates and Parkinson's disease risk." Occupational and 
environmental medicine (2014): oemed-2013. 
98 Costa, Lucio G., et al. "Neurotoxicity of pesticides: a brief review." Frontiers in bioscience: a journal and virtual library 13 (2007): 1240-
1249. 
99 Brown, T. P., et al. "Pesticides and Parkinson's disease--is there a link?" Environmental Health Perspectives 114.2 (2006): 156-164. 
100 Iregren, Anders, and Francesco Gamberale. "Human behavioral toxicology: central nervous effects of low-dose exposure to neurotoxic 
substances in the work environment." Scandinavian journal of work, environment & health (1990): 17-25. 

44 

 
 
                                                                                                                                                                                         
For  white  spirit  (solvent  and  thinner  in  paints)  the  RAC  (Risk  Assessment  Committee) 101,  in 
agreement with the assessments of the International Programme on Chemical Safety (IPCS 1996)102 
and  Scientific  Committee  on Occupational  Exposure  Limits  (SCOEL  2007)103 concluded  in  2011  that 
long-term exposure (> 10 years) may lead to the impairment of brain function and can therefore be 
associated with a high risk for the development of a chronic toxic encephalopathy. In their view the 
corresponding  decline  in  the  number  of  diagnosed  CTE  (chronic  toxic  encephalopathy)  cases  with 
the decreasing use of solvent-based paints supports the theory of white spirit as the causative agent. 
RAC  decided  for  a  classification  with  STOT-RE  1  -  H372  (Causes  damage  to  the  central  nervous 
system  through  prolonged  or  repeated  exposure).  In  that  case  the  available  animal  data  were 
inconclusive and failed to provide a molecular mechanism that could explain the long-term effects. 
The adverse effects as measured in humans are related to behavioural changes and may be difficult 
to detect in animals. 

Other examples of neurotoxicity include the toxicity to senses. Ethylbenzene104 was classified for its 
ototoxicity  with  H373  (May  cause  damage  to  hearing  organs  through  prolonged  or  repeated 
exposure). Evidence is provided by one oral animal study, where high doses caused strong hair cell 
death  in  cochleae.  There  are  no  specific  data  on  neurotoxicity  in  humans  with  mono-exposure  to 
ethylbenzene.  However,  for  other  aromatic  solvents  (e.g.  for  toluene,  xylenes  or  styrene)  there  is 
evidence  for  neurotoxicity  in  humans  and  strong  experimental  evidence  for  ototoxicity.  A  high 
frequency of hearing loss in workers involved in the production of paints and varnishes (containing 
the  following  mixture  constituents:  ethylbenzene,  xylene  and  trimethylbenzene  isomers)  was 
described by Sulkowski et al. (2002)105. 

As pointed out in the case of immunotoxicants, the role of experts for the interpretation and weight-
of-evidence  based  determination  is  essential,  as  many  neurological  tests  are  qualitative  and 
descriptive, which may complicate their evaluation and the comparison of results. According to the 
US-EPA, during the evaluation of neurotoxicity of pesticides, the overall toxic profile including hazard 
identification and characterization as well as information on the mode of action may be considered 
in the weight-of-evidence approach. To establish the toxicological profile for neurotoxicants, various 
endpoints  may  be  measured  including  neuropathological,  neurochemical,  neuropsychological  and 
behavioural characteristics to provide information about potential effects of chemicals on peripheral 
and  central  nervous  system;  these  tests  evaluate  the  toxicity  in  sensorial  organs,  neuromuscular 
effects, learning and memory capacity and histopathology changes of the nervous system.  

101 RAC Opinion proposing harmonised classification and labelling at Community level of white spirit (February 2011) 
(http://echa.europa.eu/documents/10162/13641/adopted_rac_opinion_on_white_spirit_en.pdf) 
102 IPCS (1996). White Spirit (Stoddard Solvent). Environmental Health Criteria 187. International Programme on Chemical Safety, World 
Health Organization, Geneva. http://www.inchem.org/documents/ehc/ehc/ehc187.htm 
103 SCOEL (2007). Recommendation of the Scientific Committee on Occupational Exposure; Limits for “White Spirit”. SCOEL/SUM/87, 
August 2007. 
104 RAC Annex 1 Background document to the Opinion proposing harmonised classification and labelling at EU level of Ethylbenzene; 
http://echa.europa.eu/documents/10162/13579/bd_ethylbenzene_final_pri_clean_en.pdf 
105 Sulkowski, W.J., Kowalska, S., Matyja, W., Guzek,W., Wesolowski, W., Szymczak, W., Kostrzewski, P. (2002): Effects of occupational 
exposure to a mixture of solvents to the inner ear: a field study. Int. J. Occup. Med. Environm. Health 15, 247-256 

45 

 
 
  
                                                            
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JRC Mission 

As the Commission’s  
in-house science service,  
the Joint Research Centre’s  
mission is to provide EU  
policies with independent,  
evidence-based scientific  
and technical support  
throughout the whole  
policy cycle. 

Working in close  
cooperation with policy  
Directorates-General,  
the JRC addresses key  
societal challenges while  
stimulating innovation  
through developing  
new methods, tools  
and standards, and sharing  
its know-how with  
the Member States,  
the scientific community  
and international partners. 

Serving society  
Stimulating innovation  
Supporting legislation 

ISBN 978-92-79-50319-1