human health hazard sment characterisation for biocides

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Human health hazard

characterisation for biocides:

Current practice in the EU

Dr. Carsten Kneuer German Federal Institute for Risk Assessment

Department Safety of Pesticides

Toxicology of Active Substances and Their Metabolites

Carsten Kneuer, Indoor Air, 17/18.09.2018

Set up on 1st November 2002 as an independent departmental research facility

the BfR reports to the Federal Ministry of Food and Agriculture (BMEL)

Overall goal: Strengthening of consumer health protection

Tasks

• Assessment of health risks posed by foods, products or chemicals

• Contribute to regulatory assessments incl. pesticides/biocides

• Address chemical and biological hazards

• Research to deepen the knowledge on which the assessments are built

• Communication with stakeholders

German Federal Institute for Risk Assessment


Biocides and Indoor Air Pollution – Where is the link?

• Use of biocidal products and/or treated articles as source of pollution

• Active substances as indoor air pollutants through non-biocidal use

• Risk assessment concepts and challenges

(some) legislative background and state of biocide review

programme

toxicological data requirements for biocides

source(s) of information

internal (systemic) reference doses

local vs. systemic risk assessment

cumulative risk assessment

exclusion criteria and identification of endocrine disruptors


EU Biocide Legislation - Outline

• Directive 98/8/EC, replaced by

• Regulation (EU) 528/2012

Substance Approval at EU level, by MS authorities and ECHA:

• Registration of „Existing Actives“ and evaluation in a review programme

• Assessment of „New Actives“ prior to marketing

Product authorisation at national level (mutual recognition, EU optional):

• Registration of Products with „Existing Actives“ (transitional arrangement)

• Authorization of Biocidal Products following active substance approval

Treated Articles:

• Treated Articles are only allowed to contain approved active substances


EU-Biocides legislation – regulating 22 product types

Main group 1, Disinfectants and general biocidal products (5):

• Human and veterinary hygiene products; Algaecides; Food and

Feed & Drinking water disinfectants

• e. g. ethanol/propanol, formaldehyde, quarternary ammonium

compunds, bromoacetic acid, ozone, SO2, chlorine/hypochlorite

Main group 2, Preservatives (8):

• Storage (in-can), Wood / Masonry / Fibre, rubber & leather

preservatives, Preservatives for liquid-cooling, etc.

• e.g. isothiazolones such as MIT/CMIT, borates, azole fungicides,

silver(compunds), chlorine/bromine releasers

Main group 3, Pest control (7):

• incl. insecticides, rodenticides, repellants

• e.g. coumarin derivatives, pyrethroids, carbamates, DEET

Main group 4, Other (2): Antifoulings and Embalming fluids


Overall progress of the EU Biocides Review Programme

for existing active substances per product type (09/2018)

finalised: 237 ongoing: 377


EU Biocide Legislation – Guidance for implementation

Consolidated to ensure quality, transparancy and

harmonisation across the EU

Source: https://echa.europa.eu/de/guidance-documents/

guidance-on-biocides-legislation

https://echa.europa.eu/de/guidance-documents/




1. Acute Toxicity

• Oral/dermal/inhalative route

• Skin- and eye irritationr/ skin & respiratory sensitization

2. Studies on metabolism in mammalians, absorption across skin

3. Short-term toxicity (28 d)

4. Subchronic toxicity (90 d), rodent + non-rodent

5. Chronic toxicity, one rodent and one further mammalian

6. Studies on Mutagenicity

• Gene mutation in bacteria + mammalian cells, in vitro cytogenicity

• if applicable in vivo mutagenicity

7. Studies on carcinogenicity, two mammalian species

8. Reproductive toxicity

Teratogenicity (rabbit+rodent) / studies on fertiliy (*)

9. Observations in humans

EU biocides legislation – Toxicological Data Requirements


1. Acute Toxicity

• Oral/dermal/inhalative route

• Skin- and eye irritationr/ skin & respiratory sensitization

2. Studies on metabolism in mammalians, absorption across skin

3. Short-term toxicity (28 d)

4. Subchronic toxicity (90 d), rodent + non-rodent

5. Chronic toxicity, one rodent and one further mammalian

6. Studies on Mutagenicity

• Gene mutation in bacteria + mammalian cells, in vitro cytogenicity

• if applicable in vivo mutagenicity

7. Studies on carcinogenicity, two mammalian species

8. Reproductive toxicity

Teratogenicity (rabbit+rodent) / studies on fertiliy (*)

... based on exposure considerations, or

if scientifically not necessary, or technically not feasible.

EU biocides legislation – Waiving of Data Requirements


„Systemic“ health based guidance values in biocides

assessment

Oral Dose D(o)

Inhaled Dose D(i)

Dermal Dose D(d)

Absorbed Fraction of Dose

F(i), F(o), F(d)

Total internal Dose

D(total) = D(o) x F(o)

+ D(i) x F(i)

+ D(d) x F(d)

Exposure

Internal

dose

• Also termed „internal“

reference values

• Related to the total

internal or systemic

dose

• Based typically on oral

(or inhalation) toxicity

and respective

absorption data

• Allow for assessment of

aggregate exposure to

one substance through

various routes


Guidance values in biocides assessment – General approach

1. Acceptable Exposure Level (AEL)

• internal value in mg/kg body weight(/day), applicable for whole population

• derived for three time-frames

acute, based on effects after single exposure within 24 h

medium-term, based on effects after repeated exposure

long-term, based on effects after chronic exposure

2. Acceptable Exposure Concentration (AEC)

• external and route-specific value, typically inhalation [mg/m3]

• complementing AEL values to assess local effects when these can be

expected (triggered by classification&labelling of the product)

3. Dietary Reference Values (ARfD and ADI)

• assessment of acute / chronic secondary exposure through food


Guidance values derivation – PoDs and assessment factors

Point of Departure (PoDs) / starting point:

• Lowest relevant NOAEL for threshold effects

• LOAEL -> NOAEL extrapolation possible (factor 3-10)

• BMD modelling currently not regularly used

Default assessment factors for intra- and interspecies extrapolation

• Interspecies factor = 10 (reduced to 2.5 for local respiratory effects)

• Intraspecies factor = 10

• Refined chemical specific assessment factors possible (e.g. propanol)

Additional (assessment) factors

• Oral absorption for internal guidance values such as AEL

• Severity of effect (e.g. x3 for teratogenicity) or poor database

• Extrapolation of exposure duration (e.g. x3 subacute-to-subchronic)


Cumulative Risk Assessment for Biocides

Annex VI of Regulation (EU) 528/2012:

“In carrying out the assessment, the possibility of cumulative or

synergistic effects shall also be taken into account.”

-> Development of respective ECHA Guidance for biocides

• Tiered approach for refinement, following the principles of the

WHO/IPCS Framework on Combined Exposure

• Taking into account a series of recent reports of European Scientific

Committees and relevant scientific publications

Exposure to one chemical from various sources (aggregate

exposure) = use AEL concept

Exposure to more than one (active) substance

through use of one product

from different sources or uses


based on dose additivity

refinement of exposure

as well as toxicological

assessment

HQ: Hazard Quotient

HI: Hazard Index

HI(to): target organ specific HI

using established guidance

values

aHI(to): adjusted HI(to)

using organ specific guidance

values

aHI(to*): restriction to

substances sharing a

common Mode of Action

Tiered Approach

Source: ECHA Guidance


Exclusion Criteria for Biocidal Active Substances and

Endocrine Disruption

Article 5(1) – Exclusion criteria:

CMR Cat 1A or 1B

Endocrine Disruptor

(Interim ED criteria: C2+R2 or

identified as having ED properties)

Article 5(2) – Exemption/Substitution:

Risk is negligible (risk-mitigation measures)

essential to control serious danger

avoid a disproportionate negative impact on society

Article 5(3) – "No later than 13 December 2013, the Commission

shall adopt delegated acts in accordance with Article 83 specifying

scientific criteria for the determination of endocrine-

disrupting properties.”


Identification of Endocrine Disruptors: EU Criteria (2017)

ED CRITERIA REGULATION (EU) No 2017/2100 (as of 7th June 2018)

• Causes an adverse effect

• Has an endocrine mode of action (MoA);

• The adverse effect is a consequence of the endocrine MoA (plausible

link)

WHO/IPCS (2002):

an exogenous substance or mixture

that alters function(s) of the endocrine system

and consequently causes adverse health effects

Adversity (WHO/IPCS 2004): “A change in the morphology, physiology, growth,

development, reproduction, or life span of an organism, system, or (sub)population that

results in an impairment of functional capacity, an impairment of the capacity to

compensate for additional stress, or an increase in susceptibility to other influences.


Identification of Endocrine Disruptors: EU Guidance Document

• Adopted June 5th 2018

• Developed by ECHA, EFSA and JRC

• With various third party contributions during public consultation and

through procurement

• Implementation for Biocides just started


Information on Biocides in Germany and the EU

Registered product database at the Federal Office for Chemicals:

https://www.baua.de/DE/Biozid-Meldeverordnung/Offen/offen.html

(currently 58,546 entries)

Database of Authorised Biocidal Products:

https://www.baua.de/EN/Topics/Safe-use-of-chemicals-and-

products/Chemicals-law/Biocides/Database-biocidal-products.html

Guidance on Information Requirements and Assessment:

https://echa.europa.eu/guidance-documents/guidance-on-biocides-

legislation

Database on Biocidal Active Substances:

https://echa.europa.eu/information-on-chemicals/biocidal-active-

substances

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Bundesinstitut für Risikobewertung

Max-Dohrn Str. 8-10 10589 Berlin

Tel. 0 30 - 184 12 – 0

[email protected] www.bfr.bund.de

Dr. Carsten Kneuer

human health hazard sment characterisation for biocides

Documents