WES Review 2018

Criteria for assignment of a skin notation

Accessory document to Recommending health-based
workplace exposure standards and notations

Australian workplace exposure standards

and advisory notations
Safe Work Australia (2018)
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Contents
Glossary, abbreviations and acronyms .............................................................................. 4
Background ....................................................................................................................... 5
Aim .................................................................................................................................... 6
Criteria for skin notation assignment by other agencies ..................................................... 6
Evidence of dermal absorption ....................................................................................... 8
Evidence of toxicity by the dermal route ....................................................................... 10
Extent of dermal absorption at the workplace exposure standard ................................. 12
Proposed criteria for a skin notation in Australia .............................................................. 14
Hierarchy of effects ...................................................................................................... 14
Local vs systemic effects .............................................................................................. 16
Other considerations........................................................................................................ 17
Biological monitoring .................................................................................................... 17
Effects of formulation and mixtures............................................................................... 17
Skin condition ............................................................................................................... 17
References ...................................................................................................................... 18
Appendix 1 — ECETOC decision tree for assigning a skin notation................................. 19
Glossary, abbreviations and acronyms
Glossary

ACGIH® American Conference of Kaq Permeation coefficient in the watery

Governmental Industrial epidermal layer
Hygienists

AIHA American Industrial Hygiene Kp value Skin permeation coefficient

Association

AIOH Australian Institute of Kpol Permeation coefficient in the protein

Occupational Hygienists fraction of the stratum corneum

DECOS Dutch Expert Committee on Kpsc Permeation coefficient in the lipid

Occupational Safety fraction of the stratum corneum

Dermal route Exposure via the skin, mucous LC50 Concentration of a substance in air
membranes and eyes that kills 50% of animals during the
observation period

DFG German Research Foundation LD50 Single dose of a substance that can
(Deutsche be expected to cause death in 50
Forschungsgemeinschaft) per cent of animals when
administered by a given route of
exposure

ECETOC European Centre for NIOSH National Institute for Occupational

Ecotoxicology and Toxicology of Safety and Health
Chemicals

GHS Globally Harmonized System of NOAEL No observed adverse effect level

Classification and Labelling of
Chemicals

HCIS Hazardous Chemical Information Occupational Equivalent term to a workplace

System exposure limit exposure standard

HSE Health and Safety Executive OECD Organisation for Economic

Co-operation and Development

In silico Procedure performed via a PCBU Person who conducts a business or

computer undertaking

In vitro Procedure performed in a SCOEL Scientific Committee on

controlled environment outside Occupational Exposure Limits
of a living organism

In vivo Procedure performed in a living SI ratio Skin/inhalation ratio

organism

IP Intraperitoneal WES Workplace exposure standard

IPCS International Programme on WHS Work Health and Safety

Chemical Safety

IV Intravenous

4
Criteria for assigning a skin notation
This document outlines criteria for the assignment of a skin notation, an advisory notation
to the workplace exposure standards.

Background
Exposure standards represent airborne concentrations of chemical substances in the
workers’ breathing zone which, according to current knowledge, should neither cause
adverse health effects or undue discomfort to workers (Safe Work Australia, 2013).
Under the model Work Health and Safety (WHS) laws, persons who conduct a business or
undertaking (PCBUs) have a responsibility to ensure, so far as reasonably practicable,
workers and other people are not exposed to health and safety risks arising from the
business or undertaking (section 19 of the model WHS Act).
Additionally, under the model WHS laws, PCBUs have a responsibility to ensure that no
person at the workplace is exposed to a substance or mixture in an airborne concentration
that exceeds the exposure standard for the substance or mixture (regulation 49 of the
model WHS Regulations). Therefore, in Australia, the exposure standards listed in the
Workplace Exposure Standards for Airborne Contaminants are legally enforceable and
duty holders must not exceed these standards.
Australia’s workplace exposure standards are published with advisory notations
associated with the hazardous chemical. These notations consist of:
 classification of carcinogenicity
 classification of sensitisation, and
 the potential for systemic effects due to skin absorption.
The notations are provided with the exposure standard for information only, so a PCBU
and workers can take informed action to minimise exposure and risks.
Workplace exposure standard (WES) values are generally assigned to be protective of
toxicity by the inhalation route. However, dermal exposure to some airborne chemicals
may also significantly contribute to systemic effects associated with the chemical. Where
significant exposure and toxicity may occur as a result of dermal absorption from airborne
concentrations of the chemical, a skin notation will be assigned.
This notation will inform PCBUs and workers that maintaining airborne concentrations of
the chemical at the workplace exposure standard may not be sufficiently protective as
significant additional exposure may occur via the dermal route, including the skin, mucous
membranes and eyes. PCBUs and workers can apply risk minimisation procedures as
necessary; extra precautions to minimise total exposure, via both the inhalation and
dermal routes may be warranted. This notation is used to help improve safety outcomes in
the workplace.
While a ‘skin’ notation is assigned by most international agencies that determine
workplace exposure standards, including the American Conference of Governmental
Industrial Hygienists (ACGIH®), EU Scientific Committee on Occupational Exposure Limits
(SCOEL), American Industrial Hygiene Association (AIHA), German Research Foundation
(Deutsche Forschungsgemeinschaft; DFG) and the Health Council of the Netherlands, the
criteria for assigning such a notation differ across these agencies (Lavoue et al., 2008;
Nielsen and Grandiean, 2004; Sartorelli et al., 2007).
Several chemicals in the Australian WES list have an accompanying skin notation. These
notations were generally assigned and adopted from the same source as the WES value,
either ACGIH® or UK Health and Safety Executive (HSE). In 2004-2005, a public
consultation paper was released discussing the inclusion of skin absorption notations
adopted from the HSE for some chemicals. In response to this consultation paper, the

5
Australian Institute of Occupational Hygienists (AIOH) identified that there were no clear
criteria for determining whether a ‘skin’ notation should be assigned to a chemical and
recommended that clear criteria be developed.

Aim
The aim of this document is to establish clear criteria for the assignment of a skin notation
in Australia. These criteria will be generally consistent with those used by most
international standard setting agencies.

Criteria for skin notation assignment by other agencies

The principles underlying a skin notation for a chemical are generally similar across
agencies:
 evidence of significant dermal absorption
 evidence or a suggestion of systemic toxicity by the dermal route, and
 for some agencies, the extent of dermal absorption at the workplace exposure
standard is significant.
However, the specific criteria differ across agencies (see Table 1), ranging from purely
qualitative criteria (e.g. DFG), to a more quantitative approach (e.g. US National Institute
for Occupational Safety and Health [NIOSH]). Because of these differences in specific
criteria, there is significant variability in the assignment of a skin notation for a chemical
across different agencies (Nielsen and Grandjean, 2004).
Table 1 Criteria for skin notation assignment by other agencies

Criteria for skin notation assignment

American Conference of Governmental Industrial Hygienists (ACGIH®, 2016)

 Applied to chemicals where dermal application studies have shown absorption that could cause systemic
effects following exposure.
 May accompany a sensitiser notation for substances that cause respiratory sensitisation following dermal
exposure.
 Recommends integration of data from acute dermal studies and repeated-dose dermal studies in animals
and humans, along with an ability of the chemical to be absorbed through the skin.
 LD50 less than or equal to 1000 mg/kg/day by the dermal route.
 A skin notation is not applied to chemicals that cause dermal irritation or corrosive effects in the absence of
systemic toxicity.

European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC, 1993)a /

Health Council of the Netherlands

6
Criteria for skin notation assignment

 Considers physical form of substance.

 Potential for dermal absorption:
o Human case reports of systemic effects following skin exposure
o Direct measures of dermal absorption in human beings or animals using in vivo or in vitro models
o Definitive relationship between toxic doses by the dermal route and toxic doses by other routes (if dermal
LD50 is less than 10 times the intravenous (IV), intraperitoneal (IP) or inhalation LD50), and
o Structure-activity relationship.
 Combination of toxicity and skin penetration.
 If the amount absorbed by both hands and forearms in 1 hour could amount to > 10% of the amount that can
be absorbed via the lungs on exposure to the occupational exposure limit for 8 hours (provided exposure
limit is set based on systemic effects).
 The decision tree for assigning a skin notation is shown in Appendix 1.
 Classification of a chemical as irritant or corrosive should not exclude a skin notation.

German Research Foundation (DFG, 2014)

 Skin notation can be assigned for systemic effects or respiratory sensitisation following dermal exposure.
 Criteria in order of decreasing significance:
o If field or workplace studies indicate significant dermal absorption contributes to toxic effects
o Dermal absorption has been demonstrated in animal studies and toxic effects observed (no definitive
cut-off values or LD50 value ratios indicated)
o Evidence of dermal absorption in in vitro studies (no definitive cut-off values indicated), and
o On the basis of data for analogous substances or calculations with mathematical models, dermal
absorption may be expected.

Scientific Committee on Occupational Exposure Limits (SCOEL, 2013)

 ‘Substantial contribution’ to total body burden via the dermal route – established on a case-by-case basis but
may in general be of the order of 10% or more of the uptake from the inhalation route at the workplace
exposure standard value:
o Determination of the extent of dermal absorption (from in vitro or in vivo studies; comparison of dermal
and IV or IP LD50 values)
o Case reports of systemic effects following skin exposure in human subjects, and
o Evidence of substantial variation in biological monitoring data in groups with similar inhalation exposure.
 Essentially similar to ECETOC but no hierarchy of effects – weight of evidence approach.
 A skin notation is not intended to give warning of direct effects on the skin such as corrosivity, irritation or
sensitisation.

7
Criteria for skin notation assignment

National Institute for Occupational Safety and Health (NIOSH)

 Has three skin notations:

o SK:SYS (systemic toxicity by the dermal route; similar to skin notation assignment by other agencies;
applicable to current discussion),
o SK:DIR (adverse health effects resulting in damage or destruction of skin localised at or near point of
contact, e.g. corrosion or irritancy), and
o SK:SEN (skin exposure to a chemical may cause or contribute to an immune response).
 SK:SYS assignment:
o Evidence of adverse human health effects following dermal exposure
o Evidence of dermal absorption (in vivo and in vitro tests) – critical cut-off point 10%
— if data are consistently higher than 10%, the chemical is considered to have a high potential for
dermal absorption, and
— computational prediction of > 10% skin absorption based on physicochemical properties
(e.g. molecular weight, solubility, pH).
o Acute toxicity – if LD50 < 2000 mg/kg by the dermal route (Globally Harmonized System of
Classification and Labelling of Chemicals [GHS] cut-off value)
o Repeat-dose toxicity (including reproductive and immunotoxicity studies) – if no observed adverse effect
level (NOAEL) < 1000 mg/kg from dermal study and NOAEL is based on systemic effects
o Evidence of carcinogenicity in organs and tissues excluding skin following dermal exposure (evidence of
systemic absorption), and
o If the skin/inhalation (SI) ratio is ≥ 0.1; SI ratio = dermal dose/inhalation dose at the occupational
exposure limit
a Largely
developed based on the semi-quantitative approach taken by the Health Council of the Netherlands
(Dutch Expert Committee on Occupational Safety; DECOS)

Evidence of dermal absorption

In vivo dermal absorption data

The most reliable means for determining if a hazardous chemical is absorbed through the
skin is from human or animal data. If there is evidence of systemic toxicity by the dermal
route or the chemical has been detected in the systemic circulation following dermal
exposure, there is a clear indication that the chemical has been absorbed through the skin.
Toxicity by the dermal route will be covered later in this document.
Dermal absorption is generally expressed as a percentage of the applied dose. As the skin
of rats and rabbits is more permeable than that of humans (OECD, 2004a), dermal
absorption data from these animal species provide conservative estimates of the extent of
absorption via the skin in human subjects (OECD, 2011). The permeability of the skin from
guinea pigs, pigs and monkeys is generally more similar to that of humans (OECD, 2004).
The most reliable dermal absorption data are from well-conducted studies in human
subjects.
Most agencies (ECETOC, the Health Council of the Netherlands, NIOSH, and SCOEL)
consider a dermal absorption factor of greater than ten per cent as ‘significant’ dermal
absorption (Table 1). This value corresponds to the low/high dermal absorption cut-off
value in the OECD Guidance Notes (OECD, 2011). Some agencies (e.g. SCOEL) will
assign a skin notation based solely on significant in vivo dermal absorption data.

In vitro dermal absorption data

In vitro assays using skin samples from humans or animals have been developed to
estimate the extent of dermal absorption (OECD, 2004b). Further details of these assays
will not be discussed here but are covered in the relevant OECD guidance documents
(OECD 2004b; 2004c; 2011).
The usual output from these assays could be a skin penetration rate, skin permeability
coefficient (Kp value) or a percentage of absorption that could provide an indication of the

8
expected dermal absorption in human subjects. As mentioned above, mouse, rat and
rabbit skin is more permeable than human skin, and thus provide conservative estimates
of the extent of human dermal absorption. The appropriateness of the skin from other
animal species with respect to similarities with human skin, thereby affecting the predictive
ability of the in vitro assay for skin absorption in human subjects, would need to be
considered if using the data to assign a skin notation.
Dermal absorption in human subjects is likely to be overestimated from in vitro data using
human or rat skin (OECD, 2011), but these data are considered conservative estimates.
Given the potential technical errors in the conduct of these in vitro studies (OECD, 2004c),
and the data likely overestimate the extent of dermal absorption in human subjects, it is
considered inappropriate to assign a skin notation based solely on in vitro skin absorption
data in the absence of any evidence of toxicity by the dermal route. Agencies use either
the dermal absorption estimate or the penetration rate to determine if ‘significant’
absorption of a chemical via the dermal route will occur at airborne concentrations at the
workplace exposure standard (see Extent of dermal absorption at the workplace
exposure standard), but this should be considered in conjunction with any in vivo dermal
toxicity data.

In silico (computational) prediction of dermal absorption

It is generally accepted that the ability of a compound to penetrate the skin can be related
to the physicochemical properties of the compound (e.g. molecular weight, solubility, pH)
(OECD, 2011; IPCS, 2006). NIOSH uses a predictive algorithm (the revised Robinson
model) to determine the skin permeation coefficient (Kp; expressed in cm/h) (NIOSH,
2009; Dotson et al., 2011). The revised Robinson model was considered the most reliable
compared with other predictive models (Wilschut et al., 1995). This model uses the
physicochemical properties of a chemical (molecular weight [MW] and the chemical’s
octanol-water partition coefficient [Kow]) relevant to its transport in the stratum corneum,
the outermost layer of the skin.
The following equations are used to calculate the skin permeation coefficient (Kp):
1
𝐾𝑝 =
1 1
⌊(𝐾 + 𝐾 ) + (𝐾 )⌋
𝑝𝑠𝑐 𝑝𝑜𝑙 𝑎𝑞

where:
 Kpsc is the permeation coefficient in the lipid fraction of the stratum corneum
log 𝐾𝑝𝑠𝑐 = −1.326 + 06097 × log 𝐾𝑜𝑤 − 0.1786 × 𝑀𝑊 0.5

 Kpol is the coefficient in the protein fraction of the stratum corneum, and
𝐾𝑝𝑜𝑙 = 0.0001519 × 𝑀𝑊 −0.5

 Kaq is the coefficient in the watery epidermal layer.

𝐾𝑎𝑞 = 2.5 × 𝑀𝑊 −0.5

NIOSH has noted that there are limitations in the types of chemicals to which the models
may apply based on the experimental data used to develop the model (NIOSH, 2009):
 chemicals for which experimental Kp values are not readily available to be used in
the development of the model as they are not readily absorbed through the skin
(inorganic substances, ionised substances, very high molecular weight substances)
 chemicals that reach the systemic circulation by a means that is not part of the
model (hydrophilic substances with a small molecular weight tend to penetrate hair
follicles and sweat glands), and

9
  the model does not account for evaporation; Kp values for highly volatile
substances are likely to be overestimates.
NIOSH is the only agency that will assign a skin notation based solely on computational
predictions of dermal absorption; however, this is only assigned in the absence of data that
would suggest systemic effects following dermal exposure are unlikely.

Evidence of toxicity by the dermal route

All of the agencies in Table 1 consider if there is any evidence of toxicity via the dermal
route in human subjects or animal studies. However, there are some differences as to how
these data are considered.

Human case studies

All agencies in Table 1 assign a ‘skin’ notation based on reports from worker case studies
where adverse effects following dermal exposure have been reported. For most agencies,
this evidence alone is sufficient for assignment of a skin notation (see Appendix 1). There
is no specific dermal exposure cut-off value and no clear criteria are provided by any
agency as to what might be considered an adequately reported study. As the quality of
reporting and adequacy of exposure assessments can be highly variable, reports citing the
absence of adverse effects in human subjects following dermal exposure should not be
used as a criterion to dismiss the possibility of a skin notation. However, positive findings
in human subjects following dermal exposure strongly suggest the need for a skin notation
for that particular chemical.

Acute-dose toxicity studies in animals

The standard output of an acute dermal toxicity study is a LD50 value, which will allow the
substance to be classified in accordance with the Globally Harmonized System of
Classification and Labelling of Chemicals (GHS). A LD50 value is a single dose of a
substance that can be expected to cause death in 50 per cent of animals when
administered by a given route of exposure.
Aside from DFG, all agencies in Table 1 will consider assigning a skin notation based on a
definitive dermal LD50 value or a relative LD50 value. NIOSH will consider assigning a skin
notation if the dermal LD50 value is < 2000 mg/kg, while ACGIH® uses ≤ 1000 mg/kg as the
cut-off value. The latter cut-off value has also been supported in published literature
(Kennedy et al., 1993; Nielsen and Grandjean, 2004).
The GHS hazard statements with their respective cut-off values for acute dermal toxicity
are shown in Table 2. A dose of 2000 mg/kg is the limit dose used in acute dermal toxicity
studies (OECD, 2017). As such, there are no chemicals in the Hazardous Chemical
Information System (HCIS) database1 with a H313 hazard statement (i.e. LD50 value
greater than 2000 mg/kg but less than or equal to 5000 mg/kg).

Table 2 GHS hazard statements for acute dermal toxicity

Hazard statement code Description of Hazard Statement Acute toxicity range

H310 Fatal in contact with skin 0 < LD50 ≤ 200 mg/kg

H311 Toxic in contact with skin 200 < LD50 ≤ 1000 mg/kg

H312 Harmful in contact with skin 1000 < LD50 ≤ 2000 mg/kg

H313 May be harmful in contact with skin 2000 < LD50 ≤ 5000 mg/kg

1 Database located on the Safe Work Australia website that provides information on chemicals that have been
classified in accordance with the GHS.

10
A preliminary screen of chemicals on the Australian WES list revealed:
• For those chemicals with a H312 hazard statement (i.e. dermal LD50 value between
1000 and 2000 mg/kg):
o 77% have a skin notation from at least one agency2
o 33% have a skin notation from all agencies that have a report available for that chemical
• For those chemicals with a H311 hazard statement (i.e. dermal LD50 value between
200 and 1000 mg/kg)
o 95% have a skin notation from at least one agency
o 74% have a skin notation from all agencies that have a report available for that chemical
Based on this information, a 1000 mg/kg cut-off value is considered reasonable for
assignment of a skin notation. This is not suggesting that for chemicals with dermal LD50
values > 1000 mg/kg a skin notation is not warranted. If additional data are available to
indicate a skin notation may be warranted, these data may be preferred in the place of a
LD50 value. A LD50 is a lethal dose, with mortality considered as the only end point.
Non-lethal toxicities by the dermal route may be observed following a single dose to
animals, but these toxicities are not factored when determining a LD50 value. Moreover,
single dose toxicity studies do not take into account toxicities observed following repeated
dosing (e.g. cumulative toxicity, bioaccumulation of the chemical) (Nielsen and Grandjean,
2004). A LD50 ≤ 1000 mg/kg indicates definitive toxicity by the dermal route. Therefore,
LD50 values can only reasonably be used to rule in the need for a skin notation, but not
specifically to rule out the need for such a notation.
A skin notation is warranted when the extent of dermal absorption is significant relative to
the inhalation route and may contribute to adverse effects. Some agencies consider the
acute dermal LD50 value with the LD50 value obtained by the intravenous (IV),
intraperitoneal (IP) or inhalation routes (ECETOC, Health Council of the Netherlands and
SCOEL). A comparison of the dermal LD50 value with the IV or IP LD50 value may give an
indication of the extent of dermal absorption. A comparison of the dermal LD50 value with
the inhalation LD50 value3 would give an indication of the relative toxicity and relative
extent of absorption by the two different exposure routes. ECETOC, Health Council of the
Netherlands and SCOEL consider assigning a skin notation if the dermal LD50 is less than
ten times the IV, IP or inhalation LD50 consistent with a threshold of greater than ten per
cent dermal absorption for assignment of a skin notation.

Repeat-dose toxicity studies in animals

While all agencies in Table 1 consider data from repeat-dose dermal toxicity studies in
animals, only NIOSH uses a definitive cut-off level; if the no observed adverse effect level
(NOAEL) is < 1000 mg/kg/day from the dermal toxicity study (general or reproductive
toxicity) and the NOAEL is based on systemic effects, NIOSH will consider assigning a
skin notation to this compound.
The limit dose for repeat-dose dermal toxicity studies is 1000 mg/kg/day (OECD, 1981a;
1981b). However, compared with occupational exposures, a dermal dose of
1000 mg/kg/day is extremely high and it may be a questionable cut-off value. There are
two categories in the GHS classification scheme for specific target organ toxicity following
repeated exposure. The criteria for these categories and their respective dermal (rat or
rabbit) guidance value ranges are shown in Table 3. Only chemicals demonstrating

2 Agencies examined include ACGIH®, AIHA, DFG, Health Council of the Netherlands and SCOEL.
3 The LC50 value needs to be converted to an LD50 value using this formula:
𝑚3
𝐿𝐶50 (𝑚𝑔⁄𝑚3 ) × 𝑣𝑒𝑛𝑡𝑖𝑙𝑎𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 ( ) × 𝑓 × 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑝𝑒𝑟𝑖𝑜𝑑 (ℎ)
ℎ
𝑖𝑛ℎ𝑎𝑙 𝐿𝐷50 (𝑚𝑔⁄𝑘𝑔⁄𝑑𝑎𝑦) =
𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
where: 𝑓 represents the fraction absorbed by the inhalation route.
The ventilation rate and body weight are species-specific factors.

11
adverse effects at ≤ 200 mg/kg/day by the dermal route would be classified according to
one of the two criteria listed in Table 3. This further supports the suggestion that a
repeat-dose toxicity cut-off value of 1000 mg/kg/day is considered unreasonably high as a
cut-off value for skin notation. The GHS cut-off ≤ 200 mg/kg/day is considered a more
appropriate cut-off for a skin notation. This would be consistent with the ECETOC
approach where chemicals that lack a health classification (similar to a GHS classification)
should be exempt from a skin notation (ECETOC, 1998).
Evidence of toxicity in a repeat-dose dermal toxicity study (NOAEL ≤ 200 mg/kg/day)
would over-ride a dermal LD50 value > 1000 mg/kg/day observed in an acute dose toxicity
study; the repeat-dose toxicity study considers a broader range of end points than an
acute dose toxicity study (e.g. non-lethal toxicities, specific target organ toxicity, effects
associated with cumulative exposure, potential accumulation).

Table 3 GHS hazard categories for specific target organ toxicity following repeated dosing

Category Dermal guidance value range

Category 1:
Substances that have produced significant toxicity in humans, or that,
on the basis of evidence from studies in experimental animals can be ≤ 20 mg/kg/day
presumed to have the potential to produce significant toxicity in humans
following repeated exposure.

Category 2:
Substances that, on the basis of evidence from studies in experimental 20 < dose ≤ 200 mg/kg/day
animals can be presumed to have the potential to be harmful to human
health following repeated exposure.

Extent of dermal absorption at the workplace exposure standard

While some countries have assigned a skin notation based solely on the ability of a
substance to be absorbed through the skin (e.g. Denmark, Norway, Sweden; from IPCS,
2006), dermal absorption alone does not indicate if this route of administration significantly
contributes to potential adverse effects at the workplace exposure standard concentration.
The contribution of dermal absorption to the overall total body burden may be higher at
lower airborne concentrations (SCOEL, 2013). Therefore, of particular interest for
assigning a skin notation is the extent of dermal absorption at the workplace exposure
standard level.
Both NIOSH and ECETOC have developed mathematical formulae to determine if the
extent of dermal absorption at the workplace exposure standard is significant (i.e. greater
than 10%). These approaches are summarised in Table 4. Both approaches are only valid
if the workplace exposure standard is derived based on systemic effects, and the systemic
effects are similar or are expected to be similar by the dermal and inhalation routes. There
are a number of differences between the two approaches:
 The ECETOC approach compares the extent of dermal uptake and the inhalation
dose at the workplace exposure standard, whereas the NIOSH approach compares
the overall diffusion of the chemical through the stratum corneum and into the
blood capillaries.
 There are differences in default assumptions: extent of inhalation absorption, the
size of the exposed dermal area and the duration of exposure.
Despite these differences, NIOSH compared the output from the two approaches and a
similar result was obtained (NIOSH, 2009).

12
Table 4 Approaches for comparing the dermal dose with the inhalation dose at the occupational exposure limit

Agency Approach

ECETOC  Assumptions:
o exposed area: hands and forearms (2000 cm2) for 1 hour
o 10 m3 air respired in 8 hours, and
o default inhalation absorption rate (if unknown) – 50% (in practice > 50%
appears to be assumed by DECOSa).
 Uses a dermal penetration rate (in mg/cm2/h).
 Equations:
𝐷𝑒𝑟𝑚𝑎𝑙 𝑑𝑜𝑠𝑒 = 𝑝𝑒𝑛𝑒𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 (𝑚𝑔⁄𝑐𝑚2 /ℎ) × 2000 𝑐𝑚2 × 1 ℎ
𝐼𝑛ℎ𝑎𝑙𝑎𝑡𝑖𝑜𝑛𝑎𝑙 𝑑𝑜𝑠𝑒 𝑎𝑡 𝑊𝐸𝑆 = 𝑊𝐸𝑆 (𝑚𝑔⁄𝑚3 ) × 10 𝑚3 × 𝑓
where 𝑓 = inhalation absorption factor.
 If 𝐷𝑒𝑟𝑚𝑎𝑙 𝑑𝑜𝑠𝑒 / 𝐼𝑛ℎ𝑎𝑙𝑎𝑡𝑖𝑜𝑛𝑎𝑙 𝑑𝑜𝑠𝑒 > 0.1, a skin notation is warranted.

NIOSH  The Kp value represents the overall diffusion of the chemical through the
stratum corneum and into the blood capillaries. This value can be predicted
computationally (see ‘In silico (computational) prediction of dermal
absorption’).
 Assumptions:
o exposed area: palms (360 cm2) for 8 hours
o 10 m3 air respired in 8 hours, and
o default inhalation absorption rate (if unknown) – 75%.
 Equations:
𝐷𝑒𝑟𝑚𝑎𝑙 𝑑𝑜𝑠𝑒 = 𝐾𝑝 (𝑐𝑚⁄ℎ) × 𝑤𝑎𝑡𝑒𝑟 𝑠𝑜𝑙𝑢𝑏𝑖𝑙𝑖𝑡𝑦 (𝑚𝑔⁄𝑐𝑚3 ) × 360 𝑐𝑚2 × 8 ℎ
𝐼𝑛ℎ𝑎𝑙𝑎𝑡𝑖𝑜𝑛𝑎𝑙 𝑑𝑜𝑠𝑒 𝑎𝑡 𝑊𝐸𝑆 = 𝑊𝐸𝑆 (𝑚𝑔⁄𝑚3 ) × 10 𝑚3 × 𝑓
where 𝑓 = inhalation absorption factor.
If 𝐷𝑒𝑟𝑚𝑎𝑙 𝑑𝑜𝑠𝑒 / 𝐼𝑛ℎ𝑎𝑙𝑎𝑡𝑖𝑜𝑛𝑎𝑙 𝑑𝑜𝑠𝑒 > 0.1, a skin notation is warranted.
a Dutch Expert Committee on Occupational Safety; DECOS

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Proposed criteria for a skin notation in Australia
A skin notation will be assigned if there is:
 evidence of significant dermal absorption, and
 evidence or a suggestion of systemic toxicity by the dermal route, particularly at air
concentrations close to the workplace exposure standard.
Based on the information in the previous section, the following are proposed as criteria to
consider for the assignment of a skin notation:

Criterion Comments

Reports of adverse systemic For worker case studies to be used for assigning a skin notation there
effects via the dermal route in must be clear evidence that adverse systemic effects were the result of
worker case studies at least some dermal exposure.

Dermal LD50 ≤ 1000 mg/kg Dermal LD50 values > 1000 mg/kg may give a misleading indication as
to whether a skin notation is warranted.
Only definitive LD50 values will be used.

Dermal LD50 / inhalation LD50 < 10 The ratio of dermal LD50 and inhalation LD50 values will only be
considered if the dermal LD50 value is ≤ 1000 mg/kg.
The limit dose in an acute dermal toxicity study is 2000 mg/kg (OECD,
2017), and the maximum recommended concentration for aerosols in
an acute inhalation toxicity study is 2000 mg/m3 (OECD, 2009).
If a LD50 value is greater than the maximum tested dose in an acute
dose toxicity study, then a ratio will not be examined.

Dermal repeat-dose NOAEL If the NOAEL is the maximum tested dose and the maximum tested
≤ 200 mg/kg dose is ≤ 200 mg/kg, the dermal NOAEL will not be considered when
deciding if a skin notation is warranted.

In vivo dermal absorption factor Only applicable if the WES value is derived based on systemic effects
> 10% (rather than local findings such as irritancy).

Estimated dermal exposure at The estimated dermal exposure at the workplace exposure standard is
the workplace exposure standard determined using a known in vitro penetration rate or using an
> 10% estimated permeability coefficient (determined with the NIOSH
equation), and using the ECETOC equation with a default inhalation
absorption factor of 75%.
Only applicable if the WES value is derived based on systemic effects.

These criteria are generally consistent in principle with the semi-quantitative criteria used
by SCOEL, DECOS, ECETOC and NIOSH, and the qualitative criteria used by DFG and
ACGIH®.
In a weight of evidence analysis, not all criteria have equal weighting in determining
whether a skin notation is warranted. The hierarchy of effects is covered in the next
section.

Hierarchy of effects
When data are inconsistent or limited, a weight of evidence approach will be used. Based
on this evaluation, one of four recommendations is possible:
 a skin notation is not recommended
 insufficient data to assign a skin notation, and
 a skin notation is recommended.
These recommendations will also be considered in the context of whether the WES value
is based on systemic or local effects.

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Figure 1 illustrates the significance of each piece of evidence for assigning a skin notation.
This hierarchy is generally similar to that used by ECETOC, NIOSH and DFG.

On the basis of Sufficient in isolation to assign

workplace studies a ‘skin’ notation

In vivo animal data

Decreasing significance

(toxicity or dermal absorption) Possibly sufficient in isolation to

or human dermal assign a ‘skin’ notation
absorption studies

Insufficient in isolation to assign

In vitro data a ‘skin’ notation, but could
(dermal absorption) provide supporting evidence

Insufficient in isolation to assign

In silico data
a ‘skin’ notation, but could
(dermal absorption)
provide supporting evidence

Figure 1 Hierarchy of the weight of evidence for recommending a skin notation

The only data that are considered sufficient in isolation for the assignment of a skin
notation is evidence of adverse systemic effects by the dermal route in human subjects.
Data from animals may provide evidence a skin notation is warranted, depending on how
close the data are to the relevant cut-off value.
In the absence of any in vivo data (dermal toxicity or in vivo dermal absorption data), a
skin notation will not be assigned, particularly if the only available information is a
predicted dermal absorption rate (‘insufficient data to assign a skin notation’).
The relative weight of each piece of information is shown in Table 5.
Based on the available data and the relevant weighting of the evidence, the evaluator will
decide on a recommendation regarding assignment of a skin notation:
 If a skin notation is warranted, then a recommendation to assign a skin notation will
be made.
 If a skin notation should be considered, the evaluator will decide, based on the
totality of information, whether a skin notation will be recommended. The
recommendation will be supported by a scientific argument. This argument may
include a discussion of the quality of the available information.

15
  If there are insufficient data to assign a skin notation or a skin notation is not
warranted, a skin notation will not be recommended.

Table 5 Contribution of evidence to a skin notation

Criterion Result Relevance

Adverse findings in human case study Yes A skin notation is warranted

No Provides no meaningful information

Dermal LD50 ≤ 1000 mg/kg Yes Consider assigning a skin notation

No Provides no meaningful information

Dermal LD50 / inhalation LD50 < 10 a Yes Consider assigning a skin notation

No A skin notation may not be warranted

Dermal repeat-dose NOAEL ≤ 200 mg/kg Yes Consider assigning a skin notation

No A skin notation may not be warranted

In vivo dermal absorption factor > 10% Yes Consider assigning a skin notation

No A skin notation may not be warranted

Estimated dermal exposure at WES > 10% b Yes Insufficient data to assign a skin notation

No A skin notation may not be warranted

a Only relevant if dermal LD50 value is ≤ 1000 mg/kg.
b This information is unnecessary if in vivo dermal absorption data are available.

Local vs systemic effects

A skin notation will be assigned based on evidence of systemic effects by the dermal
route. The criteria in the previous section Table 5have greater weighting if the WES value
is derived based on systemic rather than local effects. If the data suggest a skin notation
may be warranted according to the criteria and the workplace exposure standard is
derived based on local effects, the relevance of the dermal absorption and toxicity data
needs to be considered. If the NOAEL for systemic effects is close to the NOAEL for local
effects, assignment of a skin notation will be considered. If there is a significant difference
between the NOAEL for systemic effects and the NOAEL for local effects, a skin notation
may not be assigned. These will be considered on a case-by-case basis.
For chemicals that are dermal irritants or are corrosive, good industrial practices and
personal protective measures should prevent skin contact. It may seem redundant to
assign a skin notation based on systemic effects to these compounds. However, irritant or
corrosive warnings and skin notation warnings have different meanings and the provision
of protective clothing against the irritant or corrosive activity may not always be true. When
warranted to be protective for adverse systemic effects (based on the criteria in the
previous section), a skin notation will be assigned to a dermal irritant or corrosive
chemical. A skin notation will not be assigned to a dermal irritant or corrosive chemical in
the absence of systemic toxicity.

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Other considerations
Biological monitoring
For chemicals that have a skin notation, monitoring of airborne concentrations in line with
the WES may not be protective for adverse systemic effects. To ascertain total systemic
exposure, including by the dermal and inhalation routes, biological monitoring methods, if
available, would be recommended. A comprehensive set of biological exposure standards
has not been developed in Australia. However, advisory biological exposure limits are
available domestically and internationally from ACGIH®, SCOEL and DFG.

Effects of formulation and mixtures

Different formulations or chemical admixtures can influence the extent of dermal
absorption. Some vehicles or solvents can act as carriers and when pretreated on the skin
or mixed with a chemical can promote the transfer of the chemical into the skin. Skin
notations assigned by most trusted bodies do not take into account the many possible
formulations and combinations that include the chemical. As not all formulation
combinations would have been considered with the available data to assign a skin
notation, the absence of a skin notation does not imply that there is no risk of additional
exposures by the dermal route. Precautions to minimise dermal exposure would still be
warranted. If a skin notation is assigned, the extent of dermal absorption may vary
considerably, depending on the formulation/mixture. Consideration should be given to the
most appropriate type of glove depending on the mixture or formulation.

Skin condition
There are several conditions that can affect the entry of chemicals and substances through
the skin:
 some dermatological conditions
 damaged skin
 heat and humidity, and
 occluded skin, where the skin cannot perspire or respire.
Precautions to minimise dermal exposure may be warranted in these circumstances, even
in the absence of a skin notation.

17
References
American Conference of Governmental Industrial Hygienists (ACGIH ®) (2016) Threshold limit
values for chemical substances and physical agents.
DFG, Deutsche Forschungsgemeinschaft. (2014) List of MAK and BAT Values. WILEY-VCH Verlag
GmbH&Co. KGaA, Weinheim.
Dotson, G.S., C.-P. Chen, B. Gadagbui, A. Maier, H.W. Ahlers and T.J. Lentz (2011) The evolution
of skin notations for occupational risk assessment: a new NIOSH strategy.
European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) (1993) Strategy for
assigning a "skin notation". ECETOC Document No. 31 (Revised).
International Programme on Chemical Safety (IPCS) – WHO (2006) Environmental Health Criteria
235: Dermal absorption.
Kennedy Jr, G.L., W.J. Brock and A.K. Benerjee (1993) Assignment of skin notation for threshold
limit values chemicals based on acute dermal toxicity. Appl. Occup. Environ. Hyg. 8: 26-30.
Lavoue, J., A. Milon and P.O. Droz. (2008) Comparison of indices proposed as criteria for assigning
skin notation. Ann. Occup. Hyg. 52: 747-756.
National Institute for Occupational Safety and Health (NIOSH) (2009) NIOSH Current Intelligence
Bulletin 61: A Strategy for Assigning New NIOSH Skin Notations.
Nielsen, J.B. and P. Grandjean. (2004) Criteria for skin notation in different countries. Am. J.
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the testing of chemicals 410: Repeated dose dermal toxicity: 21/28-day study.
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the conduct of skin absorption studies.
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testing of chemicals 402: Acute dermal toxicity.
Safe Work Australia (2013) Guidance on the interpretation of workplace exposure standards for
airborne contaminats.
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a workshop. Regul. Toxicol. Pharmacol. 49: 301-307.
SCOEL, Scientific Committee on Occupational Exposure Limits. (2013) Methodology for the
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The validation of five mathematical skin permeation models. Chemosphere 30: 1275-1296.

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Appendix 1 — ECETOC decision tree for assigning a skin notation

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