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How to Derive Derived No-Effect Level (DNEL)

By Little Pro on 2016-06-14 Views:  Update:2017-01-18

Derived No-Effect Level (DNEL) is defined as the level of chemical exposure above which humans should not be exposed.  In human health risk assessment, the exposure level of each human population known to be or likely to be exposed is compared with the appropriate derived no-effect level (DNEL). The risk of a chemical substance to humans can be considered to be controlled/acceptable if the exposure levels estimated do not exceed the appropriate DNEL (i.e, exposure estimate/DNEL<1). In EU, DNELs shall  be communicated to downstream users via extended safety data sheets (SDS) if they are available. 

Derived No-Effect Level (DNEL) Example - Methanol

The DNEL (oral route, systematic effects) of methanol for general population is 0.088 g/kg bw /day. It means that if an adult person (assuming 60kg body weight) intakes less than 5.28g (0.088*60methanol per day by oral route, the risk of methanol causing ocular toxicity/vision damage can be controlled. Do you know how important DNEL is now?

How to Calculate Derived No-Effect Level (DNEL)?

The DNELs are usually calculated by dividing toxicological dose descriptors by an assessment factor. Since dose descriptors are usually obtained from animal studies, an assessment factor is required to allow for extrapolation to real human exposure situations and take into account of uncertainties.

The picture below shows you the relationship between LD50, LOAEL, NOAEL and DNEL on a typical dose-response curve.

Derived No-Effect Level NOAEL

The table below is an example of how to divide NOAEL by assessment factors to get Derived No-Effect Level (DNEL).

Effects  Adrenal Effects Developmental Effects
NOAEL from animal study (oral route, long-term ) 30 mg/kg bw/day (90d repeated dose) 80 mg/kg bw/day
Assessment Factor (Intraspecies) 10 10
Assessment Factor (Interspecies) 10 10
Assessment Factor (Duration) 3 1
Assessment Factor (Route extrapolation, data quality) 1 2
Total Assessment Factor (AF) 10x10x3x1=300 10x10x1x2=200
DNEL(oral route, long-term) 0.1mg/kg bw/day 0.4 mg/kg bw/day

In above case, the lowest DNEL (0.1mg/kg bw/day) will be used for risk assessment. If an adult (assuming weight is 60kg) intakes 12mg of a chemical substance per day, the estimated exposure (external dose per body weight) will be 0.2mg/kg bw/day. Since the exposure estimate is greater than DNEL, which will lead to a RCR>1, the risk will not be acceptable.

How Many Derived No-Effect Level (DNELs) You Need to Calculate?

DNELs need to be derived for each relevant exposure pattern (population, route, and duration of exposure) and each relevant health effect (local and systemic effects). Under REACH, DNELs only need to be derived for chemical substances that are classified with health hazards according to CLP regulation/GHS.

 The table below summarizes the number of DNELs you may need to derive.

Exposure Pattern Workers General Population
Acute – inhalation, systemic effects    
Acute – dermal, local effects    
Acute – inhalation, local effects    
Long-term – dermal, systemic effects    
Long-term – inhalation, systemic effects    
Long-term – oral, systemic effects  X(not relevant)  
Long-term – dermal, local effects    
Long-term – inhalation, local effects    

It is not always necessary to derive DNELs for all mentioned populations or routes or exposure duration. Depending on the exposure pattern and health effects, only relevant DNELs have to be derived. It may not always be possible to derive DNELs for all health effects. For many local effects (irritation), DNELs cannot be derived. This may also be the case, for example, for mutagen/carcinogen where no safe threshold level can be obtained. In these cases a semi-quantitative value, known as the DMEL or Derived Minimal Effect level may be developed. 

To understand how many DNELs you actually have to derive, you need to understand the use of your substance and its exposure pattern (population, route, duration of exposure) as well as the type of its adverse health effects (local or systemic effects).

Populations

DNELs may have to be derived for workers and the general population. The general population includes consumers, and humans exposed via the environment.

Only DNELs for the relevant populations will have to be derived. For example, if a substance is only used as intermediate in a chemical plant and there is no exposure to general population, there is no need to derive DNEL for the general population.

Route of Exposure

In view of the likely exposure routes, DNELs may need to be derived for oral exposure (consumers/human via the environment), inhalation exposure (workers/consumers/human via the environment), dermal exposure (workers/consumers, and potentially humans via the environment.

It is not always necessary to derive DNELs for all mentioned routes. Depending on the exposure pattern, only DNELs for the relevant routes of exposure will have to be derived. For example, there is no need to derive DNEL for inhalation route for a liquid substance which has very low vapor pressure and is unlikely to be inhaled. There is no need to derive DNELs for oral route for workers either.

Duration of Exposure

Depending on the exposure scenario, the exposure duration can vary from a single event to an exposure for several days/weeks/months per year, or it might even be continuous (as is, e.g., the case for humans exposed via the environment). Since the duration of exposure will often have an impact on the effect(s) that may arise, DNELs may have to be derived for various exposure duration.

Two main types of DNELs can be distinguished, DNELlong-term and DNELacute.

  • DNELlong-term is DNEL for effects that occur upon repeated exposure. It shall always be derived. Toxicity studies that give information on these possible ‘long-term’ effects of a substance are: repeated dose toxicity studies, reproductive toxicity studies (including developmental toxicity studies), and carcinogenicity studies. 'Long-term' is here used as a more general term, including, e.g., sub-chronic (usually 90 days) as well as chronic (usually 1.5 - 2 years) studies. 
  • DNELacute can generally be defined as a DNEL for effects that occur after exposure for a short period of time (from minutes to a few hours). There is no adverse health effects from short exposure, there is  no need to derive DNELacute. The potential for short-term high level (i.e. peak) inhalation exposure is of most concern for workers, and hence, the occupational exposure assessment should always consider the possibility for such peak inhalation exposures. 

Local Effect vs Systemic Effect

Depending on the substance and the type of adverse health effects, DNELs may have to be established for systemic effects, for local effects or for both.

  • A local effect is an effect that is observed at the site of first contact, caused irrespective of whether a substance is systemically available. This mainly  includes skin/eye irritation/corrosion, skin or respiratory sensitization. 
  • A systemic effect is defined as an effect that is normally observed distant from the site of first contact, i.e., after having passed through a physiological barrier (mucous membrane of the gastrointestinal tract or of the respiratory tract, or the skin) and becomes systemically available. This includes acute toxicity, repeated dose toxicity, genotoxicity, reproductive toxicity and carcinogenicity. 

For systemic effects, the units of DNELs are mg/m3 for inhalation, and mg/kg bw ormg/kg bw/day for oral and dermal exposure.

For local effects, the units of DNELs are mg/m3 for inhalation; and for dermal exposure: mg/cm2 skin, mg/person/day (e.g., calculated based on the deposited amount per cm2 times the actually exposed body area), or a measure of concentration (% or ppm)

How to Name Various Derived No-Effect Levels (DNELs)

Relevant DNELs are often named in the following way.

  • Population-DNEL duration-exposure route-local/systemic effect

Example 1: A solid substance (in powder form) is only used as an intermediate in a chemical plant. Workers may be exposed to the substance via inhalation or dermal contact. Studies have shown that the substance has no acute health effects  (including acute toxicity, irriation or sensitization). In this case, only the following 1 relevant DNEL needs to be derived. 

  • worker-DNEL long-term for dermal route-systemic.

Example 2: A liquid substance (non-volatile) is used as a dispersing agent in a cleaning product. Both workers and consumers may be exposed to the substance during its life-cycle stage (production, formulation and use). However, it is unlikely for workers and consumers to inhale the substance because of its low vapor pressure. Studies have shown that the substance has no local health effects (including irriation or sensitization). In this case, only the following relevant 3 DNELs need to be derived.

  • worker-DNEL long-term for dermal route-systemic.
  • general population-DNEL long-term for dermal route-systemic.
  • general population-DNEL long-term for oral route-systemic.

Example 3: Under REACH, the following relevant DNELs have been derived for ethanol based on possible exposure pattern and the health effects of ethanol (reference). Because ethanol has no adverse local effects, the DNELs for local effects do not need to be derived.

Exposure Pattern Workers General Population
Acute – inhalation, systemic effects  950 mg/m³  950 mg/m³
Acute – dermal, local effects  X(not relevant)  X(not relevant)
Acute – inhalation, local effects  X(not relevant)  X(not relevant)
Long-term – dermal, systemic effects  343 mg/kg bw/day  206 mg/kg bw/day
Long-term – inhalation, systemic effects  1900 mg/m³/day  114 mg/m³/day
Long-term – oral, systemic effects  X(not relevant)  87 mg/kg bw/day
Long-term – dermal, local effects  X(not relevant)  X(not relevant)
Long-term – inhalation, local effects  X(not relevant)  X(not relevant)

Procedure for Deriving DNELs

The picture below summarizes the procedure for deriving DNELs in 4 steps.

Derived No-effect Level DNEL

Among all 4 steps, step 2 modification of dose descriptor to correct starting point is very important. The goal is to get the corrected N(L)OAEL which matches real exposure conditions and which is in the right unit. For example, you only have an oral NOAEL (in mg/kg bw/day) from a rat study and you need to convert it to NOAEC (in mg/m3) so that you can derive DNELs for workers for inhalation route (in mg/m3), you must learn how to get corrected dose descriptors.

Read more: how to modify the dose descriptor to correct starting point

How to Choose Appropriate Assessment Factors?

Assessment factors are used to address the differences between the experimental data and the human situation, taking into account the following uncertainties in the extrapolation procedure. 

  • interspecies differences;
  • intraspecies differences;
  • differences in duration of exposure;
  • issues related to dose-response;
  • quality of whole database.

The table below summarizes default assessment factors used under REACH. The overall assessment factor is obtained by simple multiplication of individual assessment factors.

DNEL Assessment Factors

Note: Allometric scaling factors should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g., in mg/m3 in air, ppm in diet, or mg/l in the drinking water) as these are assumed to be already scaled according to the allometric principle. However, once the concentration (e.g., ppm in diet) has been converted into a dose (e.g., mg/kg/day), an allometric scaling factor has to be used to derive DNELs.

Final Example of DNEL Derivation

Assume that we need to derive DNELs for a chemical substance which is only used in industrial settings/factories (no exposure to the  general population). The substance has no local effects or acute health effects. Only NOAEL values from 90d repeated dose toxicity studies and reproductive toxicity studies (rat, oral route) are available. The table below is an example of how to derive worker-DNELlong-term for dermal route-systemic effects. In the end, the lowest DNEL (0.2mg/kg bw/day) will be used for risk assessment for dermal route.

Effects  Adrenal Effects Developmental Effects
NOAEL from animal study (oral route, rat) 30 mg/kg bw/day (from 90d repeated dose study) 80 mg/kg bw/day (from reproduct toxicity study)
Corrected NOAEL(oral to dermal route) 30 mg/kg bw/day 80 mg/kg bw/day
Assessment Factor (Intraspecies) 5 5
Assessment Factor (Interspecies) 10 10
Assessment Factor (Duration) 3 1
Assessment Factor (Route extrapolation, data quality) 1 1
Total Assessment Factor (AF) 5x10x3x1=150 5x10x1x1=50
DNEL(dermal route, long-term, systemic) 0.2mg/kg bw/day 1.6 mg/kg bw/day

Main Reference

DNEL

Good job. You have learned what DNEL is, how many DNELs you need to derive, how to choose assessment factors and how to derive DNELs. Please subscribe our newsletter to keep updated of our new articles.

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 Tags: Topics - CRAToxicology and Health Risk Assessment

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