Deriving harmonised permitted daily exposures (PDEs) for paracetamol (acetaminophen) CAS #: 103-90-2

Gromek, Kamila; Hawkins, W. Anthony; Bernier, Tanja; Sehner, Claudia; Zeller, Eva; Schwind, Markus; Pfister, Thomas D.; Kohan, Martín; Osadolor, Osahon; Glogovac, Milica; Tuschl, Gregor; Dolan, David G.; Barle, Ester Lovšin

doi:10.1016/j.yrtph.2020.104692

Cited by 4 publications

(7 citation statements)

References 55 publications

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“…In this situation, clinical doses, human data from late‐stage clinical trials, pharmacovigilance, clinical epidemiological studies that follow good epidemiologic practice guidelines, and case reports should be used judiciously as PoD (ASTM, 2020). A minimum therapeutic daily dose could also be used as a PoD for pharmaceuticals (Gromek et al, 2020; Ku, 2000; Sargent et al, 2002). For drugs administered according to dosing schedules such as once weekly, a prorated daily dose such as a single dose divided by the number of days between doses (i.e., X mg/7 days) can be used as a PoD.…”

Section: Critical Effect/point Of Departurementioning

confidence: 99%

“…A factor of 3–10 can be used when the lowest therapeutic dose is used as PoD for deriving NOAEL from the same. A lower factor of 3 can be applied for deriving a NOAEL from the lowest recommended human adult dose, when a single dose is used instead of a daily dose (Gromek et al, 2020).…”

Section: Addressing Sources Of Uncertainty Using Science‐based Afsmentioning

confidence: 99%

“…A variable factor is recommended, which is not only dependent on study duration but also on the type of study and the lifespan of the species studied (ICH Q3C‐R6, 2018). When using a human PoD, a higher AF for exposure duration is used when there is potential for adverse effects at lower doses selected as PoD (Gromek et al, 2020). An assessment of the mechanism of action will be helpful in understanding whether the chemical has the potential to accumulate over long‐term exposure and whether effects might accumulate and cause cumulative toxicity.…”

Section: Addressing Sources Of Uncertainty Using Science‐based Afsmentioning

confidence: 99%

“…The severity factor introduces an additional margin of safety if a compound has produced severe or irreversible toxicity that is not directly addressed by the PoD. If clinical data or a therapeutic dose is used as PoD, then a factor for clinical adverse effects reported can be considered according to the judgment of the expert (Gromek et al, 2020).…”

Section: Addressing Sources Of Uncertainty Using Science‐based Afsmentioning

confidence: 99%

“…A factor of 1 was used for exposure duration in Approach 3, where adult therapeutic dose is used as chronic administration is possible for antithrombotic indication. For LOAEL to NOAEL conversion (F5), a factor of 1 was used for Approaches 1 and 2 because NOAEL was used as PoD, and for Approach 3 where the therapeutic dose was used as the PoD, a factor of 3 was used (Gromek et al, 2020). For database completeness (F6), a factor of 1 was used because all the required data were available.…”

Section: Oel Calculation For Acetylsalicylic Acidmentioning

confidence: 99%

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Approaches for setting occupational exposure limits in the pharmaceutical industry

Ahuja

Krishnappa

2021

J of Applied Toxicology

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The use of pharmaceutical drugs has provided a cure for many diseases. However, unintended exposure to drugs in the manufacturing workplace can cause significant health hazards to workers. It is important to protect the workforce from these deleterious effects by limiting exposure to an acceptable level, the occupational exposure limit (OEL). OEL is defined as airborne concentrations (expressed as a time‐weighted average for a conventional 8‐h workday and a 40‐h work week) of a substance to which nearly all workers may be repeatedly exposed (for a working lifetime) without adverse effects. Determination of OELs has become very challenging over time, requiring an overall assessment of the preclinical and clinical data of the drug being manufactured. Previously, to derive OEL values, toxicologists used animal no‐observed‐adverse‐effect level (NOAEL) data, which have been replaced with the overall assessment of animal and human data, placing a higher emphasis on human health‐based data. A major advantage of working with human pharmaceuticals is that sufficient clinical data are available for them in most cases. The present manuscript reviews the latest knowledge regarding the derivation of occupational exposure limits as health‐based exposure limits (HBELs) for pharmaceuticals. We have provided examples of OEL calculations for various drugs including levofloxacin (CAS No. 100986‐85‐4), dienogest (CAS no. 65928‐58‐7), and acetylsalicylic acid (ASA, CAS no. 50–78‐2) using human data. This report will benefit professionals in the OEL domain in understanding this highly important, growing, and challenging field.

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Section: Critical Effect/point Of Departurementioning

confidence: 99%

Section: Addressing Sources Of Uncertainty Using Science‐based Afsmentioning

confidence: 99%

Section: Addressing Sources Of Uncertainty Using Science‐based Afsmentioning

confidence: 99%

Section: Addressing Sources Of Uncertainty Using Science‐based Afsmentioning

confidence: 99%

Section: Oel Calculation For Acetylsalicylic Acidmentioning

confidence: 99%

See 3 more Smart Citations

Approaches for setting occupational exposure limits in the pharmaceutical industry

Ahuja

Krishnappa

2021

J of Applied Toxicology

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Use of the benchmark‐dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N‐nitrosamines

Blum

FitzGerald

Wilks

et al. 2023

J of Applied Toxicology

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N-Nitrosamines are potent carcinogens and considered non-threshold carcinogens in various regulatory domains. However, recent data indicate the existence of a threshold for genotoxicity, which can be adequately demonstrated. This aspect has a critical impact on selecting the methodology that is applied to derive occupational exposure limits (OELs). OELs are used to protect workers potentially exposed to various chemicals by supporting the selection of appropriate control measures and ultimately reducing the risk of occupational cancer. Occupational exposures to nitrosamines occur during manufacturing processes, mainly in the rubber and chemical industry.The present study derives OELs for inhaled N-nitrosamines, employing the benchmark dose (BMD) approach if data are adequate and read-across for nitrosamines without adequate data. Additionally, benchmark dose lower confidence limit (BMDL) is preferred and more suitable point-of-departure (PoD) to calculate human health guidance values, including OEL. The lowest OEL (0.2 μg/m 3 ) was derived for nitrosodiethylamine (NDEA), and nitrosopiperidine (NPIP) (OEL = 0.2 μg/m 3 ), followed by nitrosopyrrolidine (NPYR) (0.4 μg/m 3 ), nitrosodimethylamine (NDMA), nitrosodimethylamine (NMEA), and nitrosodipropylamine (NDPA) (0.5 μg/m 3 ), nitrosomorpholine (NMOR) (OEL = 1 μg/m 3 ), and nitrosodibutylamine (NDBA) (OEL = 2.5 μg/m 3 ).Limits based on "non-threshold" TD50 slope calculation were within a 10-fold range. These proposed OELs do not consider skin absorption of nitrosamines, which is also a possible route of entry into the body, nor oral or other environmental sources. Furthermore, we recommend setting a limit for total nitrosamines based on the occupational exposure scenario and potency of components.

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Are cytostatic drugs in surface waters a potential threat?

Gouveia

Mota

Silva

et al. 2022

Science of The Total Environment

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Deriving harmonised permitted daily exposures (PDEs) for paracetamol (acetaminophen) CAS #: 103-90-2

Cited by 4 publications

References 55 publications

Approaches for setting occupational exposure limits in the pharmaceutical industry

Approaches for setting occupational exposure limits in the pharmaceutical industry

Use of the benchmark‐dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N‐nitrosamines

Are cytostatic drugs in surface waters a potential threat?

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