Analysis of trace elements (Arsenic, Cadmium, Lead, and Mercury) in over-the-counter medicines from the United Kingdom, the Kingdom of Saudi Arabia, and India

May M. Alrashdi; Abby Ragazzon-Smith; Ilya Strashnov; Andrew R. Pitt; David A. Polya

doi:10.25259/AJC_318_2024

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Original Article

2025

:18;

3182024

doi:

10.25259/AJC_318_2024

Analysis of trace elements (Arsenic, Cadmium, Lead, and Mercury) in over-the-counter medicines from the United Kingdom, the Kingdom of Saudi Arabia, and India

May M. Alrashdi^a,b,*, Abby Ragazzon-Smith^c, Ilya Strashnov^a, Andrew R. Pitt^a,d, David A. Polya^c

aDepartment of Chemistry, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester, M13 9PL, United Kingdom

bDepartment of Chemistry, College of Science, Jouf University, P.O. Box: 2014, Sakaka, Kingdom of Saudi Arabia

cDepartment of Earth and Environmental Sciences, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester, M13 9PL, United Kingdom

dManchester Institute of Biotechnology, The University of Manchester, Manchester, M1 7DN, United Kingdom

*Corresponding author: E-mail address: mmrashdi@ju.edu.sa (MM. Alrashdi)

Received: 2024-12-24, Accepted: 2025-04-28, Epub ahead of print: 2025-07-26, Published: 2025-08-04

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Abstract

Elemental impurities (EIs) in pharmaceuticals have become the subject of widespread interest. This is due to the implementation of new regulations by the United States Pharmacopoeia (USP <232>/<233>) and the International Council for Harmonisation (ICH Q3D) in 2018. These regulations mandate the monitoring of a wide range of elements, often present at low concentrations in pharmaceuticals. The aim of this study was to determine the concentrations of EIs (As, Cd, Pb, and Hg) in over-the-counter (OTC) medicines and evaluate possible human exposure to these trace elements, as well as to calculate and compare daily exposure values with the available USP <232>/<233> regulations. To do so, 38 common OTC medicines (paracetamol, cough, and ibuprofen/profen syrups) were collected from the United Kingdom (UK), the Kingdom of Saudi Arabia (KSA), and India. The samples were acid digested and then analysed using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Weighted calibration curves and USP <232>/<233> ICH Q3D validation guidelines, including standard additions methodology, were used for analytical validation. The mean concentration of As, Cd, Pb, and Hg in OTC medicines were 4.73, 1.71, 15.40, and 2.03 µg/L, respectively. The results revealed acceptable levels of As, Cd, and Hg, but the samples had a relatively high amount of Pb compared to other trace elements in various medicine types from all countries. The data obtained from this study demonstrate that commonplace non-compliance with recommended daily dosages could readily result in exposures to Pb, reaching up to 50% of the Permitted Daily Exposure (PDE) limits for Pb in pharmaceutical products as defined by USP<232> (5 μg/day). When supplemented by exposures from other sources, this level of exposure has the potential to cause adverse health effects, particularly in young children. The use of a weighted calibration curve was shown to improve the accuracy of the analysis, particularly for concentrations close to method detection limits (DLs), whilst standard additions methodology was found to reduce matrix effects.

Keywords

Heath risk assessment

Over-the-counter (OTC) medicines

Permitted Daily Exposure

Trace elements

USP <232>/<233>

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1. Introduction

Pharmaceutical products may contain elemental impurities (EI) that can have toxic and other detrimental effects. These EIs, even at low concentrations, may be toxic, and awareness of their concentrations as well as consumption rates is required in order to protect human health [1,2]. For instance, arsenic (As), cadmium (Cd), and lead (Pb) are classified as human carcinogens according to the International Agency for Research on Cancer [3]. Further, mercury (Hg) can affect the nervous system [4]. With multiple pathways of exposure to trace elements such as As in water and food (rice) (reported in India) [5], and lead in medicines (reported in Jordan) [6], amongst other places, the risks arising from EIs in pharmaceuticals, particularly over-the-counter (OTC), has become a significant concern because of potential adverse health effects. OTC medicines, which can be purchased without a prescription, are widely available. This has led to an increase in self-medication by individuals. OTC medicines are usually considered by the general public to be relatively safe [7,8]. However, self-administering medication could present risks as a result of incorrect dosage, leading to potential side effects, adverse reactions, and interactions with other drugs [9-11]. The possible hazards of OTC medications have been demonstrated by a report from a parliamentary committee [12], in addition to a collaborative statement on medication addiction in the United Kingdom (UK) [13].

In 2018, the United States Pharmacopoeia (USP) <232>/<233> and the Q3D guidelines established by the International Conference on Harmonisation (ICH) have played a crucial role in controlling EIs. These guidelines provide specific, selective, and quantitative instrumental techniques for this purpose [14]. Challenges associated with analyzing samples with different matrices indicate the development of analytical methods and sample preparation methods as important factors for efficacious analysis [15]. Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) have been widely recognized as suitable methods for the measurement of element impurities [16,15]. The new ICH Q3D guidelines have classified the elements As, Cd, Hg, and Pb as class 1 elements because they are toxic elements with limited or no use in the manufacture of pharmaceuticals. USP <232>/<233> ICH Q3D guidelines specify permitted daily exposures (PDE) of these EIs expressed in units of μg/day in the final pharmaceutical product based on toxicological data and the route of administration, as presented in Table 1 [14].

Table 1. PDEs (µg/day) for EIs As, Cd, Pb, and Hg for different exposure routes according to USP <232>/<233> ICH Q3D guidelines after [14].

Element	Oral (µg/day)	Parenteral (µg/day)	Inhalation (µg/day)
As	15	15	2
Cd	5	2	2
Pb	5	5	5
Hg	30	3	1

These guidelines aim to reduce the adverse effects of EIs and mitigate their potential harm. The presence of the trace elements As, Cd, Pb, and Hg does not have any therapeutic benefit and may potentially have detrimental effects on the stability and shelf life of the active pharmaceutical ingredients (APIs) [14,17]. It is important to note that while USP does not provide specific definitions for age-related PDEs, children are more vulnerable than adults to the harmful effects of increased metal exposure. Children are particularly more likely to suffer from nutritional deficiencies, which can result in higher absorption of metals [18]. Additionally, children are at higher risk of exceeding trace element limits because they have a higher surface area to body mass ratio and consume more water and food relative to their weight compared to adults [19-21]. Therefore, children are more susceptible to the negative impacts of heavy metal exposure. Early-life exposure to heavy metals can result in modified gene expression, heightened susceptibility to disease in later life, and diminished ability to recover from future neurological injuries such as strokes [18,22].

The permissible daily exposure limit for each element by USP is based on an intake of 10 g of the medicine and a body weight of 50 kg [23]. The calculation of USP limits for EIs in units of µg/kg of body weight per day (µg/kg-bw/day), with an assumed average body weight of 50 kg [23], results in the following limits: 0.3 µg/kg-bw/day for As, 0.1 µg/kg-bw/day for Cd, 0.1 µg/kg-bw/day for Pb, and 0.6 µg/kg-bw/day for Hg. By comparison, the European Food Safety Authority (EFSA) Panel on Contaminants in the food chain [24] established a Benchmark Dose Lower Confidence Limit (BMDL₀₁) for inorganic arsenic of 0.3 µg/kg-bw/day, which aligns with the limit set by USP. However, it exceeds the BMDL₀₅ value of 0.06 µg/kg-bw/day recently reported by the EFSA [25] for the risk of skin cancer. The Food and Agriculture Organisation and the World Health Organisation (FAO & WHO) have established a Provisional Tolerable Weekly Intake (PTWI) [26] for Cd at a level of 1 µg/kg-bw/day, which exceeds the limit set by the USP. Lead (Pb) previously had an FAO & WHO recommended PTWI of 3.57 µg/kg-bw/day, indicating a higher tolerance than the limit set by the USP, although the PTWI has now been withdrawn due to safety concerns. The PTWI for Hg, as established by FAO & WHO, is 0.23 µg/kg-bw/day. This limit is more stringent than the USP limit of 0.6 µg/kg-bw/day. These variations reflect differences between the risk assessment approaches inherent in the USP and the FAO & WHO guidelines.

The regulation and monitoring of trace elements or EIs in OTC medicines differ among countries, reflecting variations in their regulatory frameworks and enforcement mechanisms. Medicines in e.g. India are considered OTC unless they are specifically labelled as prescription medicines only [27], unlike in more regulated countries such as the UK and the Kingdom of Saudi Arabia (KSA). In the UK and KSA, ICH Q3D guidelines are followed and which set limits on EIs based on toxicity and daily exposure limits [28,29]. In India, the Central Drugs Standard Control Organization (CDSCO) monitors primary impurities through the Indian Pharmacopoeia, drawing from global standards such as the ICH but adapted to the country’s vast and diverse pharmaceutical manufacturing environment [30].

The presence of EIs can be related to environmental influences and may originate from catalysts, reagents used in synthetic excipients, formulation ingredients, and processing containers [31,14]. Due to regulations on water quality, substantial water contamination is relatively uncommon in pharmaceutical manufacturing settings, notwithstanding a study by [32] which demonstrated how contaminated irrigation water in unregulated regions can introduce harmful metals into medicinal preparations. Despite these concerns, there are limited studies on trace elements in OTC medicines, certainly compared to studies focused on herbal medicines [33-36] and traditional medicines [6,37-39]. Therefore, the objectives of this study were (i) to improve analytical methods and apply to areas of application in which they have been infrequently used, viz. notably the levels of trace elements in OTC medicines, (ii) to determine the concentration of trace element (As, Cd, Hg, and Pb), impurities in pharmaceutical products, specifically oral OTC medicines, (iii) to estimate potential plausible human exposure to these trace elements from OTCs, and to compare calculated daily exposure values with the USP <232>/<233> regulations and (iv) to compare trace impurity concentrations and exposures in countries, UK, KSA, and India, with different regulatory and monitoring regimes.

Table 2 available published data for As, Cd, Pb, and Hg concentrations in OTC medicine samples collected from pharmacies, which are available without prescription. The aim of this review of studies available from the Web of Science database was to understand the concentration range of elements, enabling the evaluation of health risks based on previous and recent studies in OTC medicines analysis, and to better understand the overall requirements for the development of analytical methods. This has indicated that the concentration of these toxic elements could be a concern, leading to potential exposure to As, Cd, Pb, and Hg from OTC medications, which could potentially impact individuals who consume these medications, particularly children.

Table 2. Reported concentrations of As, Cd, Pb, and Hg in OTC medicines.

Element	Country of Sale	Concentration (µg/kg), (µg/L) and/or daily exposure (µg/day)	Affected age or groups	OTC medicine	Reference
As	India	Ranging from 5000 to 248000 µg/L	11-year-old female	Ayurveda medicines	[40]
	Denmark	30 to 3200 µg/kg Ranging from 0.07 to 13 µg/day	Adult (60 kg body weight)	Dietary supplement	[41]
	Nigeria	350 µg/kg	Adult	Painkiller medicines	[42]
	USA	531 μg/kg 1.42 µg/day	Pregnant women	Dietary supplements	[43]
	USA	510 μg/kg 1.58 µg/day	Children	Dietary supplements	[43]
	USA	85.7 µg/day	Adult	Dietary supplements	[44]
	UK	> 0.01 μg/kg > 0.000048 µg/day	12 years old and over	Paracetamol	[45]
	UK	> 0.01 μg/kg > 0.000048 µg/day	12 years old and over	Cold and cough remedies	[45]
	Denmark	> 0.03 µg/L	Adult	Ibuprofen	[46]
Cd	Nigeria	Ranging from 10 to 2450 µg/L.	Children	Various types of medicines including cough syrup and paracetamol syrup	[47]
	USA	368 μg/kg	Children and pregnant women	Dietary supplements	[63]
	USA	8.89 μg/day	Adult	Dietary supplements	[44]
	Pakistan	520 μg/kg	Adult and children	Calcium supplements	[49]
	Brazil	54.50 µg/kg	Adult and children	Omega-3 dietary Supplements	[50]
	Nigeria	90 µg/kg	Children	Cough syrup	[47]
	North Macedonia	> 1 µg/kg	Adult and children	Ibuprofen	[51]
	UK	103 µg/kg (0.48 µg/day)	12 years old and over	Paracetamol	[45]
		101 µg/kg (0.56 µg/day)
		86 µg/kg (0.39 µg/day)
		135 µg/kg (0.68 µg/day)
	UK	124 µg/kg (5.96 µg/day)	12 years old and over	Cold and cough remedies	[45]
		76 µg/kg (1.45 µg/day)
		144 µg/kg (7.57 µg/day)
		149 µg/kg (8.49 µg/day)
		114 µg/kg (10.14 µg/day)
	Denmark	> 0.01 µg/L	Adult	Ibuprofen	[52]
Pb	USA	316 µg/kg	Adult	Ibuprofen	[53]
	Korea	1080 µg/kg 5 µg/day	Children, adults and 65-year-olds	Dietary calcium supplement	[54]
	Jordan	2000 µg/kg Ranging from 5 to 6 μg/day	(6–12 months, body weight 10 kg)	Natural cough syrup and flu drop	[6]
	China	73.80 μg/kg 5.54 μg/day	Adult	Herbal medicines	[36]
	USA	48600 μg/kg 486 µg/day	Children and pregnant women	Dietary Supplements	[63]
	USA	5070 μg/kg 27 µg/day	Children and pregnant women	Dietary Supplements	[48]
	Brazil	7068 μg/kg	Children	Iron supplements	[52]
	Nigeria	70 µg/kg.	Children	Paracetamol syrup	[47]
	Nigeria	140 µg/L	Children	Cough syrup	[47]
	North Macedonia	> 45 µg/kg	Adult and children	Ibuprofen	[51]
	UK	412 µg/kg (1.91 µg/day)	12 years old and over	Paracetamol	[45]
		701 µg/kg (3.87 µg/day)
		754 µg/kg (3.44 µg/day)
		827 µg/kg (4.17 µg/day)
Pb	UK	434 µg/kg (20.93 µg/day)	12 years old and over	Cold and cough remedies	[45]
		526 µg/kg (50.97 µg/day)
		543 µg/kg (10.33 µg/day)
		362 µg/kg (19.02 µg/day)
		376 µg/kg (21.47 µg/day)
		403 µg/kg (35.89 µg/day)
	Denmark	> 0.02 µg/L	Adult	Ibuprofen	[46]
Hg	Poland	16.70 µg/kg	Adult and children	Dietary supplements	[55]
	Poland	45.80 µg/kg	Adult and children	OTC medicines - Not specified	[55]
	China	1168 μg/kg	Adult	OTC traditional medicine	[39]
	North Macedonia	> 7 µg/kg	Adult and children	Ibuprofen	[51]
	UK	0.13 µg/kg	12 years old and over	Paracetamol	[45]
	UK	187 µg/kg (18.1 µg/day)	12 years old and over	Cold and cough remedies	[45]
	UK	156 µg/kg (8.2 µg/day)	12 years old and over	Cold and cough remedies	[45]

2. Materials and Methods

2.1. Data & data quality objectives (DQOs)

Analytical requirements for As, Cd, Pb, and Hg in OTC medicines arising from the study aims included accuracy and precision of better than ± 10% at 3 × detection limit (DL) with a DL of better than 0.01 µg/L.

2.2. Samples

Thirty-eight common OTC medicines, including paracetamol, Ibuprofen/profen, and cough syrups, from the UK, the KSA, and India, were examined in this study. The OTC medicines were acquired from well-known pharmacies in Manchester (UK) and Riyadh city (KSA). Medicines, including homeopathic and Ayurveda medicine categories of medicines used in India [56], were collected from several medical stores/pharmacies in Bihar and Kerala states in India. Samples were stored at room temperature (20 - 25°C) and digested within 48 hours of opening the package. Pharmaceutical products were only included in the study if they met the following criteria: (i) they stated that they were suitable for children (and consequently all the products were liquid syrups), (ii) OTC sale was officially authorized by the relevant government bodies [57,58] and (iii) maximum recommended daily doses of at least 7.5 mL/day (with potential risk to consumers if they were found to contain levels of EIs above the recommended PDE). Some of the medicines contained APIs such as paracetamol or herbal extracts. Table 3 summarise the maximum recommended daily dose (mL/day) for patients of various ages.

Table 3. Lists of analysed OTC medicines from UK, KSA and India (Name of OTC medicine, Country of Sale, Maximum recommended daily dosage for various ages).

Name of OTC medicine	Country of sale	Age	Maximum recommended daily dosage (mL/day)
Paracetamol syrup 1	UK	(2-3 months)	10
Paracetamol syrup 1	UK	(6-24 Months)	20
Paracetamol syrup 2	UK	(2-4 Years)	30
Paracetamol syrup 2	UK	(4-6 Years)	40
Paracetamol syrup 3	KSA	(2-5 Years)	20
		(6-10 Years)	40
		(11-12 Years)	60
Paracetamol syrup 4	KSA	(6-24 Months)	15
		(2-8 Years)	22.5
		(8-10 Years)	45
		(10-12 Years)	60
Paracetamol syrup 5	KSA	(6-24 Months)	20
		(2-8 Years)	30
		(8-12 Years)	60
Paracetamol syrup 6	India	(<12 years)	32
Paracetamol syrup 7	India	(1-5 years)	40
Paracetamol syrup 8	India	(1-6 Years)	40
Paracetamol syrup 8	India	(6-12 Years)	80
Paracetamol syrup 9	India	Children > 3 months	40
Paracetamol syrup 10	India	(1-9 Years)	20
Paracetamol syrup 10	India	(9-12 years)	54
Paracetamol syrup 11	India	(2 months-12 years)	52
Paracetamol syrup 12	India	(<12 years)	52
Cough syrup 1 (Demulcent)	UK	(3 Months to 5 Years)	20
Coughs syrup 2 (Herbal)	UK	(Adult and >12 Years)	12
Coughs syrup 3 (Demulcent)	UK	(1-5 Years)	20
Coughs syrup 3 (Demulcent)	UK	(>5 Years)	40
Cough Syrup 4 (Demulcent)	UK	(Adult and >12 Years)	30
Cough syrup 5 (Demulcent)	UK	(Adult and >12 Years)	40
Cough syrup 6 (Demulcent)	KSA	(6-10 Years)	15
Cough syrup 6 (Demulcent)	KSA	(Adult and >12 Years)	22.5
Cough syrup 7 (Demulcent)	KSA	(6-12 Years)	20
Cough syrup 7 (Demulcent)	KSA	(Adult and >12 Years)	40
Cough syrup 8 (Demulcent)	KSA	(6-9 Years)	15
Cough syrup 8 (Demulcent)	KSA	(Adult)	22.5
Cough syrup 9 (Herbal)	KSA	(> 6 Years)	15
Cough syrup 9 (Herbal)	KSA	(adult)	22.5
Cough syrup 10 (Herbal)	KSA	(6-9 Years)	15
Cough syrup 10 (Herbal)	KSA	(Adult)	22.5
Cough syrup 11 (Demulcent)	KSA	(> 6 Years)	30
Cough syrup 11 (Demulcent)	KSA	(Adult)	45
Cough syrup 12 (Demulcent)	India	(< 6 years)	15
		(6 to 12 years)	30
		(Adult)	60
Cough syrup 13 (Ayurvedic)	India	(Adult)	15
Cough syrup 14 (Demulcent)	India	(2-5 Years)	10
Cough syrup 14 (Demulcent)	India	(5-12 Years)	20
Cough syrup 15 (Ayurvedic)	India	(< 12 years)	15
Cough syrup 16 (Ayurvedic)	India	(< 12 years)	30
Cough syrup 17 (Homeopathy)	India	(Adult and children)	25
Cough syrup 18 (Homeopathy)	India	(Children)	10
Cough syrup 18 (Homeopathy)	India	(adult)	20
Cough syrup 19 (Demulcent)	India	(< 6 years)	15
		(6 to 12 years)	30
		(Adult)	60
Cough syrup 20 (Demulcent)	India	(< 12 years)	20
Cough syrup 20 (Demulcent)	India	(> 12 years)	40
Cough syrup 21 (Ayurvedic)	India	(< 12 years)	45
Ibuprofen/Profen syrup 1	UK	(1-6 Years)	15
Ibuprofen/Profen syrup 1	UK	(7-9 Years)	30
Ibuprofen/Profen syrup 2	UK	(6 Months - 2 Years)	7.5
		(3-7 Years)	20
		(8-12 Years)	40
Ibuprofen/Profen syrup 3	KSA	(3 Months - 12 years)	45
Ibuprofen/Profen syrup 4	KSA	(1-2 Years)	7.5
		(3-7 Years)	15
		(8-12 Years)	30
Ibuprofen/Profen syrup 5	KSA	(1-6 Years)	15
		(7-9 Years)	30
		(10-12 Years)	45

2.3. Sample preparation and analysis

2.3.1. Reagents and calibration standards

Analytical reagent (AR) grade nitric acid (70% wt/wt HNO₃) (Fisher Scientific (AR), UK) was used for sample and standard preparation after being purified using sub-boiling acid distillation (DST-1000 acid purification system, Savillex). Arsenic (As) (Reagecon, 1000 µg/mL, Ireland), Cadmium (Cd), Lead (Pb) (Sigma-Aldrich, 1000 µg/mL, USA) and Mercury (Hg) (Sigma-Aldrich, 10,000 µg/mL, USA) standards for ICP were used for calibration standard preparation. All solutions were prepared using 18.2 MΩ type 1 ultrapure laboratory water (Avidity Science). Nine calibration standard solutions were prepared with concentrations of 0.00 (blank), 0.01, 0.05, 0.10, 0.25, 0.50, 1.00, 2.50, 5.00, and 10.00 µg/L. To filter the samples, 0.2 µm nylon filters (Fisher Scientific) and 10 mL syringes (IVS10, HMC premedical S.P.A) were used.

2.3.2. Accuracy and precision

ICH/USP target elements standard A Certified Reference Material (CRM) (Agilent) was used to ensure the accuracy of the analyses. The components of this CRM meet the needs of the analysis of EIs in pharmaceuticals based on USP <232>/<233> ICH Q3D guidelines. A weighted calibration curve was employed (Miller and Miller, 2018) to account for analytical imprecision, which is heteroscedastic, i.e., it varies with concentration. Pharma internal standard 1 in 2% HNO₃ (Agilent) was used as an internal standard. The samples were also spiked following the standard addition method by a combined As, Cd, Pb, and Hg standard (5 µg/L) as recommended by USP 233 [59,60] to assess the accuracy of the analytical method/procedure, and in particular the impact of the digestion/dilution method. Blank samples were used to evaluate any contamination that could have arisen from handling in the laboratory. Precision was determined by analyzing samples in triplicate and repeating analyses at varying times throughout an analytical session.

2.3.3. Sample preparation

The samples and the certified reference material (CRM) were digested using concentrated nitric acid (70% wt/wt HNO₃) (Fisher Scientific (AR) then sub-distilled) by closed vessel microwave digestion as recommended by USP 233 [59]. Typically, 2 mL of sample or CRM was digested in triplicate in 5 mL sub-distilled concentrated nitric acid (70% wt/wt) for both non-spiked and spiked sample preparation. Samples were spiked with As, Cd, Pb (5 µg/L), and Hg (100 µg/L) standard at approximately 50% (0.5 J), 100% (1.0 J), and 150% (1.5 J), where J is the concentration of each EI in the medicines. An Au (gold) solution (10 mL of 1000 µg/L diluted to a final concentration of 100 µg/L) was added to the samples to stabilize Hg in solution. Then, after the microwave digestion, all samples were diluted up to 100 mL with deionized water for a 50-fold dilution factor. A number of CRM samples were also diluted 2500 times with 2% HNO₃ to obtain concentrations within the optimal sensitivity ranges of the instrument. All samples were filtered using 0.2 µm nylon filters using 10 mL syringes.

2.3.4. Analytical instrumentation

A CEM Mars (240/50) Microwave System with MARSXpress vessel (50 mL) was used to digest samples for trace element analysis. The digestion program (Table 4) was designed by CEM to digest organic materials using nitric acid as the primary reagent and using MARSXpress vessels. The concentration measurements of As, Cd, and Pb were carried out with an ICP-MS/MS (Agilent 8900), whereas a single quadrupole system was used for measurement of Hg concentrations (ICP-MS Agilent 7700). Typical ICP-MS experimental conditions for both instruments have beem summarized in Table 5.

Table 4. Microwave digestion parameters employed for the analysis of EIs (As, Cd, Pb, and Hg) in OTC medicine samples.

Stage	Parameter
Stage	Maximum power (W)	Ramp time (min)	Temperature (°C)	Hold time (min)
1	800	10	180	10
2	800	15	210	15
3	400	01	100	10

Table 5. Operating conditions of the Agilent 8900 ICP-MS/MS for analysis of As, Cd, and Pb, and of the Agilent 7700 ICP-MS for analysis of Hg.

Operational parameter	ICP-MS/MS Agilent 8900 operating conditions		ICP-MS Agilent 7700 operating conditions
Acquisition (ACQ) mode	Spectrum		Spectrum
Peak pattern	1 point		1 point
Replicates	4		5
Stabilization time (sec)	35		10
RF power (W)	1550		1550
Nebulizer gas flow (L/min)	1.09		1.00
Nebulizer pump (rps)	0.10		0.30
Sampling depth (mm)	8.0		8.0
Spray chamber temperature (°C)	2		2
Collision gases	O₂		He
Integration time/mass (sec)	MS/MS Mode Q1 -> Q2 (m/z) ¹¹¹Cd -> ¹¹¹Cd ²⁰⁸Pb -> ²⁰⁸Pb ⁷⁵As -> ⁷⁵As-¹⁶O ¹¹⁵In -> ¹¹⁵In ²⁰⁹Bi -> ²⁰⁹Bi ⁷²Ge -> ⁷²Ge	1 1 1 0.1 0.1 0.1	Hg 201 Au 197 Rh 103	3 0.1 1

2.4. Statistical test for input variables

The Tukey-Kramer statistical test [61] was applied to the resulting data using Microsoft Excel 2016 to determine whether the means of the concentrations of As, Cd, Pb, and Hg in OTC medicines from the UK, KSA, and India were significantly different from each other.

3. Results and Discussion

3.1. Analytical quality control data

The accuracy of the method was evaluated using ICH/USP target elements standard A (CRM). Recoveries of 92%, 97%, 94%, and 107% for As, Cd, Pb, and Hg, respectively, were found as shown in Table 6. The accuracy of the method was also assured using USP 233 acceptance criteria [59,60], where spike recovery rates between 70-145% for each concentration (50%, 100%, and 150% of elemental concentration) (see Figure 1). The precision of the analyses was assessed by replicate analyses with relative standard deviations (RSD) typically less than 6%.

Table 6. Accuracy and repeatability results of the analytical method obtained using ICH/USP target elements standard A (CRM) expressed as % recoveries and standard deviation SD respectively, n=3.

Analyte	Certified Value (µg/mL) ± Standard deviation	Obtained Value (µg/mL) ± Standard deviation	Recovery
As	15.00 ± 0.07	13.81 ± 0.10	92% ± 1%
Cd	5.00 ± 0.03	4.83 ± 0.15	97% ± 3%
Pb	4.99 ± 0.03	4.71 ± 0.14	94% ± 3%
Hg	30.00 ± 0.13	32.25 ± 1.95	107% ± 6%

Percentage recoveries for OTC medicines spiked with known concentration standards of As, Cd, Pb, and Hg at 50%, 100%, and 150% of the medicine elemental concentration. All recoveries were within the acceptable range of values of recoveries (70% to 150%) (dashed red lines) according to [60].

3.2. EIs concentrations in OTC medicines.

The mean concentration of As, Cd, Pb, and Hg in OTC medicines from the UK, KSA, and India was found to be 4.7, 1.7, 15.4, and 2.0 µg/L, respectively. These concentrations were significantly lower than previously reported (see Table 2), with the exceptions of As in the study conducted by [44], Cd in the study by [50], and As, Cd, and Pb in the study by [52], which exhibited lower levels. This could be due to differences in source materials or manufacturing processes in the countries targeted in this study compared to previous studies. In addition, developments in production techniques and regulatory updates over time, including updated safety standards and permitted exposure limits, may have contributed to the differences in results.

Concentrations (µg/L) of As, Cd, Pb, and Hg in individual OTC medicines have been shown in Table 7. It was found that the mean concentration of As was 6.7, 4.3, and 2.0 µg/L in paracetamol, cough syrups, and Ibuprofen/Profen syrups, respectively. The highest concentration was observed in paracetamol syrup 5 (KSA). It was found that the mean concentration of Cd was 1.0, 1.6, and 4.1 µg/L in paracetamol, cough syrups, and Ibuprofen/Profen syrups, respectively. The highest concentration was observed in Ibuprofen/Profen syrup 2 (UK). It was found that the mean concentration of Hg was 2.0, 3.4, and 2.0 µg/L in paracetamol, cough syrups, and Ibuprofen/Profen syrups, respectively. The highest concentration was observed in paracetamol syrup 7 (India). It was found that the mean concentration of Pb was 16, 16, and 13 µg/L in paracetamol, cough syrups, and Ibuprofen/Profen syrups, respectively. The highest concentration of Pb was observed in cough syrup 3 (UK).

Table 7. Analyzed concentrations (µg/L) of trace elements (As, Cd, Pb, and Hg) in paracetamol, cough, and ibuprofen/profen syrups from the UK, KSA, and India. Analyzed using ICP-MS according to USP <232>/<233>. Standard deviations (SD) based on triplicate measurements.

Medicine (OTC)	Origin	Analysed Concentration ± standard deviation (SD) (µg/L)
Medicine (OTC)	Origin	As	Cd	Pb	Hg
Paracetamol syrup 1	UK	2.03 ± 0.02	0.91 ± 0.03	11.08 ± 0.33	2.17 ± 0.20
Paracetamol syrup 2	UK	2.79 ± 0.03	1.24 ± 0.04	3.05 ± 0.09	1.54 ± 0.18
Paracetamol syrup 3	KSA	6.13 ± 0.06	0.94 ± 0.03	15.22 ± 0.46	1.19 ± 0.06
Paracetamol syrup 4	KSA	2.47 ± 0.02	2.64 ± 0.08	18.53 ± 0.56	0.98 ± 0.10
Paracetamol syrup 5	KSA	33.16 ± 0.33	0.75 ± 0.02	5.47 ± 0.16	0.99 ± 0.12
Paracetamol syrup 6	India	10.65 ± 0.11	0.79 ± 0.02	0.59 ± 0.02	0.6 ± 0.15
Paracetamol syrup 7	India	1.12 ± 0.03	0.82 ± 0.01	34.30 ± 1.03	7.69 ± 0.38
Paracetamol syrup 8	India	1.65 ± 0.05	0.49 ± 0.01	17.98 ± 0.54	0.71 ± 0.04
Paracetamol syrup 9	India	11.46 ± 0.34	0.94 ± 0.01	41.48 ± 1.24	3.46 ± 0.17
Paracetamol syrup 10	India	4.15 ± 0.12	1.08 ± 0.01	17.90 ± 0.54	<0.01
Paracetamol syrup 11	India	1.63 ± 0.05	0.73 ± 0.01	12.39 ± 0.37	0.41 ± 0.02
Paracetamol syrup 12	India	2.67 ± 0.08	0.18 ± 0.01	16.76 ± 0.50	<0.01
Cough syrup 1 (Demulcent)	UK	5.77 ± 0.06	1.52 ± 0.05	10.89 ± 0.33	2.16 ± 0.16
Cough syrup 2 (Herbal)	UK	3.17 ± 0.03	3.25 ± 0.10	37.69 ± 1.13	2.86 ± 0.22
Cough syrup 3 (Demulcent)	UK	3.46 ± 0.03	1.05 ± 0.03	56.05 ± 1.68	5.22 ± 0.05
Cough syrup 4 (Demulcent)	UK	0.48 ± 0.01	1.05 ± 0.03	1.18 ± 0.04	1.92 ± 0.06
Cough syrup 5 (Demulcent)	UK	1.46 ± 0.01	0.83 ± 0.02	16.14 ± 0.48	1.82 ± 0.14
Cough syrup 6 (Demulcent)	KSA	2.38 ± 0.02	1.85 ± 0.06	3.28 ± 0.10	1.51 ± 0.17
Cough syrup 7 (Demulcent)	KSA	3.21 ± 0.03	1.49 ± 0.04	2.03 ± 0.06	1.23 ± 0.10
Cough syrup 8 (Demulcent)	KSA	6.10 ± 0.06	1.44 ± 0.04	3.27 ± 0.10	3.50 ± 0.08
Cough syrup 9 (Herbal)	KSA	2.84 ± 0.03	0.93 ± 0.03	18.36 ± 0.55	2.03 ± 0.06
Cough syrup 10 (Herbal)	KSA	1.39 ± 0.01	1.85 ± 0.06	13.13 ± 0.39	1.56 ± 0.07
Cough syrup 11 (Demulcent)	KSA	2.14 ± 0.02	2.27 ± 0.07	8.01 ± 0.24	5.70 ± 0.03
Cough syrup 12 (Demulcent)	India	7.77 ± 0.08	0.78 ± 0.02	0.34 ± 0.01	0.72 ± 0.39
Cough syrup 13 (Ayurvedic)	India	11.38 ± 0.34	1.45 ± 0.01	25.10 ± 0.75	0.81 ± 0.04
Cough syrup 14 (Demulcent)	India	1.35 ± 0.04	0.30 ± 0.01	27.41 ± 0.82	1.09 ± 0.05
Cough syrup 15 (Ayurvedic)	India	2.23 ± 0.07	0.32 ± 0.01	13.99 ± 0.42	2.89 ± 0.14
Cough syrup 16 (Ayurvedic)	India	3.45 ± 0.10	0.56 ± 0.01	25.91 ± 0.78	0.14 ± 0.01
Cough syrup 17 (Homeopathy)	India	1.46 ± 0.04	1.35 ± 0.01	3.92 ± 0.12	1.39 ± 0.07
Cough syrup 18 (Homeopathy)	India	2.91 ± 0.09	7.80 ± 0.08	25.04 ± 0.75	1.13 ± 0.06
Cough syrup 19 (Demulcent)	India	1.85 ± 0.06	0.68 ± 0.01	9.19 ± 0.28	1.13 ± 0.06
Cough syrup 20 (Demulcent)	India	2.21 ± 0.07	0.49 ± 0.01	6.04 ± 0.18	<0.01
Cough syrup 21 (Ayurvedic)	India	22.84 ± 0.69	1.79 ± 0.02	19.74 ± 0.59	<0.01
Ibuprofen/Profen syrup 1	UK	1.87 ± 0.02	0.53 ± 0.02	5.34 ± 0.16	1.63 ± 0.08
Ibuprofen/Profen syrup 2	UK	2.18 ± 0.02	12.88 ± 0.39	6.06 ± 0.18	4.88 ± 0.03
Ibuprofen/Profen syrup 3	KSA	0.90 ± 0.01	0.55 ± 0.02	4.89 ± 0.15	1.26 ± 0.27
Ibuprofen/Profen syrup 4	KSA	1.91 ± 0.02	3.44 ± 0.10	5.79 ± 0.17	1.62 ± 0.15
Ibuprofen/Profen syrup 5	KSA	2.95 ± 0.03	2.88 ± 0.09	41.77 ± 1.25	1.20 ± 0.29

Tukey’s test was conducted at a significance level (α) = 0.05, to compare differences in many groups (k) = 8 with the degrees of freedom = 30. The mean concentration of each of As, Pb, and Hg in the eight groups (no Ibuprofen/Profen syrups from India were analysed) of OTC medicines from UK, KSA and India were not significantly different between groups with a (Tukey) q statistic < q critical (4.601), as presented in Table S1. However, the mean concentration of Cd in Ibuprofen/Profen UK was significantly higher than the mean of the Paracetamol India group, with a q statistic of 4.989 [62].

Table S1

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3.3. Trace element daily exposure and health risk assessment

Model trace element daily exposures were calculated based on their concentrations and the maximum daily dose of each medicine (Table 3). Then, the calculated daily intake values of As, Cd, Pb, and Hg were compared with the USP <232> and <233> EI limits (in Table 1). Figure 2 shows the model’s daily exposure to trace elements from OTC medicines expressed as a percentage of PDE. The model indicated that the daily exposures of As, Cd, and Hg were low, as the maximum daily exposure rates for these trace elements were found to be 13% (As) from Paracetamol 5 (KSA), 10% (Cd) from Ibuprofen/profen 1 (UK) and 1% (Hg) from paracetamol 7 (India) with respect to the PDE. However, the exposure to lead was relatively high, reaching up to 50% of PDE. It was estimated that paracetamol 9 (India) and Ibuprofen/profen 3 (KSA) contribute approximately 33% and 38% of this PDE, while cough Syrup 1 (UK) accounts for 45%. Such higher exposures were also a concern in the study reported for paracetamol and cough medicines [45] (see Table 2). Therefore, there is potential over-exposure in the event of non-compliance with the recommended daily dosage, which may result in serious adverse health effects, particularly for the most sensitive groups, such as children, who generally have immaturely developed body systems less able to counteract overdoses than adults [63]. The U.S Food and Drug Administration (FDA) recently established interim reference levels (IRLs) for lead intake to protect public health. These IRLs were set at 2.2 µg/day for children and 8.8 µg/day for females of childbearing age [64]. The Agency for Toxic Substances and Disease Registry (ATSDR) reports that children absorb up to 100% of lead ingested on an empty stomach and approximately 50% of lead ingested after eating food. The equivalent values for adults are lower, viz. 60 to 80% (on an empty stomach) and 20% (after eating food) [65]. Furthermore, according to a study by the National Association of Pediatric Nurse Practitioners, 40–70% of ingested lead can be absorbed by children, pregnant women, and the malnourished [66]. Because even small amounts of lead can be harmful, children who consume many OTC products may be at increased risk of cumulative lead exposure. In addition, other sources such as contaminated food, water, and environmental factors may also contribute to overall lead exposure [64,67].

Model daily exposures of As, Cd, Pb, and Hg from the UK, KSA, and India. OTC medicines expressed as percentage (%) of PDE. Where % of PDE calculated by: ((Element concentration x maximum recommended daily dosage)/permnitted daily exposure x 100).

In addition, a lack of awareness among some parents (e.g., in the East Midlands of the UK) has previously been noted regarding the potential negative effects of non-prescription OTC medications when used in a manner contrary to recommended dosages and age restrictions [68]. Studies by [69] in Palestine and [70] in Sri Lanka reported that most parents lacked knowledge of the recommended paracetamol dosage per kilogram of body weight and the daily maximum dose. Over 50% of parents administered paracetamol without medical advice [69,70]. Literate and educated parents are less likely to make pharmaceutical errors when choosing, measuring, and giving their children medicines [63].

4. Conclusions

The concentrations of the EIs in OTC medicines from the KSA, the UK, and India have been analysed by ICP-MS/MS. The potential health risks for children and adults have been evaluated based on the recommended daily dosage. This study focused on measurements of As, Cd, Hg, and Pb concentrations in paracetamol, cough, and ibuprofen/profen syrups. The results of the analysis of these medicines showed that the concentrations of Pb are slightly higher, up to 56 µg/L, compared to the concentrations of other trace elements in various medicine types, varied between different countries, with no significant difference in their mean (Tukey-Kramer test was applied for statistical analysis). The obtained data indicated that non-compliance with the recommended daily dosage may result in potential exposure to Pb up to 50% of PDE limits for Pb in pharmaceutical products (5 μg/day) by USP<232>, with the higher risk for adverse health effects, especially in young children. Children are a higher risk group since they may absorb up to 100% of ingested lead and are frequently subject to a lack of parents’ awareness regarding the appropriate dosage of medication for their age. Although trace element analysis in OTC medicines is an effective and useful approach to help ensure health benefits, safety, and quality control, this approach is limited by several factors, including complex sample preparation, quality control requirements, and expense. There are limited accurate and comprehensively representative data on consumption available for exposure estimates, particularly with respect to specific sub-populations, such as children and pregnant women, who could be more exposed and at higher risk.

Acknowledgment

MMA acknowledges with thanks the receipt of a PhD scholarship from Jouf University, Kingdom of Saudi Arabia Ministry of Education and the Saudi Arabia Cultural Bureau (SACB) in United Kingdom.The late Dr. Philip Riby, whose contributions are acknowledged here. We acknowledge our colleague Ajmal Roshan for providing OTCs from India.

We acknowledge the University of Manchester Analytical Geochemistry Unit (MAGU) laboratory team, notably Rosie Byrne and Jordan Gaskell.

The Ministry of Education - Kingdom of Saudi Arabia and the Saudi Arabia Cultural Bureau (SACB) in United Kingdom.

CRediT authorship contribution statement

May M. Alrashdi: Conceptualization; methodology; validation; formal analysis; investigation; writing – original draft; funding acquisition; Abby Ragazzon-Smith: Methodology; Ilya Strashnov: methodology, supervision; Andrew R. Pitt: Methodology, supervision; David A. Polya: Conceptualization; supervision; All authors contributed to the review and editing of the paper.

Declaration of competing interest

The authors declare that they have no competing interests.

Declaration of Generative AI and AI-assisted technologies in the writing process

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Supplementary data

Supplementary material to this article can be found online at https://dx.doi.org/10.25259/AJC_318_2024.

References

Li G., Schoneker D., Ulman K.L., Sturm J.J., Thackery L.M., Kauffman J.F.. Elemental impurities in pharmaceutical excipients. Journal of Pharmaceutical Sciences. 2015;104:4197-4206. https://doi.org/10.1002/jps.24650
[Google Scholar]
Barin J.S., Mello P.A., Mesko M.F., Duarte F.A., Flores E.M.. Determination of elemental impurities in pharmaceutical products and related matrices by ICP-based methods: A review. Analytical and Bioanalytical Chemistry. 2016;408:4547-4566. https://doi.org/10.1007/s00216-016-9471-6
[Google Scholar]
IARC. List of classifications by cancer sites with sufficient or limited evidence in humans. International Agency for Research on Cancer 2019:1-130. Retrieved 13 February 2022, from https://monographs.iarc.who.int/wp-content/uploads/2019/07/Classifications_by_cancer_site.pdf
[Google Scholar]
Poulin J., Gibb H., Prüss-Üstün A.World Health Organization. Mercury: Assessing the environmental burden of disease at national and local levels, p 10; [Last accessed 2024 March 23]. Available from: https://iris.who.int/handle/10665/43875
Mondal D., Polya D.A.. Rice is a major exposure route for arsenic in Chakdaha block, Nadia district, West Bengal, India: A probabilistic risk assessment. Applied Geochemistry. 2008;23:2987-2998. https://doi.org/10.1016/j.apgeochem.2008.06.025
[Google Scholar]
Alhusban A.A., Ata S.A., Shraim S.A.. The safety assessment of toxic metals in commonly used pharmaceutical herbal products and traditional herbs for infants in jordanian market. Biological Trace Element Research. 2019;187:307-315. https://doi.org/10.1007/s12011-018-1367-1
[Google Scholar]
Ruiz M.E.. Risks of self-medication practices. Current Drug Safety. 2010;5:315-323. https://doi.org/10.2174/157488610792245966
[Google Scholar]
Sansgiry S., Bhansali A., Bapat S., Xu Q.. Abuse of over-the-counter medicines: A pharmacist’s perspective. Integrated Pharmacy Research and Practice. 2016;6:1-6. https://doi.org/10.2147/iprp.s103494
[Google Scholar]
Cooper R.J.. ‘I can’t be an addict. I am.’ Over-the-counter medicine abuse: A qualitative study. BMJ Open. 2013;3:e002913. https://doi.org/10.1136/bmjopen-2013-002913
[Google Scholar]
Ylä-Rautio H., Siissalo S., Leikola S.. Drug-related problems and pharmacy interventions in non-prescription medication, with a focus on high-risk over-the-counter medications. International Journal of Clinical Pharmacy. 2020;42:786-795. https://doi.org/10.1007/s11096-020-00984-8
[Google Scholar]
Sánchez-Sánchez E., Fernández-Cerezo F.L., Díaz-Jimenez J., Rosety-Rodriguez M., Díaz A.J., Ordonez F.J., Rosety M.Á, Rosety I.. Consumption of over-the-counter drugs: Prevalence and type of drugs. International Journal of Environmental Research and Public Health. 2021;18:5530. https://doi.org/10.3390/ijerph18115530
[Google Scholar]
Reay G., MP B. I.. All-party parliamentary drugs misuse group. An inquiry into physical dependence and addiction to prescription and over-the-counter medication. London: All-Party Parliamentary Drugs Misuse Group; 2009. [Last accessed 2024 March 23]. Available from https://d3hgrlq6yacptf.cloudfront.net/5f44fd4229433/content/pages/documents/1506087965.pdf
RCGP. Addiction to medicines consensus statement, Royal College of General Practitioners; [Last accessed 2024 March 23]. Available from https://www.judiciary.uk/wp-content/uploads/2017/12/2017-0320-Response-by-RCGP.pdf
USP, ICH. United States Pharmacopeial and International council for harmonisation guideline for elemental impurities Q3D(R2) (Center for Drug Evaluation and Research); [Last accessed 2023 January 19]. Available from https://database.ich.org/sites/default/files/Q3D-R2_Guideline_Step4_2022_0308.pdf.
Aleluia A.C.M., Nascimento M.deS., dos Santos A.M.P., dos Santos W.N.L., de Freitas Santos Júnior A., Ferreira S.L.C.. Analytical approach of elemental impurities in pharmaceutical products: A worldwide review. Spectrochimica Acta Part B: Atomic Spectroscopy. 2023;205:106689. https://doi.org/10.1016/j.sab.2023.106689
[Google Scholar]
Santos Júnior A.íbal, Sá R., Silva L., Magalhães H., Tarantino T., Korn M.. In vitro monitoring of macro and microelements in multimineral preparations across dissolution profiles by inductively coupled plasma optical emission spectrometry (ICP OES) Journal of the Brazilian Chemical Society. 2017;28:2163-2171. https://doi.org/10.21577/0103-5053.20170065
[Google Scholar]
Liba A., McCurdy E.. Proposed new USP general chapters <232> and <233> for elemental impurities: The application of ICP-MS for pharmaceutical analysis. Agilent publication 2011:1-6. [Last accessed 2022 June 06]. Available from https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=bde473c0276c1d77f885943ebd151595b3b335ef.
[Google Scholar]
Villarreal, V., Castro, M.J. Exposure to lead and other heavy metals: Child development outcomes. In: Pediatric Neurotoxicology (Cham: Springer International Publishing), 143-165. https://doi.org/10.1007/978-3-319-32358-9_8
Selevan S.G., Kimmel C.A., Mendola P.. Identifying critical windows of exposure for children’s health. Environ Health Perspect. 2000;108:451. https://doi.org/10.2307/3454536
[Google Scholar]
Moya J., Bearer C.F., Etzel R.A.. Children’s behavior and physiology and how it affects exposure to environmental contaminants. Pediatrics. 2004;113:996-1006. https://doi.org/10.1542/peds.113.s3.996
[Google Scholar]
ATSDR. Principles of Pediatric Environmental Health Agency for Toxic Substances and Disease Registry; [Last accessed 2024 April 15]. Available from https://www.atsdr.cdc.gov/csem/ped_env_health/docs/ped_env_health.pdf
Schneider J.S., Decamp E.. Postnatal lead poisoning impairs behavioral recovery following brain damage. Neurotoxicology. 2007;28:1153-1157. https://doi.org/10.1016/j.neuro.2007.06.007
[Google Scholar]
DeStefano A., Zaidi K., Cecil T., Giancaspro G., USP E.I.A.P.. Elemental Impurities-Information. The United States Pharmacopeial Convention. 2010;36:2-9. [Last accessed 2024 April 21]. Available from https://www.usp.org/sites/default/files/usp/document/our-work/chemical-medicines/key-issues/elementalImpuritiesInformation.pdf.
[Google Scholar]
EFSA. Scientific opinion on arsenic in food. EFSA Journal. 2009;7:1351. https://doi.org/10.2903/j.efsa.2009.1351
[Google Scholar]
EFSA, Schrenk D., Bignami M., Bodin L., Chipman J.K., Del Mazo J., Grasl-Kraupp B., Hogstrand C., Hoogenboom L.R., Leblanc J.C., Nebbia C.S., Nielsen E., Ntzani E., Petersen A., Sand S., Vleminckx C., Wallace H., Barregård L., Benford D., Broberg K., Dogliotti E., Fletcher T., Rylander L., Abrahantes J.C., Gómez Ruiz J.Á, Steinkellner H., Tauriainen T., Schwerdtle T.. Update of the risk assessment of inorganic arsenic in food. EFSA journal. European Food Safety Authority. 2024;22:e8488. https://doi.org/10.2903/j.efsa.2024.8488
[Google Scholar]
FAO WHO. General standard for contaminants and toxins in food and feed (CXS 193–1995) Food and Agriculture Organization of the United Nations. 2019;44 [Last accessed 2022 April 11]. Available from https://knowledge4policy.ec.europa.eu/publication/general-standard-contaminants-toxins-food-feed-codex-stan-193-1995_en.
[Google Scholar]
Marathe P.A., Kamat S.K., Tripathi R.K., Raut S.B., Khatri N.P.. Over-the-counter medicines: Global perspective and Indian scenario. Journal of Postgraduate Medicine. 2020;66:28-34. https://doi.org/10.4103/jpgm.JPGM_381_19
[Google Scholar]
MHRA. Joins international partnerships to set global standards for medicines and medical devices regulation. Medicines and Healthcare products Regulatory Agency; [Last accessed 2024 September 22]. Available from https://www.gov.uk/government/news/mhra-joins-international-partnerships-to-set-global-standards-for-medicines-and-medical-devices-regulation--2.
SFDA. General Considerations for Preclinical Studies Submissions. 2024 [Last accessed on 22 September] Available from https://www.sfda.gov.sa/sites/default/files/2024-03/General-ConsiderationsPreclinicalStudiesSubmissions.pdf
[Google Scholar]
CDSCO. Pharmaceutical Standards and Guidelines. 2023 [Last accessed on 22 September 2024] Available from https://cdsco.gov.in/opencms/opencms/en/Home
[Google Scholar]
Parente E.. Elemental and inorganic impurities. In: Specification of Drug Substances and Products. Elsevier; 2020. p. :367-392. https://doi.org/10.1016/B978-0-08-102824-7.00014-2
[Google Scholar]
Abou-Arab A.A.K., Soliman Kawther M., El Tantawy M.E., Badeaa R.I., Khayria N.. Quantity estimation of some contaminants in commonly used medicinal plants in the Egyptian market. Food Chemistry. 1999;67:357-363. https://doi.org/10.1016/s0308-8146(99)00082-5
[Google Scholar]
Hina B., Rizwani G.H., Naseem S.. Determination of toxic metals in some herbal drugs through atomic absorption spectroscopy. Pakistan Journal of Pharmaceutical Sciences. 2011;24:353-358. PMID: 21715269.
[Google Scholar]
Siriangkhawut W., Sittichan P., Ponhong K., Chantiratikul P.. Quality assessment of trace Cd and Pb contaminants in Thai herbal medicines using ultrasound-assisted digestion prior to flame atomic absorption spectrometry. Journal of Food and Drug Analysis. 2017;25:960-967. https://doi.org/10.1016/j.jfda.2016.12.011
[Google Scholar]
Gonçalves D.A., de Souza I.D., Rosa A.C.G., Melo E.S.P., ádua, Goncalves A.-M.B., de Oliveira L.C.S., do Nascimento V.A.. Multi-wavelength calibration: Determination of trace toxic elements in medicine plants by ICP OES. Microchemical Journal. 2019;146:381-386. https://doi.org/10.1016/j.microc.2019.01.021
[Google Scholar]
Yang C.M., Chien M.Y., Chao P.C., Huang C.M., Chen C.H.. Investigation of toxic heavy metals content and estimation of potential health risks in Chinese herbal medicine. Journal of Hazardous Materials. 2021;412:125142. https://doi.org/10.1016/j.jhazmat.2021.125142
[Google Scholar]
Jayawardene I., Saper R., Lupoli N., Sehgal A., Wright R.O., Amarasiriwardena C.. Determination of in vitro bioaccessibility of Pb, As, Cd and Hg in selected traditional Indian medicines. Journal of Analytical Atomic Spectrometry. 2010;25:1275-1282. https://doi.org/10.1039/C003960H
[Google Scholar]
Shen Y., Zheng C., Jiang X., Wu X., Hou X.. Integration of hydride generation and photochemical vapor generation for multi-element analysis of traditional Chinese medicine by ICP-OES. Microchemical Journal. 2015;123:164-169. https://doi.org/10.1016/j.microc.2015.06.002
[Google Scholar]
Jin P., Liang X., Xia L., Jahouh F., Wang R., Kuang Y., Hu X.. Determination of 20 trace elements and arsenic species for a realgar-containing traditional Chinese medicine Niuhuang Jiedu tablets by direct inductively coupled plasma–mass spectrometry and high performance liquid chromatography–inductively coupled plasma–mass spectrometry. Journal of Trace Elements in Medicine and Biology. 2016;33:73-80. https://doi.org/10.1016/j.jtemb.2015.09.006
[Google Scholar]
Khandpur S., Malhotra A.K., Bhatia V., Gupta S., Sharma V.K., Mishra R., Arora N.K.. Chronic arsenic toxicity from Ayurvedic medicines. International Journal of Dermatology. 2008;47:618-621. https://doi.org/10.1111/j.1365-4632.2008.03475.x
[Google Scholar]
Hedegaard R.V., Rokkjær I., Sloth J.J.. Total and inorganic arsenic in dietary supplements based on herbs, other botanicals and algae—a possible contributor to inorganic arsenic exposure. Analytical and Bioanalytical Chemistry. 2013;405:4429-4435. https://doi.org/10.1007/s00216-013-6835-z
[Google Scholar]
Nduka J.K., Kelle H.I., Ogoko E.C.. Hazards and risk assessment of heavy metals from consumption of locally manufactured painkiller drugs in Nigeria. Toxicology Reports. 2020;7:1066-1074. https://doi.org/10.1016/j.toxrep.2020.08.009
[Google Scholar]
Wolle M.M., Rahman G.M.M., ‘Skip’ Kingston H.M., Pamuku M.. Speciation analysis of arsenic in prenatal and children’s dietary supplements using microwave-enhanced extraction and ion chromatography–inductively coupled plasma mass spectrometry. Analytica Chimica Acta. 2014;818:23-31. https://doi.org/10.1016/j.aca.2014.01.060
[Google Scholar]
Avula B., Wang Y.H., Smillie T.J., Duzgoren-Aydin N.S., Khan I.A.. Quantitative determination of multiple elements in botanicals and dietary supplements using ICP-MS. Journal of Agricultural and Food Chemistry. 2010;58:8887-8894. https://doi.org/10.1021/jf101598g
[Google Scholar]
Thiab S.H.. The Development of Analytical Procedures for Analysis of Trace Metals in Pharmaceutical Formulations and the Speciation of Arsenic in Antacids. Journal 2018 [Last accessed 2024 April 15]. Available from https://www.researchgate.net/publication/360521849_The_Development_of_Analytical_Procedures_for_Analysis_of_Trace_Metals_in_Pharmaceutical_Formulations_and_the_Speciation_of_Arsenic_in_Antacids
[Google Scholar]
Holmfred E., Alrijjal A., Chamberlain C.P., Maher K., Stürup S.. Determination of trace elements in ibuprofen drug products using microwave-assisted acid digestion and inductively coupled plasma-mass spectrometry. Heliyon. 2023;10:e23566. https://doi.org/10.1016/j.heliyon.2023.e23566
[Google Scholar]
Orisakwe O.E., Nduka J.K.. Lead and cadmium levels of commonly administered pediatric syrups in Nigeria: A public health concern? Science of the Total Environment. 2009;407:5993-5996. https://doi.org/10.1016/j.scitotenv.2009.08.033
[Google Scholar]
Dolan S.P., Nortrup D.A., Bolger P.M., Capar S.G.. Analysis of dietary supplements for arsenic, cadmium, mercury, and lead using inductively coupled plasma mass spectrometry. Journal of Agricultural and Food Chemistry. 2003;51:1307-1312. https://doi.org/10.1021/jf026055x
[Google Scholar]
Waheed S., Rahman S., Siddique N., Faiz Y.. Calcium supplements as additional source of trace elements in health and disease Part 1: Adequacy and safety of chelated calcium supplements. Journal of Radioanalytical and Nuclear Chemistry. 2013;298:1453-1461. https://doi.org/10.1007/s10967-013-2550-7
[Google Scholar]
Corazza M.Z., Tarley C., ésarR. T.. Development and feasibility of emulsion breaking method for the extraction of cadmium from omega-3 dietary supplements and determination by flow injection TS-FF-AAS. Microchemical Journal. 2016;127:145-151. https://doi.org/10.1016/j.microc.2016.02.021
[Google Scholar]
Jancevska K., Petrushevski G., Bogdanoska M., Stafilov T., Ugarkovic S.. ICP-OES elemental impurities study on different pharmaceutical dosage forms of Ibuprofen using microwave-assisted digestion procedure. Macedonian Journal of Chemistry and Chemical Engineering. 2021;40:35. https://doi.org/10.20450/mjcce.2021.2100
[Google Scholar]
Kauffman J.F., Westenberger B.J., Robertson J.D., Guthrie J., Jacobs A., Cummins S.K.. Lead in pharmaceutical products and dietary supplements. Regulatory Toxicology and Pharmacology. 2007;48:128-134. https://doi.org/10.1016/j.yrtph.2007.03.001
[Google Scholar]
Kim M., Kim C., Song I.. Analysis of lead in 55 brands of dietary calcium supplements by graphite furnace atomic absorption spectrometry after microwave digestion. Food Additives & Contaminants. 2003;20:149-153. https://doi.org/10.1080/0265203021000053588
[Google Scholar]
Barbosa U.A., dos Santos I.F., dos Santos A.M.P., Ferreira S.L.C.. Determination of Lead in iron supplements by electrothermal atomization atomic absorption spectrometry. Analytical Letters. 2016;49:799-807. https://doi.org/10.1080/00032719.2015.1079206
[Google Scholar]
Kowalski A., Frankowski M.. Levels and potential health risks of mercury in prescription, non-prescription medicines and dietary supplements in Poland. Regulatory Toxicology and Pharmacology. 2015;73:396-400. https://doi.org/10.1016/j.yrtph.2015.08.001
[Google Scholar]
Ayush-GOV. 2023. Ministry of Ayush, Ayush Services. Retrieved 20 May 2023, Available from: https://www.ayush.gov.in/.
NHS. Prescribing of over the counter medicines is changing. 2018 [Last accessed 2024 April 15]. Available from https://www.england.nhs.uk/wp-content/uploads/2018/08/1a-over-the-counter-leaflet-v1.pdf
[Google Scholar]
SFDA. Drugs List. 2023 [Last accessed 2024 April 15]. Available from https://www.sfda.gov.sa/en/drugs-list
[Google Scholar]
USP. United States Pharmacopeia (USP) Elemental Impurities Procedures. 2015 [Last accessed 2024 April 15]. Available from https://www.usp.org/sites/default/files/usp/document/our-work/chemical-medicines/key-issues/c233.pdf
[Google Scholar]
USP. Complete Sample Preparation Guide for Analysis of Elemental Impurities USP 232/233. 2017 [Last accessed 2024 April 21]. Available from https://www.usp.org/sites/default/files/usp/document/harmonization/gen-chapter/20250425HSm5193.pdf
[Google Scholar]
Colman A.M.. Tukey-HSD test. A Dictionary of Psychology, Oxford University Press; 2008. DOI: 10.1093/acref/9780199534067.001.0001
Socscistatistics. Tukey Q Critical Values Calculator Social Science Statistics Retrieved 24 August 2023, Available from: https://www.socscistatistics.com/pvalues/qcalculator.aspx.
Anderson C., Rolfe P., Brennan-Hunter A.. Administration of over-the-counter medication to children at home--a survey of parents from community health centers. Journal of Community Health Nursing. 2013;30:143-154. https://doi.org/10.1080/07370016.2013.806716
[Google Scholar]
FDA. Lead in Food and Foodwares. 2022 US Food and Drug Administration [last accessed on 6 March 2025] Available from https://www.fda.gov/food/environmental-contaminants-food/lead-food-and-foodwares
[Google Scholar]
ATSDR. Lead Toxicity. 2017 Agency For Toxic Substances and Disease Registry. [Last accessed on 10 May 2023] Available from https://www.atsdr.cdc.gov/toxprofiles/tp13-c1-b.pdf
[Google Scholar]
Hildebrand M.P.. Lead toxicity in a newborn. Journal of Pediatric Health Care : Official Publication of National Association of Pediatric Nurse Associates & Practitioners. 2011;25:328-331. https://doi.org/10.1016/j.pedhc.2011.03.008
[Google Scholar]
CDC. Lead in Foods, Cosmetics, and Medicines. Journal 2024
[Google Scholar]
Birchley N., Conroy S.. Parental management of over-the-counter medicines. Paediatric Nursing. 2002;14:24-28. https://doi.org/10.7748/paed.14.9.24.s21
[Google Scholar]
Daifallah A., Jabr R., Al-Tawil F., Elkourdi M., Salman Z., Koni A., Samara A., Al-Jabi S.W., Zyoud S.’edH.. An assessment of parents’ knowledge and awareness regarding paracetamol use in children: A cross-sectional study from Palestine. BMC Public Health. 2021;21 https://doi.org/10.1186/s12889-021-10432-5
[Google Scholar]
Wanni Arachchi T.I., Gamage M.W.K., Jayasinghe S.S.. Administration of paracetamol to children; do parents adhere to recommendations? Galle Medical Journal. 2019;23:15. https://doi.org/10.4038/gmj.v23i2.7977
[Google Scholar]

1. Introduction

2. Materials and Methods

2.1. Data & data quality objectives (DQOs)
2.2. Samples
2.3. Sample preparation and analysis
2.4. Statistical test for input variables

3. Results and Discussion

3.1. Analytical quality control data
3.2. EIs concentrations in OTC medicines.
3.3. Trace element daily exposure and health risk assessment

4. Conclusions

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[1] Li G., Schoneker D., Ulman K.L., Sturm J.J., Thackery L.M., Kauffman J.F.. Elemental impurities in pharmaceutical excipients. Journal of Pharmaceutical Sciences. 2015;104:4197-4206. https://doi.org/10.1002/jps.24650
[Google Scholar]

[2] Barin J.S., Mello P.A., Mesko M.F., Duarte F.A., Flores E.M.. Determination of elemental impurities in pharmaceutical products and related matrices by ICP-based methods: A review. Analytical and Bioanalytical Chemistry. 2016;408:4547-4566. https://doi.org/10.1007/s00216-016-9471-6
[Google Scholar]

[3] IARC. List of classifications by cancer sites with sufficient or limited evidence in humans. International Agency for Research on Cancer 2019:1-130. Retrieved 13 February 2022, from https://monographs.iarc.who.int/wp-content/uploads/2019/07/Classifications_by_cancer_site.pdf
[Google Scholar]

[4] Poulin J., Gibb H., Prüss-Üstün A.World Health Organization. Mercury: Assessing the environmental burden of disease at national and local levels, p 10; [Last accessed 2024 March 23]. Available from: https://iris.who.int/handle/10665/43875

[5] Mondal D., Polya D.A.. Rice is a major exposure route for arsenic in Chakdaha block, Nadia district, West Bengal, India: A probabilistic risk assessment. Applied Geochemistry. 2008;23:2987-2998. https://doi.org/10.1016/j.apgeochem.2008.06.025
[Google Scholar]

[6] Alhusban A.A., Ata S.A., Shraim S.A.. The safety assessment of toxic metals in commonly used pharmaceutical herbal products and traditional herbs for infants in jordanian market. Biological Trace Element Research. 2019;187:307-315. https://doi.org/10.1007/s12011-018-1367-1
[Google Scholar]

[7] Ruiz M.E.. Risks of self-medication practices. Current Drug Safety. 2010;5:315-323. https://doi.org/10.2174/157488610792245966
[Google Scholar]

[8] Sansgiry S., Bhansali A., Bapat S., Xu Q.. Abuse of over-the-counter medicines: A pharmacist’s perspective. Integrated Pharmacy Research and Practice. 2016;6:1-6. https://doi.org/10.2147/iprp.s103494
[Google Scholar]

[9] Cooper R.J.. ‘I can’t be an addict. I am.’ Over-the-counter medicine abuse: A qualitative study. BMJ Open. 2013;3:e002913. https://doi.org/10.1136/bmjopen-2013-002913
[Google Scholar]

[10] Ylä-Rautio H., Siissalo S., Leikola S.. Drug-related problems and pharmacy interventions in non-prescription medication, with a focus on high-risk over-the-counter medications. International Journal of Clinical Pharmacy. 2020;42:786-795. https://doi.org/10.1007/s11096-020-00984-8
[Google Scholar]

[11] Sánchez-Sánchez E., Fernández-Cerezo F.L., Díaz-Jimenez J., Rosety-Rodriguez M., Díaz A.J., Ordonez F.J., Rosety M.Á, Rosety I.. Consumption of over-the-counter drugs: Prevalence and type of drugs. International Journal of Environmental Research and Public Health. 2021;18:5530. https://doi.org/10.3390/ijerph18115530
[Google Scholar]

[12] Reay G., MP B. I.. All-party parliamentary drugs misuse group. An inquiry into physical dependence and addiction to prescription and over-the-counter medication. London: All-Party Parliamentary Drugs Misuse Group; 2009. [Last accessed 2024 March 23]. Available from https://d3hgrlq6yacptf.cloudfront.net/5f44fd4229433/content/pages/documents/1506087965.pdf

[13] RCGP. Addiction to medicines consensus statement, Royal College of General Practitioners; [Last accessed 2024 March 23]. Available from https://www.judiciary.uk/wp-content/uploads/2017/12/2017-0320-Response-by-RCGP.pdf

[14] USP, ICH. United States Pharmacopeial and International council for harmonisation guideline for elemental impurities Q3D(R2) (Center for Drug Evaluation and Research); [Last accessed 2023 January 19]. Available from https://database.ich.org/sites/default/files/Q3D-R2_Guideline_Step4_2022_0308.pdf.

[15] Aleluia A.C.M., Nascimento M.deS., dos Santos A.M.P., dos Santos W.N.L., de Freitas Santos Júnior A., Ferreira S.L.C.. Analytical approach of elemental impurities in pharmaceutical products: A worldwide review. Spectrochimica Acta Part B: Atomic Spectroscopy. 2023;205:106689. https://doi.org/10.1016/j.sab.2023.106689
[Google Scholar]

[16] Santos Júnior A.íbal, Sá R., Silva L., Magalhães H., Tarantino T., Korn M.. In vitro monitoring of macro and microelements in multimineral preparations across dissolution profiles by inductively coupled plasma optical emission spectrometry (ICP OES) Journal of the Brazilian Chemical Society. 2017;28:2163-2171. https://doi.org/10.21577/0103-5053.20170065
[Google Scholar]

[17] Liba A., McCurdy E.. Proposed new USP general chapters <232> and <233> for elemental impurities: The application of ICP-MS for pharmaceutical analysis. Agilent publication 2011:1-6. [Last accessed 2022 June 06]. Available from https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=bde473c0276c1d77f885943ebd151595b3b335ef.
[Google Scholar]

[18] Villarreal, V., Castro, M.J. Exposure to lead and other heavy metals: Child development outcomes. In: Pediatric Neurotoxicology (Cham: Springer International Publishing), 143-165. https://doi.org/10.1007/978-3-319-32358-9_8

[19] Selevan S.G., Kimmel C.A., Mendola P.. Identifying critical windows of exposure for children’s health. Environ Health Perspect. 2000;108:451. https://doi.org/10.2307/3454536
[Google Scholar]

[20] Moya J., Bearer C.F., Etzel R.A.. Children’s behavior and physiology and how it affects exposure to environmental contaminants. Pediatrics. 2004;113:996-1006. https://doi.org/10.1542/peds.113.s3.996
[Google Scholar]

[21] ATSDR. Principles of Pediatric Environmental Health Agency for Toxic Substances and Disease Registry; [Last accessed 2024 April 15]. Available from https://www.atsdr.cdc.gov/csem/ped_env_health/docs/ped_env_health.pdf

[22] Schneider J.S., Decamp E.. Postnatal lead poisoning impairs behavioral recovery following brain damage. Neurotoxicology. 2007;28:1153-1157. https://doi.org/10.1016/j.neuro.2007.06.007
[Google Scholar]

[23] DeStefano A., Zaidi K., Cecil T., Giancaspro G., USP E.I.A.P.. Elemental Impurities-Information. The United States Pharmacopeial Convention. 2010;36:2-9. [Last accessed 2024 April 21]. Available from https://www.usp.org/sites/default/files/usp/document/our-work/chemical-medicines/key-issues/elementalImpuritiesInformation.pdf.
[Google Scholar]

[24] EFSA. Scientific opinion on arsenic in food. EFSA Journal. 2009;7:1351. https://doi.org/10.2903/j.efsa.2009.1351
[Google Scholar]

[25] EFSA, Schrenk D., Bignami M., Bodin L., Chipman J.K., Del Mazo J., Grasl-Kraupp B., Hogstrand C., Hoogenboom L.R., Leblanc J.C., Nebbia C.S., Nielsen E., Ntzani E., Petersen A., Sand S., Vleminckx C., Wallace H., Barregård L., Benford D., Broberg K., Dogliotti E., Fletcher T., Rylander L., Abrahantes J.C., Gómez Ruiz J.Á, Steinkellner H., Tauriainen T., Schwerdtle T.. Update of the risk assessment of inorganic arsenic in food. EFSA journal. European Food Safety Authority. 2024;22:e8488. https://doi.org/10.2903/j.efsa.2024.8488
[Google Scholar]

[26] FAO WHO. General standard for contaminants and toxins in food and feed (CXS 193–1995) Food and Agriculture Organization of the United Nations. 2019;44 [Last accessed 2022 April 11]. Available from https://knowledge4policy.ec.europa.eu/publication/general-standard-contaminants-toxins-food-feed-codex-stan-193-1995_en.
[Google Scholar]

[27] Marathe P.A., Kamat S.K., Tripathi R.K., Raut S.B., Khatri N.P.. Over-the-counter medicines: Global perspective and Indian scenario. Journal of Postgraduate Medicine. 2020;66:28-34. https://doi.org/10.4103/jpgm.JPGM_381_19
[Google Scholar]

[28] MHRA. Joins international partnerships to set global standards for medicines and medical devices regulation. Medicines and Healthcare products Regulatory Agency; [Last accessed 2024 September 22]. Available from https://www.gov.uk/government/news/mhra-joins-international-partnerships-to-set-global-standards-for-medicines-and-medical-devices-regulation--2.

[29] SFDA. General Considerations for Preclinical Studies Submissions. 2024 [Last accessed on 22 September] Available from https://www.sfda.gov.sa/sites/default/files/2024-03/General-ConsiderationsPreclinicalStudiesSubmissions.pdf
[Google Scholar]

[30] CDSCO. Pharmaceutical Standards and Guidelines. 2023 [Last accessed on 22 September 2024] Available from https://cdsco.gov.in/opencms/opencms/en/Home
[Google Scholar]

[31] Parente E.. Elemental and inorganic impurities. In: Specification of Drug Substances and Products. Elsevier; 2020. p. :367-392. https://doi.org/10.1016/B978-0-08-102824-7.00014-2
[Google Scholar]

[32] Abou-Arab A.A.K., Soliman Kawther M., El Tantawy M.E., Badeaa R.I., Khayria N.. Quantity estimation of some contaminants in commonly used medicinal plants in the Egyptian market. Food Chemistry. 1999;67:357-363. https://doi.org/10.1016/s0308-8146(99)00082-5
[Google Scholar]

[33] Hina B., Rizwani G.H., Naseem S.. Determination of toxic metals in some herbal drugs through atomic absorption spectroscopy. Pakistan Journal of Pharmaceutical Sciences. 2011;24:353-358. PMID: 21715269.
[Google Scholar]

[34] Siriangkhawut W., Sittichan P., Ponhong K., Chantiratikul P.. Quality assessment of trace Cd and Pb contaminants in Thai herbal medicines using ultrasound-assisted digestion prior to flame atomic absorption spectrometry. Journal of Food and Drug Analysis. 2017;25:960-967. https://doi.org/10.1016/j.jfda.2016.12.011
[Google Scholar]

[35] Gonçalves D.A., de Souza I.D., Rosa A.C.G., Melo E.S.P., ádua, Goncalves A.-M.B., de Oliveira L.C.S., do Nascimento V.A.. Multi-wavelength calibration: Determination of trace toxic elements in medicine plants by ICP OES. Microchemical Journal. 2019;146:381-386. https://doi.org/10.1016/j.microc.2019.01.021
[Google Scholar]

[36] Yang C.M., Chien M.Y., Chao P.C., Huang C.M., Chen C.H.. Investigation of toxic heavy metals content and estimation of potential health risks in Chinese herbal medicine. Journal of Hazardous Materials. 2021;412:125142. https://doi.org/10.1016/j.jhazmat.2021.125142
[Google Scholar]

[37] Jayawardene I., Saper R., Lupoli N., Sehgal A., Wright R.O., Amarasiriwardena C.. Determination of in vitro bioaccessibility of Pb, As, Cd and Hg in selected traditional Indian medicines. Journal of Analytical Atomic Spectrometry. 2010;25:1275-1282. https://doi.org/10.1039/C003960H
[Google Scholar]

[38] Shen Y., Zheng C., Jiang X., Wu X., Hou X.. Integration of hydride generation and photochemical vapor generation for multi-element analysis of traditional Chinese medicine by ICP-OES. Microchemical Journal. 2015;123:164-169. https://doi.org/10.1016/j.microc.2015.06.002
[Google Scholar]

[39] Jin P., Liang X., Xia L., Jahouh F., Wang R., Kuang Y., Hu X.. Determination of 20 trace elements and arsenic species for a realgar-containing traditional Chinese medicine Niuhuang Jiedu tablets by direct inductively coupled plasma–mass spectrometry and high performance liquid chromatography–inductively coupled plasma–mass spectrometry. Journal of Trace Elements in Medicine and Biology. 2016;33:73-80. https://doi.org/10.1016/j.jtemb.2015.09.006
[Google Scholar]

[40] Khandpur S., Malhotra A.K., Bhatia V., Gupta S., Sharma V.K., Mishra R., Arora N.K.. Chronic arsenic toxicity from Ayurvedic medicines. International Journal of Dermatology. 2008;47:618-621. https://doi.org/10.1111/j.1365-4632.2008.03475.x
[Google Scholar]

[41] Hedegaard R.V., Rokkjær I., Sloth J.J.. Total and inorganic arsenic in dietary supplements based on herbs, other botanicals and algae—a possible contributor to inorganic arsenic exposure. Analytical and Bioanalytical Chemistry. 2013;405:4429-4435. https://doi.org/10.1007/s00216-013-6835-z
[Google Scholar]

[42] Nduka J.K., Kelle H.I., Ogoko E.C.. Hazards and risk assessment of heavy metals from consumption of locally manufactured painkiller drugs in Nigeria. Toxicology Reports. 2020;7:1066-1074. https://doi.org/10.1016/j.toxrep.2020.08.009
[Google Scholar]

[43] Wolle M.M., Rahman G.M.M., ‘Skip’ Kingston H.M., Pamuku M.. Speciation analysis of arsenic in prenatal and children’s dietary supplements using microwave-enhanced extraction and ion chromatography–inductively coupled plasma mass spectrometry. Analytica Chimica Acta. 2014;818:23-31. https://doi.org/10.1016/j.aca.2014.01.060
[Google Scholar]

[44] Avula B., Wang Y.H., Smillie T.J., Duzgoren-Aydin N.S., Khan I.A.. Quantitative determination of multiple elements in botanicals and dietary supplements using ICP-MS. Journal of Agricultural and Food Chemistry. 2010;58:8887-8894. https://doi.org/10.1021/jf101598g
[Google Scholar]

[45] Thiab S.H.. The Development of Analytical Procedures for Analysis of Trace Metals in Pharmaceutical Formulations and the Speciation of Arsenic in Antacids. Journal 2018 [Last accessed 2024 April 15]. Available from https://www.researchgate.net/publication/360521849_The_Development_of_Analytical_Procedures_for_Analysis_of_Trace_Metals_in_Pharmaceutical_Formulations_and_the_Speciation_of_Arsenic_in_Antacids
[Google Scholar]

[46] Holmfred E., Alrijjal A., Chamberlain C.P., Maher K., Stürup S.. Determination of trace elements in ibuprofen drug products using microwave-assisted acid digestion and inductively coupled plasma-mass spectrometry. Heliyon. 2023;10:e23566. https://doi.org/10.1016/j.heliyon.2023.e23566
[Google Scholar]

[47] Orisakwe O.E., Nduka J.K.. Lead and cadmium levels of commonly administered pediatric syrups in Nigeria: A public health concern? Science of the Total Environment. 2009;407:5993-5996. https://doi.org/10.1016/j.scitotenv.2009.08.033
[Google Scholar]

[48] Dolan S.P., Nortrup D.A., Bolger P.M., Capar S.G.. Analysis of dietary supplements for arsenic, cadmium, mercury, and lead using inductively coupled plasma mass spectrometry. Journal of Agricultural and Food Chemistry. 2003;51:1307-1312. https://doi.org/10.1021/jf026055x
[Google Scholar]

[49] Waheed S., Rahman S., Siddique N., Faiz Y.. Calcium supplements as additional source of trace elements in health and disease Part 1: Adequacy and safety of chelated calcium supplements. Journal of Radioanalytical and Nuclear Chemistry. 2013;298:1453-1461. https://doi.org/10.1007/s10967-013-2550-7
[Google Scholar]

[50] Corazza M.Z., Tarley C., ésarR. T.. Development and feasibility of emulsion breaking method for the extraction of cadmium from omega-3 dietary supplements and determination by flow injection TS-FF-AAS. Microchemical Journal. 2016;127:145-151. https://doi.org/10.1016/j.microc.2016.02.021
[Google Scholar]

[51] Jancevska K., Petrushevski G., Bogdanoska M., Stafilov T., Ugarkovic S.. ICP-OES elemental impurities study on different pharmaceutical dosage forms of Ibuprofen using microwave-assisted digestion procedure. Macedonian Journal of Chemistry and Chemical Engineering. 2021;40:35. https://doi.org/10.20450/mjcce.2021.2100
[Google Scholar]

[52] Kauffman J.F., Westenberger B.J., Robertson J.D., Guthrie J., Jacobs A., Cummins S.K.. Lead in pharmaceutical products and dietary supplements. Regulatory Toxicology and Pharmacology. 2007;48:128-134. https://doi.org/10.1016/j.yrtph.2007.03.001
[Google Scholar]

[53] Kim M., Kim C., Song I.. Analysis of lead in 55 brands of dietary calcium supplements by graphite furnace atomic absorption spectrometry after microwave digestion. Food Additives & Contaminants. 2003;20:149-153. https://doi.org/10.1080/0265203021000053588
[Google Scholar]

[54] Barbosa U.A., dos Santos I.F., dos Santos A.M.P., Ferreira S.L.C.. Determination of Lead in iron supplements by electrothermal atomization atomic absorption spectrometry. Analytical Letters. 2016;49:799-807. https://doi.org/10.1080/00032719.2015.1079206
[Google Scholar]

[55] Kowalski A., Frankowski M.. Levels and potential health risks of mercury in prescription, non-prescription medicines and dietary supplements in Poland. Regulatory Toxicology and Pharmacology. 2015;73:396-400. https://doi.org/10.1016/j.yrtph.2015.08.001
[Google Scholar]

[56] Ayush-GOV. 2023. Ministry of Ayush, Ayush Services. Retrieved 20 May 2023, Available from: https://www.ayush.gov.in/.

[57] NHS. Prescribing of over the counter medicines is changing. 2018 [Last accessed 2024 April 15]. Available from https://www.england.nhs.uk/wp-content/uploads/2018/08/1a-over-the-counter-leaflet-v1.pdf
[Google Scholar]

[58] SFDA. Drugs List. 2023 [Last accessed 2024 April 15]. Available from https://www.sfda.gov.sa/en/drugs-list
[Google Scholar]

[59] USP. United States Pharmacopeia (USP) Elemental Impurities Procedures. 2015 [Last accessed 2024 April 15]. Available from https://www.usp.org/sites/default/files/usp/document/our-work/chemical-medicines/key-issues/c233.pdf
[Google Scholar]

[60] USP. Complete Sample Preparation Guide for Analysis of Elemental Impurities USP 232/233. 2017 [Last accessed 2024 April 21]. Available from https://www.usp.org/sites/default/files/usp/document/harmonization/gen-chapter/20250425HSm5193.pdf
[Google Scholar]

[61] Colman A.M.. Tukey-HSD test. A Dictionary of Psychology, Oxford University Press; 2008. DOI: 10.1093/acref/9780199534067.001.0001

[62] Socscistatistics. Tukey Q Critical Values Calculator Social Science Statistics Retrieved 24 August 2023, Available from: https://www.socscistatistics.com/pvalues/qcalculator.aspx.

[63] Anderson C., Rolfe P., Brennan-Hunter A.. Administration of over-the-counter medication to children at home--a survey of parents from community health centers. Journal of Community Health Nursing. 2013;30:143-154. https://doi.org/10.1080/07370016.2013.806716
[Google Scholar]

[64] FDA. Lead in Food and Foodwares. 2022 US Food and Drug Administration [last accessed on 6 March 2025] Available from https://www.fda.gov/food/environmental-contaminants-food/lead-food-and-foodwares
[Google Scholar]

[65] ATSDR. Lead Toxicity. 2017 Agency For Toxic Substances and Disease Registry. [Last accessed on 10 May 2023] Available from https://www.atsdr.cdc.gov/toxprofiles/tp13-c1-b.pdf
[Google Scholar]

[66] Hildebrand M.P.. Lead toxicity in a newborn. Journal of Pediatric Health Care : Official Publication of National Association of Pediatric Nurse Associates & Practitioners. 2011;25:328-331. https://doi.org/10.1016/j.pedhc.2011.03.008
[Google Scholar]

[67] CDC. Lead in Foods, Cosmetics, and Medicines. Journal 2024
[Google Scholar]

[68] Birchley N., Conroy S.. Parental management of over-the-counter medicines. Paediatric Nursing. 2002;14:24-28. https://doi.org/10.7748/paed.14.9.24.s21
[Google Scholar]

[69] Daifallah A., Jabr R., Al-Tawil F., Elkourdi M., Salman Z., Koni A., Samara A., Al-Jabi S.W., Zyoud S.’edH.. An assessment of parents’ knowledge and awareness regarding paracetamol use in children: A cross-sectional study from Palestine. BMC Public Health. 2021;21 https://doi.org/10.1186/s12889-021-10432-5
[Google Scholar]

[70] Wanni Arachchi T.I., Gamage M.W.K., Jayasinghe S.S.. Administration of paracetamol to children; do parents adhere to recommendations? Galle Medical Journal. 2019;23:15. https://doi.org/10.4038/gmj.v23i2.7977
[Google Scholar]

Analysis of trace elements (Arsenic, Cadmium, Lead, and Mercury) in over-the-counter medicines from the United Kingdom, the Kingdom of Saudi Arabia, and India

Abstract

Keywords

Heath risk assessment

Over-the-counter (OTC) medicines

Permitted Daily Exposure

Trace elements

USP <232>/<233>

1. Introduction

2. Materials and Methods

2.1. Data & data quality objectives (DQOs)

2.2. Samples

2.3. Sample preparation and analysis

2.3.1. Reagents and calibration standards

2.3.2. Accuracy and precision

2.3.3. Sample preparation

2.3.4. Analytical instrumentation

2.4. Statistical test for input variables

3. Results and Discussion

3.1. Analytical quality control data

3.2. EIs concentrations in OTC medicines.

3.3. Trace element daily exposure and health risk assessment

4. Conclusions

Acknowledgment

CRediT authorship contribution statement

Declaration of competing interest

Declaration of Generative AI and AI-assisted technologies in the writing process

Supplementary data

References

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