Gambia and Uzbekistan Children

Tragedies Cough Syrup

Contaminated with Toxic
Compounds DEG and EG

(Minor Theoretical Project)

DBT STAR College Scheme

S.D. College, Barnala

Submitted to – Dr. Kulbhushan Rana

Submitted by – Manjot Singh (2223020036)
Preeti (2223020027)
Deepmala (2223020012)
Class – B.Sc. I
 Gambia And Uzbekistan Children Tragedies:
Cough Syrup Contaminated with
Toxic Compounds, Diethylene Glycol & Ethylene Glycol
Manjot Singh*, Preeti, Deepmala and Kulbhushan Rana
Department of Chemistry, S.D. College Barnala – 148101, Punjab, India
E-mail: - [email protected]
Abstract
This paper presents an investigation into the cause of recent deaths of 69 children in Gambia and 18
children in Uzbekistan. According to WHO four substandard cough syrup variants-Promethazine oral
solution, Kofexmalin Baby Syrup, Makeoff Baby Cough Syrup and Magrip NCold Syrup whose
manufacturer is Maiden Pharmaceuticals Limited, Sonipat, Haryana are responsible for this in Gambia.
The health agency further said that laboratory analysis of samples of each of the four products has
confirmed that they contained unacceptable amount of two contaminants – diethylene glycol (DEG)
and ethylene glycol.Similarly Uzbekistan health ministry has linked the death of 18 children to cough
syrup Dok-1 Max contaminated with ethylene glycol manufactured by Noida based Marion Biotech .
The toxic effects of the two chemicals includes as pain, vomiting, diarrhoea, inability to pass urine,
altered mental state and acute kidney injury which could lead to death. Patients who survive develop
kidney failure and remain dialysis-dependent. All patients are likely to suffer significant morbidity.
Instances of contamination and deaths linked to DEG and ethylene glycol are not new. Such cases have
been reported before in India, USA, Bangladesh, Austria, Panama and Nigeria. Because of its adverse
effects on humans, DEG & Ethylene glycols are not allowed for use in food & drugs.

Keyword: - Diethylene Glycol (DEG), Ethylene Glycol, Acute Kidney Injury,Morbidity

Introduc*on :
December 2021 and December 2022 could not have been more contras6ng for for India's
pharmaceu6cal industry. In December 2021 it was hailed for developing vaccines that inoculated
billions against the Corona viruses and underlined its moniker as the pharmacy of the world .This year
two Indian drug manufacturing firms stand accused by two countries of producing toxic cough syrups
linked to the death of children, at least 69 in the Gambia and 18 in Uzbekistan. The Gambia case was
highlighted by the World Health Organisa6on1 while the second case has been flagged by the
Uzbekistan Health Ministry . In both countries batches were spiked with diethylene glycol(DEG) and
ethylene glycol(EG). These are industrial chemicals that have no business being inside boTles of
cough syrup. According to World Health Organisa6on four substandard cough syrup variants
Promethazine oral solu6on, Kofaxmalin Baby cough syrup, Make off Baby cough syrup and Magarip
N cold cough syrup whose manufacturer is Maiden Pharmaceu6cal Limited,Sonipat,Haryana are
responsible for this in Gambia.The health agency further said that laboratory analysis of samples of
each of the four products has confirmed that they contained unacceptable amount of two
contaminants diethylene glycol and ethylene glycol . Similarly Uzbekistan Health ministry has linked
the death of 18 children to cough syrup Doc-1 Max contaminated with ethylene glycol manufactured
by Noida based Marine Biotech .
The toxic effect of the two chemicals includes as pain, vomi6ng, diarrhoea, inability to pass urine,
altered mental state and acute kidney injury which could lead to death. Pa6ents who survive develop
kidney failure and remain dialysis dependent. All pa6ents are likely to suffer significant morbidity.
DEG2 and EG 3 are organic compounds with the formula (HOCH 2CH2)2O and (CH 2OH)2 respec6vely.
Both are colourless, odourless and hygroscopic liquid with sweet taste. Diethylene glycol is used in
the manufacture of saturated and unsaturated polyester resins, polyurethane and plas6cizers. DEG

is used as a building block in organic synthesis. It is also a solvent for nitrocellulose, raisins, dies, oils
and other organic compound. It is humectant for tobacco, cork, prin6ng ink and glue. It is also
component in break fluids, lubricants, wallpapers strippers and ar6ficial fog. The major use of
ethylene glycol is as an an6-freezing agent in the coolant.EG is used in the natural gas industry to
remove water vapour from the natural gas before further processing. Minor uses of Ethylene glycol
include the manufacture of capacitor. EG is also used in the manufacture of some vaccines but it is
not itself present in these injec6ons. EG is used as a protec6ng group in organic synthesis to protect
carbonyl compounds such as ketones and aldehydes. It also can be used in vaccine manufacture or
as a formaldehyde subs6tute when preserving biological specimen.

Toxicology :
Despite the discovery of DEG toxicity in 1937 and its involvement in mass poisonings around the
world the informa6on available regarding human toxicity is limited. Some authors suggest the
minimum toxic dose is es6mated at 0.14 milligram per kg of body weight and the lethal dose is
between 1 and 1.63 gram per kg of body weight4 while some suggest the LD50 in adult is of
approximately 1 ml per kg and other suggest this is the LD
30. Because of its adverse effect on human’s
diethylene glycol is not allowed for use in foods and drugs. Ethylene Glycol has been shown to be
toxic to humans5and is also toxic to domes6c pets such as cats and dog. A toxic dose requiring medical
treatment varies but is considered more than 0.1 ml per kg body weight of pure substance that is
roughly 16 ml of 50% ethylene glycol for an 80 kilogram adult and 4 ml for a 20 kilogram child. The
6
orally lethal dose in human has been reported as approximately 1.4 ml per kg of pure ethylene glycol
that is approximately 224 ml of 50% ethylene glycol for an 80 kilogram adult and 56 ml for 20
kilogram child. Ethylene Glycol has a low vapour pressure. It does not evaporate readily at normal
temperature and therefore high concentra6on in air or intoxica6ons are unlikely to occur following
inhala6onal exposure. EG is not well absorbed through skin meaning poisoning following dermal
exposures is also uncommon. The principal method of absorp6on is through oral inges6on. Dermal
absorp6on is very low unless it is administered on broken or damaged skin. Afer inges6on DEG is
absorbed through the gastrointes6nal track and distributed by the bloodstream throughout the
body, reaching peak blood concentra6on within 30 to 120 minutes. Once DEG reaches the liver it is
metabolised by enzymes4. Rat models suggest DEG is metabolised in the liver by enzyme NAD-
dependent alcohol dehydrogenase into a hydrogen ion, NADH and 2-
hydroxyethoxyacetaldehyde(C4H8O3). Shortly afer 2-hydroxyethoxyacetaldehyde is metabolised by
the enzyme aldehyde dehydrogenase into weak acid 2- hydroxyethoxyace6c acid (HEAA) with
chemical formula C 4H8O4.Later on HEAA leaves the liver through the blood stream, being par6ally
filter in the Kidneys for elimina6on. Based on available literature scien6st suggest unmetabolized
DEG and HEAA are par6ally reabsorbed through glomerular filtra6on. As a consequence, the
concentra6ons of the week acid HEAA and metabolites may cause renal delay, leading to metabolic
acidosis and further labour and kidney damage.
The three main systems affected by ethylene glycol poisonings are the central nervous nervous
system, metabolic processes and the kidney. The central nervous system is affected early in the
course of poisoning as the result of a direct ac6on of ethylene glycol. Similar to ethanol, It causes
intoxica6on followed by drowsiness or coma. Seizure may occur due to a direct effect. The toxic
mechanism of ethylene glycol poisoning is mainly due to the metabolites of EG. Ini6ally it is
metabolised by alcohol dehydrogenase (ADH) to glycolaldehyde which is then oxidized to glycolic
acid by aldehyde dehydrogenase. The increase in metabolites may cause cerebral edema. The
metabolic effects occur 12 to 36 hours post inges6on, causing metabolic acidosis which is mainly due
to a accumulated glycolic acid.
The kidney toxicity of ethylene glycol occurs 24 to 72 hours post inges6on and is caused by a direct
cytotoxic effect of glycolic acid. The glycolic acid is than metabolised to glyoxylic acid and finally to
oxalic acid. Oxalic acid binds with calcium to form calcium oxalate crystals which may deposit and
cause damage to many areas of the body including brain, heart, kidney and lungs. The most significant
effect is accumula6on of calcium oxalate crystal in the Kidneys which cause kidney damage leading
to anuric acute kidney failure. The rate limi6ng step in this cascade is the conversion of glycolic acid
to glyoxylic acid7. Accumula6on of glycolic acid in the body is mainly responsible for toxicity8.

Signs and symptoms :

The symptoms of poisoning typically occur in three characteris6c intervals2
First phase: Gastrointes6nal symptoms such as nausea, vomi6ng, abdominal pain and diarrhoea
develop. Some pa6ent may develop early neurological symptoms like altered mental status, central
nervous system, depression, coma and mild hypertension.
Second Phase: In one to three days afer inges6on pa6ents develop metabolic acidosis, which cause
acute kidney failure oliguria, increasing serum crea6nine concentra6ons and later anuria.

Final Phase: At least 5 to 10 days after ingestion most of the symptoms are related to neurological
complications such as progressive lethargy, facial paralysis, dysphonia, dilated and non-reactive
pupils, quadriplegia and coma leading to death.
Treatment :
Fomepizole and ethanol should be quickly administered to prevent diethylene glycol and ethylene
glycol poisoning.
• Fomepizole is an alcohol dehydrogenase (ADH)inhibitor with 8000 6mes more affinity than
ethanol. Fomepizole, also known as 4-methylpyrazole, is a medication used to
treat methanol and ethylene glycol poisoning. It may be used alone or together
with hemodialysis. It is given by injection into a vein. Ethylene glycol is first metabolized
to glycolaldehyde by alcohol dehydrogenase. Glycolaldehyde then undergoes further oxidation
to glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the primary toxins responsible for
the metabolic acidosis, and for the renal damage, seen in ethylene glycol poisoning.
• Methanol is first metabolized to formaldehyde by alcohol dehydrogenase. Formaldehyde then

undergoes further oxidation, via formaldehyde dehydrogenase, to become formic

acid.[6] Formic acid is the primary toxin responsible for the metabolic acidosis, and for the
visual disturbances, associated with methanol poisoning.
By competitively inhibiting the first enzyme, alcohol dehydrogenase, in the metabolism of
ethylene glycol and methanol, fomepizole slows the production of the toxic metabolites.
The slower rate of metabolite production allows the liver to process and excrete the
metabolites as they are produced, limiting the accumulation in tissues such as the kidney
and eye. As a result, much of the organ damage is avoided.
Fomepizole is most effective when given soon after ingestion of ethylene glycol or
methanol. Delaying its administration allows for the generation of harmful metabolites.
This treatment has minimal adverse effect because of constant serum concentra6on. However, it is
very expensive medica6on 9. Ethanol is compe66ve ADH substrate. A constant blood concentra6on
of 1 to1.5 gram per litre should be maintained to acceptably saturate the enzyme. For late diagnosis
where ethanol or Fomepizole is ineffec6ve because DEG has already been metabolised,
haemodialysis becomes the only treatment available 10. Haemodialysis may either be given alone or
in combina6on with ethanol or fomepizole.

Epidemiology :
The physical proper6es of DEG make it an excellent counterfeit for pharmaceu6cal grade glycerine
(glycerol) and has caused many deaths in different countries.
In 1937 – The Massengill incident (United States)

In 1937, S. E. Massengill Co. (a Tennessee drug company), manufactured sulfanilamide

dissolved with diethylene glycol, to create a liquid alternative of this drug. The company
tested the new product, Elixir sulfanilamide, for viscosity, appearance and fragrance. At the
time, the food and drug laws did not require toxicological analysis before releasing for sale.
When 105 people died in 15 states during the months of September and October, the trail
led back to the elixir, and the toxic potential of this chemical was revealed. This episode was
the impetus for the Federal Food, Drug, and Cosmetic Act of 1938. This law, though
extensively amended in subsequent years, remains the central foundation of FDA regulatory
authority to the present day.

In 1969 – South Africa

In Cape Town, South Africa, seven children developed vomiting, diarrhea, and dehydration, and died
of kidney failure after administration of over-the-counter sedatives. Soon, patients started to
present anuria, acidic breathing, hepatomegaly, and unresponsiveness. Patients were treated with
fluid hydration and correction of acidosis, but some were not able to survive. Postmortem examination
revealed damage in the kidneys and liver, and laboratory testing found DEG instead of propylene
glycol in the sedatives.

In 1985 -Spain
Five pa6ents died for being treatment for burn developed sudden a kidney failure. Further
inves6ga6on revealed all pa6ents were treated with topical silver sulfadiazine ointment that
contained 7 g/kg of DEG.
In 1985 – Austria

During the month of July 1985, Austrian wines were found to contain up to 1,000 parts per
million of DEG, giving them a desirable sweetness. Austrian wine was banned in many
countries and the U.S. Bureau of Alcohol, Tobacco and Firearms started to test all imported
wine.
In November, The New York Times published a wine recall that the Federal Government
released after the Bureau of Alcohol, Tobacco and Firearms tested 1,000 bottles. 45
Austrian, 5 German and 12 Italian wines tested positive for DEG. Some wines contained less
than 10 parts per million of DEG, a small amount that could not be detected by laboratory
analysis in Europe. This triggered the installation of more sensitive laboratory equipment in
Banafi laboratories, Italy, and stronger alcohol regulations in Austria.
After recalling millions of wine bottles, the Austrian Government experienced difficulty in
finding a way to destroy the product. During September 1986, the Ministry of Public Works
started testing a mixture of wine with salt to melt hazardous ice during winter. The primary
results revealed that the mixture was more effective than using salt alone. The next year, an
Austrian electric power plant (Österreichische Draukraftwerke) inCarinthia announced that
technicians developed a way to produce energy through burning 30 million liters of
contaminated wine.

In 1986- India
21 pa6ent’s death resulted in Bombay because of the use of glycerine contaminated with 18.5% v/
v of DEG13.

In 1990 – Nigeria
47 children died in Jos University hospital Nigeria with anuria, fever and vomi6ng because they had
received acetaminophen syrup14 contaminated with DEG to treat upper respiratory infec6ons.
In 1992 - Bangladesh

In Bangladesh between 1990 and 1992, 339 children developed kidney failure, and most of them died,
after being given paracetamol (acetaminophen) syrup contaminated with diethylene glycol. The
outbreak forced the government to ban the sale of paracetamol elixirs in December 1992, causing a
decline of 53% in the admission of patients with kidney failure and an 84% decline in admissions by
unexplained kidney failure.

In 1992 - Argen*na

A propolis syrup manufactured by Huilen lab in Buenos Aires Argen6na contained DEG and caused
the death of 29 people.
In1995-96 - Hai*
Between November 1995 and June 1996, almost 109 children admitted to the University
Hospital in Port-au-Prince, Haiti, presented with acute kidney failure. By June 1996, with no
idea what was causing the epidemic, thePan American Health Organization (PAHO) Haiti
representative contacted the World Health Organization (WHO, the parent agency of PAHO),
and WHO requested that the Centers for Disease Control and Prevention investigate.
Lead CDC investigator Dr.Katherine O'Brien conducted a case-control investigation, looking
for potential clues to the epidemic. The study revealed a strong association between
ingestion of two locally produced acetaminophen liquid products (Afebril and Valodon) and
illness. Laboratory testing at CDC of samples taken from parents revealed significant
contamination with DEG. The factory of the medication manufacturer, Pharval, was
subsequently investigated by Dr. Joel Selanikio (also of CDC, and anEpidemic Intelligence
Service classmate of Katherine O'Brien). Testing of medication samples taken from the
factory samples by both CDC and by an independent commercial lab located in Miami,
revealed contamination by DEG of 16.4% and higher. With the available technology of the
era, the CDC determined the glycerin used in the syrup preparation was contaminated with
approximately 24% DEG. As a result of the case-control findings, and subsequent
investigation at the factory, public warnings were issued by the Ministry of Health and
bottles of the two medications were taken from pharmacy shelves and destroyed. These
measures quickly ended the advance of the epidemic.
Only 88 children deaths were recalled by doctors or had medical records. Nearly half of the
victims were under the age of two.
Ending June 1996, the FDA had discovered counterfeit glycerin traced back to Chemical
Trading and Consulting (a German broker), which bought 72 barrels of the syrup from Vos
B.V., aDutch company. Vos records revealed the syrup had been bought from Sinochem
International Chemicals Company through a German trader, Metall-Chemie. In July 1996,
the American Embassy in China contacted Sinochem and requested a list of Chinese
glycerin makers, but the company refused to reveal the names. It was not until September
1996 that Sinochem provided a name of the manufacturer of the tainted syrup. They
identified Tianhong Fine Chemicals Factory as the manufacturer. While the FDA tried to find
out Tianhong's address, Chinese officials were reluctant to become involved. One year and a
half after the FDA began to trace the poisonous shipments, an inspector, Ted Sze, finally
visited the Tianhong Fine Chemicals Factory in Dalian, northeastern China. Once he was
inside, there was nothing to do: the plant had already been shut down. The Dutch
authorities assessed a $250,000 fine against Vos B.V., for not alerting anyone when they
tested the syrup and found impurities.

2006-2011- Panama
219 deaths reported in Panama because of DEG contaminated medicines.
2007 – Worldwide toothpaste incident [16]
 In May 2007, a Panamanian namedEduardo Arias discovered a 59-cent toothpaste that was
labeled containing DEG. Panamanian officials traced the toothpaste to a local company in
the Colón Free Trade Zone. In fact, the company bought the product in China and had
already re-exported toothpaste to Costa Rica, Dominican Republic and Haiti, making
Panama kick off a local warning. For the end of the month, the Chinese government
committed to investigate the "supposedly" tainted toothpaste that had been recalled in
Panama and Dominican Republic, but stated that, as per an essay written in 2000, a
toothpaste containing 15.6% was not dangerous.
On June 1, 2007, the FDA warned consumers to avoid toothpaste from China, although
there was no information if these toothpastes had already entered the US, and started
testing any imported Chinese toothpaste. Days later, Colgate-Palmolive found counterfeit
toothpaste with its name, which was contaminated with DEG and found at dollar-type
discount stores in New York, New Jersey, Pennsylvania and Maryland. The toothpaste was
labeled as "Manufactured in South Africa" and contained misspellings like "isclinically",
"SOUTH AFRICA" and "South African Dental Assoxiation". Although there were no reports of
anyone harmed, several people in the eastern US reported experiencing headaches and
pain after using the product It was later discovered that a great number of tubes with
poison ended up in hospitals for the mentally ill, prisons, juvenile detention centers, other
hospitals and many other state institutions.
In July 2007, health authorities in the UK detected a counterfeit Sensodyne toothpaste on
sale at a car boot sale in Derbyshire Soon, other countries also recalling Chinese-made
toothpaste were Belize, Canada, Mozambique, Saudi Arabia, New Zealand, Spain, Italy,
Japan, and Ireland, plus an Indianapolis, Indiana US hotel-supplier that distributed Chinese
toothpaste in Barbados, Belgium, Bermuda, Britain, Canada, Dominican Republic, France,
Germany, Ireland, Italy, Mexico, Spain, Switzerland, Turks and Caicos, the United Arab
Emirates and United States. What began as a local alert revealed a global problem in more
than 30 countries and involving more than thirty brands The world outcry made Chinese
officials ban the practice of using diethylene glycol in toothpaste.

In 2008 death of 84 children in Nigeria aged between 2 months to 7 years happened due to use of
medicine MyPikinBaby a teething mixture tainted with DEG.
2019-20 , 10 people died in Belo Horizonte, Brazil because of consump6on of one brand of beer
manufactured by Brewery Backers contaminated with DEG.
In 2020 - India

In the first week of 2020, around 17 children from Ramnagar, in the union territory of Jammu and
Kashmir, were hospitalised, more than half of whom died of kidney failure. The regional drug controller
authorities after investigation found out that a faulty batch of the Coldbest PC cough syrup contained
34.97% of diethylene glycol, which resulted in poisoning and subsequent renal failures. The product
was recalled and after an investigation, the Drug Controller General of India, VG Somani, said at India
Pharma 2020, that the GMP was not followed, and negligence was found during the production
process itself. The Himachal Pradesh government is filing a criminal case against the company and its
executives.

In 2022-23- Gambia /Uzbekistan [17][18]

The WHO issued a medical product alert for four "contaminated" Indian pediatric medicines,
manufactured by a firm in Haryana's Sonepat, saying these drugs identified in Gambia had
been potentially linked with acute kidney injuries and 70 deaths among children in the west
African country. The cough and cold syrups produced by Maiden Pharmaceuticals Limited,
Sonepat in India. WHO said laboratory analysis of samples of each of the four products
confirmed that they contain unacceptable amounts of diethylene glycol and ethylene glycol
as contaminants.

Subsequently, on 21 October 2022, 99 children were reported dead in Indonesia after

ingesting the cough syrups. As a result authorities in Indonesia banned all syrup medicines.
However, they advised that the syrups suspected of causing the deaths in Gambia, were not
sold locally in Indonesia.

Conclusion :
Supply of substandard medicines by the companies that led to the death of children has brought bad
reputa6on to the Indian Pharma Industry and also likely to have an impact on the trust of
interna6onal agencies on Indian Pharma export. These deaths will impact India's reputa6on of being
“Pharmacy of the World”. India eyeing a massive boost to the pharmaceu6cal sector over the coming
years for which the reputa6on of the domes6c industry needs to be above board. Contamina6on is
always a risk in the pharmaceu6cal industry. Adop6ng good manufacturing prac6ces can help
maintain high standards of quality and comply with statutory regula6ons.
Acknowledgement- Author is indebted to Department of Biotechnology Government of India for
funding (SD College Barnala under DBT Star College Scheme) to present this paper in Na6onal
Conference on” Environment , Food security and Health with reference to climate change February
7-9, 2023.
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