Tris(1,3-dichloro-2-propyl)phosphate
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Tris(1,3-dichloroisopropyl)phosphate (TDCPP) is a
chlorinated In chemistry, halogenation is a chemical reaction which introduces one or more halogens into a chemical compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, drugs. ...
organophosphate In organic chemistry, organophosphates (also known as phosphate esters, or OPEs) are a class of organophosphorus compounds with the general structure , a central phosphate molecule with alkyl or aromatic substituents. They can be considered ...
. Organophosphate chemicals have a wide variety of applications and are used as
flame retardant Flame retardants are a diverse group of chemicals that are added to manufactured materials, such as plastics and textiles, and surface finishes and coatings. Flame retardants are activated by the presence of an combustion, ignition source and pr ...
s,
pesticide Pesticides are substances that are used to control pests. They include herbicides, insecticides, nematicides, fungicides, and many others (see table). The most common of these are herbicides, which account for approximately 50% of all p ...
s,
plasticizer A plasticizer ( UK: plasticiser) is a substance that is added to a material to make it softer and more flexible, to increase its plasticity, to decrease its viscosity, and/or to decrease friction during its handling in manufacture. Plasticizer ...
s, and nerve gases. TDCPP is structurally similar to several other organophosphate flame retardants, such as tris(2-chloroethyl) phosphate (TCEP) and tris(chloropropyl)phosphate (TCPP). TDCPP and these other chlorinated organophosphate flame retardants are all sometimes referred to as "chlorinated tris".


Manufacture

TDCPP is produced by the reaction of
epichlorohydrin Epichlorohydrin (abbreviated ECH) is an organochlorine compound and an epoxide. Despite its name, it is not a halohydrin. It is a colorless liquid with a pungent, garlic-like odor, moderately soluble in water, but miscibility, miscible with most p ...
with
phosphorus oxychloride Phosphoryl chloride (commonly called phosphorus oxychloride) is a colourless liquid with the formula . It hydrolyses in moist air releasing phosphoric acid and fumes of hydrogen chloride. It is manufactured industrially on a large scale from phos ...
.


Uses


Flame retardant

Until the late 1970s, TDCPP was used as a
flame retardant Flame retardants are a diverse group of chemicals that are added to manufactured materials, such as plastics and textiles, and surface finishes and coatings. Flame retardants are activated by the presence of an combustion, ignition source and pr ...
in children’s pajamas in compliance with the U.S. Flammable Fabrics Act of 1953. This use was discontinued after children wearing fabrics treated with a very similar compound, tris(2,3-dibromopropyl) phosphate, were found to have mutagenic byproducts in their urine. Following the 2005 phase-out of PentaBDE in the United States, TDCPP became one of the primary flame retardants used in flexible
polyurethane foam Polyurethane foam is a solid polymeric foam based on polyurethane chemistry. As a specialist synthetic fibre, synthetic material with highly diverse applications, polyurethane foams are primarily used for thermal insulation and as a cushioning mat ...
used in a wide variety of consumer products, including automobiles, upholstered furniture, and some baby products. TDCPP can also be used in rigid polyurethane foam boards used for
building insulation Building insulation is material used in a building (specifically the building envelope) to reduce the flow of thermal energy. While the majority of insulation in buildings is for thermal insulation, thermal purposes, the term also applies to ...
. In 2011 it was reported that TDCPP was found in about a third of tested baby products. Some fabrics used in camping equipment are also treated with TDCPP to meet CPAI-84, a standard established by the Industrial Fabrics Association International to evaluate the flame resistance of fabrics and other materials used in tents. Current total production of TDCPP is not well known. In 1998, 2002, and 2006, production in the United States was estimated to be between 4,500 and 22,700 metric tons, and thus TDCPP is classified as a high production volume chemical.


Presence in the environment

TDCPP is an additive flame retardant, meaning that it is not chemically bonded to treated materials. Additive flame retardants are thought to be more likely to be released into the surrounding environment during the lifetime of the product than chemically bonded, or reactive, flame retardants. TDCPP degrades slowly in the environment and is not readily removed by waste water treatment processes.


Indoors

TDCPP has been detected in indoor dust, although concentrations vary widely. A study of house dust in the U.S. found that over 96% of samples collected between 2002 and 2007 contained TDCPP at an average concentration of over 1.8 ppm, while the highest was over 56 ppm. TDCPP was also detected in 99% of dust samples collected in 2009 in the Boston area from offices, homes, and vehicles. The second study found an average concentration similar to that of the previous study but a greater range of concentrations: one sample collected from a vehicle contained over 300 ppm TDCPP in the dust. Similar concentrations have been reported for dust samples collected in Europe and Japan. TDCPP has also been measured in indoor air samples. Its detection in air samples, however, is less frequent and generally at lower concentrations than other organophosphate flame retardants such as TCEP and TCPP, likely due to its lower vapor pressure.


Outdoors

Although TDCPP is generally found at the highest concentrations in enclosed environments, such as homes and vehicles, it is widespread in the environment. Diverse environmental samples, ranging from surface water to wildlife tissues, have been found to contain TDCPP. The highest levels of contamination are generally near urban impacted areas; however, samples from even relatively remote reference sites have contained TDCPP.


Human exposure

Humans are thought to be exposed to TDCPP and other flame retardants through several routes, including inhalation, ingestion, and skin contact with treated materials. Rodent studies show that TDCPP is readily absorbed through the skin and gastrointestinal tract. Infants and young children are expected to have the highest exposure to TDCPP and other indoor contaminants for several reasons. Compared to adults, children spend more time indoors and closer to the floor, where they are exposed to higher amounts of dust particles. In addition, they frequently put their hands and other objects into their mouths without washing. Several studies show that TDCPP can accumulate in human tissues. It has been detected in semen, fat, and breast milk, and the metabolite bis (1,3-dichloropropyl) phosphate (BDCPP) has been detected in urine.


Health effects


Acute

Organophosphate toxicity is classically associated with acetylcholinesterase inhibition.
Acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...
is an
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
responsible for breaking down the neurotransmitter
acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
. Many organophosphates, especially those designed to act as nerve agents or pesticides, bind with the
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...
on acetylcholinesterase, preventing it from breaking down acetylcholine. In rodent studies, TDCPP was found to have very low capacity to inhibit acetylcholinesterase, and it is considered to have low
acute toxicity Acute toxicity describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short period of time (usually less than 24 hours). To be described as ''acute'' toxicity, the adverse effect ...
. Animals that were given very high doses (>1 g/kg/day) exhibited clinical signs of organophosphate poisoning, including muscle weakness, loss of coordination, hyperactivity, and death.


Chronic


Cancer

Several studies suggest that TDCPP may be
carcinogenic A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and Biological agent, biologic agent ...
. Rodents that were fed TDCPP over two years showed increased tumor formation in the liver and brain. Metabolites of TDCPP were also determined to be mutagenic in bacteria using the
Ames test The Ames test is a widely employed method that uses bacteria to test whether a given chemical can cause mutations in the DNA of the test organism. More formally, it is a bioassay, biological assay to assess the mutagenic potential of chemical com ...
. In 2011, TDCPP was listed as a carcinogen under California Proposition 65, a law that identifies and regulates chemicals determined by the
California Environmental Protection Agency The California Environmental Protection Agency (CalEPA) is a state cabinet-level agency within the government of California. The mission of CalEPA is to restore, protect and enhance the environment, to ensure public health, environmental quali ...
‘to cause cancer, birth defects or other reproductive harm.’


Reproduction

Men living in homes with high concentrations of TDCPP in house dust were more likely to have decreased sperm counts and increased serum
prolactin Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...
levels. Women typically have higher concentrations of the hormone prolactin than men do. Release of prolactin is regulated by the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
. Prolactin is important for regulating
lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...
,
sex drive In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...
, and other
hormones A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physiology and behavior. Hormones a ...
.


Development

TDCPP and other similar organophosphate flame retardants have been found to disrupt normal development. Chickens exposed to TDCPP as embryos developed abnormally: Exposure to 45 ug/g resulted in shorter head-to-bill lengths, decreased body weight, and smaller gallbladders, while 7.64 ug/g lowered free
thyroxine Thyroxine, also known as T4, is a hormone produced by the thyroid gland. It is the primary form of thyroid hormone found in the blood and acts as a prohormone of the more active thyroid hormone, triiodothyronine (T3). Thyroxine and its acti ...
(T4) levels in the blood. Similarly, zebrafish raised in water containing TDCPP died or developed severe malformations. When the TDCPP exposure began very early during
embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...
, by the 2 cell stage, the developing embryos were more severely affected. TDCPP was found to affect several neurodevelopmental processes in a neuronal cell line.
PC12 cells PC12 is a Cell culture#Common cell lines, cell line derived from a pheochromocytoma of the rat adrenal medulla, that have an Embryonic stem cell, embryonic origin from the neural crest that has a mixture of neuroblast, neuroblastic cells and eosin ...
showed decreased cell replication and growth, increased
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
, and altered
cellular differentiation Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
. In a developing organism, these effects could change the way the brain cells communicate and function, resulting in permanent changes in nervous system function.


Thyroid

TDCPP exposure was found to alter
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
expression of several genes that regulate
thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...
function in
zebrafish The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...
embryos and larvae. Early life exposure also changed thyroid hormone levels in both zebrafish and chick embryos:
triiodothyronine Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. Production of T3 and its prohormone thyroxi ...
(T3) levels increased in exposed zebrafish while
thyroxine Thyroxine, also known as T4, is a hormone produced by the thyroid gland. It is the primary form of thyroid hormone found in the blood and acts as a prohormone of the more active thyroid hormone, triiodothyronine (T3). Thyroxine and its acti ...
(T4) levels decreased in both species. TDCPP may affect brain development and function via the thyroid system. Thyroid hormones are critical for normal growth and development and for proper function in the
endocrine system The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant Organ (biology), organs. In vertebrat ...
. The developing brain in particular is highly sensitive to thyroid hormone disruptions. Disruptions to the thyroid system of either the mother or the fetus during early brain development are associated with lower IQ scores and increased risk for ADHD or other neurobehavioral disorders.


References

{{reflist Organochlorides Organophosphates Phosphate esters Flame retardants