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Contract No. IOM-2794-04-001
The National Academies
HEALTH EFFECTS OF
PROJECT SHAD
CHEMICAL AGENT:
DIETHYLPHTHALATE
[CAS # 84-66-2]
Prepared for the National Academies
by
The Center for Research Information, Inc. 9300 Brookville Rd
Silver Spring, MD 20910
http:// www.medresearchnow.com
(301) 346-6501
cri@ix.netcom.com
2004
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
ii
ACKNOWLEDGEMENTS
Submitted to Dr. William Page, Program Officer, Advisory Panel for
the Study of Long-term Health Effects of Participation in Project SHAD
(Shipboard Hazard and Defense), Institute of Medicine, the National
Academies.
This report is subject to the copyright and reproduction arrangements defined in
Contract No. IOM-2794-04-001 of the National Academies.
This report and any supplements were prepared by the Center for Research
Information, Inc. which is solely responsible for its contents.
Although this draft is the definitive submission on its subject matter, the Center for
Research Information recognizes its ethical and contractual obligation to update,
revise, or otherwise supplement this report if new or necessary information on its
subject matter should arise, be requested, or be ascertained during the contract
period.
The Principal Investigator wishes to acknowledge and thank Matthew Hogan, Linda
Roberts, Lawrence Callahan, Judith Lelchook and Emnet Tilahun for research
assistance, editorial content assistance, and project input.
Principal Investigator: Victor Miller
Text Draft & Editing: Victor Miller & Matthew Hogan
Project Manager: Matthew Hogan
Administration: Linda Roberts
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
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SPECIAL NOTE ON PSYCHOGENIC SEQUELAE OF PERCEIVED
EXPOSURE TO BIOCHEMICAL WARFARE AGENTS
This report deals primarily with the biological health challenges engendered by the agent
that is the subject of the report. Nevertheless, this report also incorporates, by reference
and attachment, a supplement entitled "Psychogenic Effects of Perceived Exposure to
Biochemical Warfare Agents".
The supplement addresses and describes a growing body of health effects research and
interest centered upon the psychogenic sequelae of the stress experienced personally from
actual or perceived exposure to chemical and biological weaponry. Because awareness
of exposure to agents in Project SHAD logically includes the exposed person also
possessing a perception of exposure to biochemical warfare agents, the psychogenic
health consequences of perceived exposure may be regarded as additional health effects
arising from the exposure to Project SHAD agents. This reasoning may also apply to
simulants and tracers. Therefore, a general supplement has been created and submitted
under this contract to address possible psychogenic effects of perceived exposure to
biological and chemical weaponry.
Because such health effects are part of a recent and growing public concern, it is expected
that the supplement may be revised and expanded over the course of this contract to
reflect the actively evolving literature and interest in the issue.
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
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TABLE OF CONTENTS
I. EXECUTIVE SUMMARY……………………..… 1
II. BACKGROUND DATA……………………….… 3 Identification & Physical Chemistry…………………………………… 4
Manufacture & Use……………………………………………………… 4
Kinetics…………………………………………………………………… 4
III. HEALTH EFFECTS/TOXICITY…………………… 6
Overview…………………………………………………………………. 6
Acute/Subchronic/Chronic Concerns………………………………….. 7
Reproductive Toxicity…………………………………………………… 8
Carcinogenicity……………………………………………………….…. 9
Genotoxicity……………………………………………………………… 10
IV. PSYCHOGENIC EFFECTS……………….……… 11
V. TREATMENT & PREVENTION…………………….. 12
VI. SECONDARY SOURCE COMMENT………… 13
VII. BIBLIOGRAPHY WITH ABSTRACTS…….. 14
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
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I. EXECUTIVE SUMMARY
Diethylphthalate (more commonly rendered in the scientific literature as two words
“diethyl phthalate”) is a phthalic acid ester with the chemical formula C12H14O4 , and
commonly identified by Chemical Abstracts Service (CAS) registry number 84-66-2. It
ordinarily appears as a bitter-tasting colorless or water-white liquid with no odor, or a
slight aromatic odor. It is slightly soluble in water, while also soluble in alcohol, ether,
benzene, and acetone. Diethylphthalate is miscible with vegetable oils, esters, and
aromatic hydrocarbons. It is manufactured by refluxing one equivalent of phthalic
anhydride with a greater than two-fold excess of ethanol in the presence of one percent of
concentrated sulfuric acid. It is also classed as a phthalic anhydride ester (PAE).
Diethylphthalate is a widely encountered compound in daily life. Automobile parts,
toothbrushes, tools, and food packaging are ordinary products in which one can
frequently find diethylphthalate. Aspirin, insecticides, and cosmetics can also contain it.
The most common industrial use for diethylphthalate is as a “plasticizer” -- an agent for
making plastics more flexible. In Project SHAD, diethylphthalate was used as a simulant
for VX Nerve Agent. Because of its common use in so many household and personal
consumer products, exposure through many pathways (oral, dermal, respiratory) has been
studied.
The Threshold Limit Value for diethylphthalate of the American Conference of
Governmental Industrial Hygienists (ACGIH) is 5.0mg/m3 based on an 8-hour workday
time-weighted average. The pharmacology and kinetics of diethylphthalate exposure
indicate slow absorption by the skin, the metabolic conversion of absorbed
diethyphthalate into ethanol and the monoester monoethyl phthalate, followed by rapid
excretion, mostly in the urine.
The effects of diethylphthalate are fairly extensively studied. The chemical shares with
other phthalates the characteristic of being among the least toxic of substances in
industrial use. In vivo human studies or case reports of serious direct physiological
insult as a result of diethylphthalate exposure are not to be found, with the exception of
mucous membrane/pulmonary irritation, or a general anesthetic effect at very high
concentrations/doses, along with unusual sensitive skin reactions in exceptional
sensitized individual cases. An in vitro study on a human skin model did produce a
strong cytotoxic reaction but this has not been duplicated in vivo.
Animal studies provide powerful corroboration of diethylphthalate’s low toxicity. Only
very high acute oral doses have produced lethality in animals. Otherwise, non-toxic
systemic effects usually seen in animal testing are decreased weight gain with alterations
in liver and kidney size, likely attributable to hypertrophy. Animal studies indicate that
diethylphthalate is only mildly or moderately irritating when applied to the skin or the
eye.
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Evidence of carinogenicity is at best equivocal. In rodent studies a carcinoma/adenoma
positive dose-response versus control results was found in only one sex of one species,
and the response did not differ significantly from a historical mean for the species and
gender. Evidence of genotoxicity is also weak, with only in vitro sister-chromatid
exchanges (SCE) a confirmed effect, but these occurred only in the presence of an S9
fraction from a sensitive species in which a correlation between SCEs and
carcinogenicity is regarded as tenuous. Both the Environmental Protection Agency (EPA)
and ACGIH regard diethylphthalate to be a substance without evidence of cancer risk
[EPA class D; ACGIH class A4]; human case reports or epidemiological study of
carcinogenesis from diethylphthalate have not been found.
Some concern may exist for toxicity in the reproductive/developmental area. Skeletal
abnormalities in rodent offspring have been seen after maternal administration of high
doses. Chicken embryos die at a faster rate after direct injection of diethylphthalate. A
lowering of testosterone levels in rodents has been seen following diethylphthalate
exposure, though no fertility or testicular damage was seen. A lowering of human sperm
motility was observed after direct in vitro administration of diethylphthalate. Concerns
have been raised on risks to pregnant human females and offspring in light of the
detected presence of significant amounts of diethylphthalate in the blood of pregnant
women in urban areas.
One comprehensive and relatively recent (2001) review of diethylphthalate toxicity
concludes that there are ultimately “no toxic endpoints of concern” for the substance in
regard to acute toxicity, eye irritation, dermal irritation, dermal sensitization,
phototoxicity, photoallergenicity, percutaneous absorption, subchronic toxicity,
teratogenicity, reproductive toxicity, genetic toxicity, chronic toxicity, carcinogenicity,
and potential human exposure.
Psychogenic effects specifically of diethylphthalate exposure have not been found in the
literature, but the general effects of a perceived exposure to chemical warfare agents are
treated in the supplement provided under this contract entitled “Psychogenic Effects of
Perceived Exposure to Biochemical Warfare Agents.”
Secondary literature tends to be comprehensive. It appears that the similarity in names
and characteristics of the PAE class may cause confusion in reportage of effects,
however.
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II. BACKGROUND DATA
Identification & Physical Chemistry
Project SHAD Chemical Agent Name: Diethylphthalate.
CAS#: 84-66-2
More Commonly Appearing Name: Diethyl Phthalate
Abbreviation: DEP (Common Use), D (Project SHAD)
Alternate Names: anozol; 1,2-benzenedicarboxylic acid diethyl ester; o-
benzenedicarboxylic acid diethyl ester; carboxylic acid, diethyl ester; diethyl ester
phthalic acid; diethyl o-phthalate; diethyl-o-phenylenediacetate; DPX-F5384; estol 1550;
ethyl phthalate; NCI-C60048; neantine; palatinol; phthalol; phthalsaeurediaethylester;
placidol E (HSDB 2004, RTECS 2004)
Chemical Formula: C12H14O4
Chemical Structure (CHEMIDplus 2004):
Molecular Weight: 222.23
Specific gravity: 1.232 (14 oC)
Vapor Pressure: 14mm Hg (163 oC)
Conversion rate: 9.07 mg/m3 = 1 ppm
Boiling Point: 298 oC
Melting Point: -40.5 oC
Sources: HSDB 2004, RTECS 2004; Chem ID/TOXNET 2004.
Diethylphthalate is classified among the phthalic anhydride esters (PAEs) (Kamrin 1991).
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Diethylphthalate is produced by refluxing one equivalent of phthalic anhydride with a
greater than two-fold excess of ethanol in the presence of one percent of concentrated
sulfuric acid (Fed. Reg. 60(171): 46076-9 (September 5, 1995) 46076-46079).
Diethylphthalate is soluble in alcohol, ether, acetone, benzene. It is miscible with
vegetable oils, ketones, esters, and aromatic hydrocarbons; it is partly miscible with
aliphatic solvents. Diethylphthalate is soluble in water at a rate of 1000 mg/l (25 oC).
Diethylphthalate in pure form is usually encountered as a stable, usually colorless (but
sometimes white), oily liquid with a bitter taste (HSDB 2004, RTECS 2004).
Manufacture and Use
Eastman Kodak Company and Unitex Chemical Company are the major American
manufacturers of diethylphthalate (HSDB 2004).
During Project SHAD, diethylphthalate was used as a simulant for VX Nerve Agent
(Project 65-17 2004).
Diethylphthalate is a widely used chemical in industrial and consumer products. It chief
use is as a “plasticizer” -- an agent for making plastics more flexible. Automobile parts,
toothbrushes, tools, and food packaging are ordinary products in which one can often find
diethylphthalate. Aspirin and insecticides may also contain it (HSDB 2004).
Because of diethylphthalate’s common use in so many household and personal consumer
products, human exposure is likely to occur through many pathways (oral, dermal,
respiratory). Cosmetic products using diethylphthalate include bath preparations, eye
shadows, hair sprays, wave sets, nail polish, nail polish remover, nail extenders,
detergents, aftershave lotions, and skin care preparations (HSDB 2004; Api 2001).
Diethylphthalate is also used to manufacture celluloid. It has been used as a solvent for
cellulose acetate in varnishes; as a fixative for perfumes; as a wetting agent; as a camphor
substitute (HSDB 2004; Api 2001).
Diethylphthalate has served also as a diluent in polysulfide dental impression materials;
and as a solvent for nitrocellulose and cellulose acetate. It is used as a plasticizer in solid
rocket propellants and cellulose ester plastics such as photographic films and sheets,
blister packaging, and tape applications (HSDB 2004; Api 2001).
Kinetics
Diethylphthalate can be absorbed through the skin, the lungs, and the digestive tract (Api
2001).
Dermal absorption has been extensively studied. In vitro testing by the Research Institute
on Fragrance Materials has lead to establishing a human skin steady-state abortion rate of
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Health Effects of Diethylphthalate
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1.27 + 0.11 mg/cm2/hr (Api 2001). Dermal absorption by human skin is about 30 times
slower than that of experimental in vitro tissue (Api 2001).
Data on inhalation absorption cannot be found.
After absorption, diethylphthalate tends to accumulate most in the kidneys and liver, with
blood, spleen, and fat cells. Diethylphthalate is usually rapidly metabolized into its
monoester, monoethyl phthalate, and ethyl alcohol (ethanol) (Kamrin 1991). The
hydrolysis enzymes of diethylphthalate are not well-characterized (Api 2001).
Excretion occurs primarily through the urine (WHO 2003; Api 2001).
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Health Effects of Diethylphthalate
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III. HEALTH EFFECTS/TOXICITY
Overview
The toxicology of diethylphthalate has been the subject of extensive study. With other
phthalates, it shares the characteristic of being among the least toxic of substances in
industrial use. As the discussion in this section will indicate, human or clinical studies
reporting serious direct physiological insult as a result of diethylphthalate exposure show
only rare, transient, and mostly minor occurrences in high dose situations or with
sensitive individuals. These include irritation from heated diethylphthalate, central
nervous system depression after heavy exposure, along with rare dermal sensitivity in
individuals with a pre-disposition for dermal sensitization
A recent (2001) comprehensive review of diethylphthalate toxicity concludes that there
are “no toxic endpoints of concern” in the following areas: acute toxicity, eye irritation,
dermal irritation, dermal sensitization, phototoxicity, photoallergenicity, percutaneous
absorption, subchronic toxicity, teratogenicity, reproductive toxicity, genetic toxicity,
chronic toxicity, carcinogenicity, and potential human exposure (Api 2001).
In many experimental tests, the lowest observed effect level exceeds the maximum tested
dose. A table in the next subsection below will provide toxicity values found in key
studies. Indications of genotoxicity or carcinogenicity have been authoritatively deemed
to be at most equivocal and key authorities do not consider diethylphthalate a cancer risk
The Threshold Limit Value/Time Weighted Average (TLV-TWA) for diethyphthalate of
the American Conference of Government Industrial Hygienists (ACGIH) is 5 mg/m3
as
an 8-hour time weighted average. (WHO 2003). This TLV level in practice amounts to
about 50mg inhaled per person each work day for a lifetime (Api 2001). The highest
consumer food with diethylphthalate content (presumably from contamination from
packaging) in a UK study were quiches, averaging 2-3 mg/kg (human). Nevertheless 4
mg (absolute amount) was found to be the average ordinary human exposure/intake per
person per day (Kamrin 1991). Indoor air concentration of diethylphthalate recorded in
Tokyo recently was 0.1 µg/m3
(Otake 2004).
In general, significant systemic toxicity is not indicated -- high dose oral subchronic and
chronic tests on rats shows only gains in liver weight as an effect, which was attributable
to hypertophy and not toxicity, along with moderate decreased weight gain. (Api 2001;
Kamrin 1991) Guinea pigs experienced only slight liver and kidney damage when
exposed orally to a high dose of 1 mg/kg daily for up to 12 consecutive days.
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Acute/Subchronic/Chronic Concerns
There is a broad consensus in the literature that diethylphthalate is generally of low acute
toxicity. (NTP 1995; Api 2001; WHO 2003). The following Lethal Dose 50 percent kill
(LD50) values tend to support this:
ROUTE ANIMAL LD50
Oral guinea pig 8,600 mg/kg
Oral mouse 6,172 mg/kg
Oral rat 8,600 mg/kg
Oral rabbit 1 gm/kg
Intraperitoneal mouse 2,749 mg/kg
Intraperitoneal rat 5,058 µL/kg
Subcutaneous guinea pig 3 gm/kg
Unreported route guinea pig 3 gm/kg
Unreported route mouse 8,600 mg/kg
Unreported route rat 9,500 mg/kg
(Adapted from RTECS 2004)
Human toxic effect lowest levels (Lowest Observed Adverse Effect Levels -- LOAELs)
have been reported to show at these concentrations:
Oral Human 357 µL/kg
Inhalation Human 1,000 mg/m3
(Adapted from RTECS 2004)
In humans, coughing and lacrimation occur at the inhalation dose 1.0 g/m3 (note: 200
times the Threshold Limit Value (TLV)). Miosis, dyspnea, amd general anesthetic effects
followed human oral exposure at the dose level above. Central nervous system
depression signs were seen in the animals prior to death. (RTECS 2004; HSDB 2004)
Acute doses in the range of .07-0.3g/kg delivered intravenously are the lowest levels for
lethality in mice and rabbits. Dermal exposure of rats at levels lower than 11g/kg, the
highest dose administered, failed to kill any (Api 2001).
No studies or record of human fatality from acute or chronic exposure have been found.
Animal and human studies indicate at most mild to moderate irritant toxicity to skin and
eyes. An administration to clipped rat skin of 2ml/kg at 6 hour intervals each day for two
weeks evoked erythema, desquamation, and mild epidermal thickening. Some irritation
was found in a 24 hour epicutaneous test on guinea pigs; moderate irritation only was
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found on closed patch tests on rabbit skin. No effects occurred in a semiocclusive patch
test of exposure to 0.5 ml of diethylphthalate for four hours (Api 2001).
Intradermal administration to test animals have produced significant irritation. Ocular
exposure in one standard rabbit test elicited no obvious irritation (Lawrence 1975). Other
rabbit tests have shown some transitory severe conjunctival irritation, but the use of the
solvent ethanol may have been to blame (Api 2001).
Humans showed no primary irritation from applications of undiluted diethylphthalate
epicutaneously. An in vitro model of human skin showed marked cytotoxicity but this
could not be duplicated in vivo (Api 2001). A computer “mouse” containing
diethylphthalate appears to have induced dermatitis in the hands of two women according
to one case study (WHO 2003).
No dermal sensitization was elicited in guinea pigs and humans not prone to allergic
reactions or previously exposed have shown no little or no sensitization in volunteer
testing and case studies. A small proportion (1/30) workers previously exposed to
diethylphthalate exhibited some dermatitis (WHO 2003).
No significant photoxicity or photoallerginicity was elicited in tests on human volunteers
(Api 2001).
Chronic studies reveal that at very high doses (> 25g/kg/day) organ weight loss and
decreased weight gain are typically noted (RTECS 2004; Api 2001). Reports describing
cases of human toxic effects from chronic exposures were not found. Chronic rodent
testing also cited below in the subsection on carcinogenesis indicated no general toxic
effects from exposure (WHO 2003; NTP 1995).
Study or reports of neurological toxicity have not been found, other than a general central
nervous system depression at high toxic doses (Api 2001). Two studies found no toxic
pathology in the brain after administration orally of up to 3.7 g/kg in rats or mice (Brown
et al 1978; WHO 2003).
Reproductive Toxicity
Concerns may exist in the area of reproductive toxicity. Administration of
diethylphthalate to rats and mice has led to the increase in skeletal defects or rib number
alteration in offspring. (WHO 2003; Field et al 1993; Kamrin 1991; Singh et al 1972).
Testing of rats yielded no embryotoxicty or teratogenicity except an extra rib when
administration of up to 3.2g/kg (oral) diethylphthalate and 5.6 g/kg (percutaneous)
diethylphthalate occurred at the time of organogenesis. Fetal weight was lower in the
high-dose group (WHO 2003).
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Direct injections of diethylphthalate (0.025 ml) into chicken eggs prior to embryonic
stage development has induced an increased level of deaths, with a small percentage of
malformations among the survivors (Api 2001). . A multigeneration developmental study of mice noted no signs of toxicity/defects in the
F0 generation after high oral dosing of 3.6g/kg for 14 weeks after cohabitation, and none
also in the subsequent (unexposed) generation F1, except for a reduced number of pups
per litter, mild inhibition of body weight gain, reduction by 30% in epididymal sperm
concentration, and moderate increase in liver and prostate weight (WHO 2003; NTP
1984). A NOAEL (no observed adverse effect level) for reproductive toxicity after
administration for over 14 weeks after gestation in pregnant SD rats was established at
750 mg/kg per day (WHO 2003).
No study indicating human maternal or developmental toxicity have been found.
Concerns have been raised, nonetheless, by the substantial presence of diethylphthalate in
the blood of pregnant women in urban areas (Adibi et al. 2003).
There has been some indication of possible detrimental effects by diethylphthalate on the
male reproductive system. In the multigenerational study cited above a reduction of 30%
in epididymal sperm concentration and an increase in prostate weight were noted. Human
sperm treated in vitro showed impairment in motility after less than 18 minutes of
exposure (Fredricsson et al 1993). Testosterone levels in rat testes and serum decreased
after an oral exposure to 2% diethylphthalate in the diet. Nevertheless, no other toxic
male reproductive injury was found anywhere in the rat, including no testicular damage
or Sertoli cell impairment (Api 2001). Mice showed no reproductive system effects of
any kind at the same level of dosing (Api 2001).
Leydig cells showed ultrastructural changes in male rats receiving 2g/kg daily for two
days. Smooth endoplasmic reticulum focal dilation and vesiculation, mitochondrial
swelling, and increased macrophage activity associated with the Leydig cell surface were
noted (Jones et al1993; WHO 2003).
Enormous oral doses induced some testicular weight changes in rats These occurred only
at a level of 44g-354g/kg delivered daily over 2-16 weeks (Brown et al 1978; RTECS
2004).
In vivo human studies or reports of testicular or male reproductive toxicity from
diethylphthalate have not been found.
Carcinogenicity
Key authorities deem the available evidence insufficient to declare diethylphthalate
carcinogenic. The EPA classifies diethyl phthalate as class D, unclassifiable as to human
carcinogenicity. The ACGIH classifies diethylphthalate as A4, not classifiable as a
human carcinogen (WHO 2003; US EPA 2004).
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Evidence of carcinogenicity remains at best “equivocal” (WHO 2003; Api 2001). A
National Toxicology Program dermal study found no evidence of site-specific dermal
carcinogenicity in male and female rats in 2 year dermal administration studies applying
up to 1.6 g/kg of diethylphthalate per day (Api 2001).
Another dermal test of up to 1.1 g/kg per day of diethylphthalate in acetone for 103
weeks in both rats and mice turned up no neoplasia at the site of application, but at high
doses there was some increase in combined hepatocellular adenoma or carcinoma in male
mice. A non-dose-related increase in carcinomas occurred in female mice. This has been
regarded as equivocal as the rate among males was similar to the historical neoplasm
mean rate in males of that mice strain and because the female response was not dose-
related. Additionally the results were not duplicated in the tested rat species. (NTP
1995; Api 2001; WHO 2003)
Diethylphthalate was also dermally tested over a period of one year with cancer promoter
12-O-tetradecanoylphorbol-13-acetate and with initiator 7,12-dimethylbenz[a]anthracene.
No initiator or promoter activity was observed (NTP 1995).
Genotoxicity
Diethylphthalate was found not to be mutagenic in Salmonella strains TA 98, TA 100,
TA 1535 or TA 1537 with or without liver fraction S9 (NTP 1995). No in vivo studies
have been reported (WHO 2003). Chromosomal aberrations were also absent in Chinese
hamster ovary cells with and without S9 liver fraction. Nevertheless, sister-chromatid
exchanges (SCEs) were noted at 167-750 µg/ml concentrations but only with rat liver S9.
While this was regarded as some evidence for potential DNA damage in vivo, the NTP
cautioned that the endpoint is highly sensitive and it does not correlate well with
carcinogenicity in rodents (NTP 1995).
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IV. PSYCHOGENIC EFFECTS
There are no known studies addressing psychogenic effects of exposure to
diethylphthalate. The general effects of perceived exposure to chemical or biological
warfare agents are treated in the supplement “Psychogenic Effects of Perceived Exposure
to Biochemical Warfare Agents.”
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Health Effects of Diethylphthalate
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V. TREATMENT/PREVENTION
Standard protection procedures, and limitations of them, regarding diethyl phthalate
overexposure is provided below (Mallinckrodt Baker Inc. 2004):
Ventilation System:
A system of local and/or general exhaust is recommended to keep employee exposures
below the Airborne Exposure Limits. Local exhaust ventilation is generally preferred
because it can control the emissions of the contaminant at its source, preventing dispersion
of it into the general work area….
Personal Respirators (NIOSH Approved):
If the exposure limit is exceeded and engineering controls are not feasible, a half facepiece
particulate respirator (NIOSH type P95 or R95 filters) may be worn for up to ten times the
exposure limit or the maximum use concentration specified by the appropriate regulatory
agency or respirator supplier, whichever is lowest.. A full-face piece particulate respirator
(NIOSH type P100 or R100 filters) may be worn up to 50 times the exposure limit, or the
maximum use concentration specified by the appropriate regulatory agency, or respirator
supplier, whichever is lowest. Please note that N filters are not recommended for this
material. For emergencies or instances where the exposure levels are not known, use a full-
facepiece positive-pressure, air-supplied respirator. WARNING: Air-purifying respirators
do not protect workers in oxygen-deficient atmospheres.
Skin Protection:
Wear protective gloves and clean body-covering clothing.
Eye Protection: Use chemical safety goggles and/or full face shield where dusting or splashing of solutions
is possible. Maintain eye wash fountain and quick-drench facilities in work area.
Exposure to diethylphthalate has rarely been reported as harmful so no systematic
treatment methods specific to diethylphthalate are reported. TOXNET suggests applying
the emergency medical treatment protocol for dibutyl phthalate (HSDB 2004).
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VI. SECONDARY SOURCE COMMENT
Secondary literature tends to be comprehensive.
The International Agency for Research on Cancer (IARC) provides no evaluation for
diethylphthalate (CAS 84-66-2). (See http://www.iarc.fr/).
Occasional references to gastrointestinal irritation (nausea) from oral exposure arise in
the literature, including Project SHAD’s Glossary (Project 112 2004; Mallinckrodt Baker
2004). The Merck Index claims polyneuritis as a possible effect (O’Neil 2001). But no
primary information on such toxic effects has been found, nor have they been reported in
recent reviews (WHO 2003; Api 2001; NTP 1995). It is suggested that the insertion of
dibutyl phthalate’s medical handling procedures in TOXNET’s discussion of
diethylphthalate treatment inside its diethylphthalate HSDB monograph, and which
includes statements describing dibutyl phthalate’s toxic effects of nausea and
polyneuritis, may be responsible for such confusion, or at least reflect a pattern of easy
confoundment that can give rise to such errors (HSDB 2004).
One author notes aptly that the similarity in common abbreviations and in the productive
uses of the two phthalic acid esters DEP (diethylphthalate) and DEHP (di (ethylhexyl)
phthalate) can lead to confusion (Kamrin 1991).
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VII. BIBLIOGRAPHY WITH ABSTRACTS
{The following bibliography may contain supplementary material beyond those
cited in the text. Abstracts are reproduced without alteration from how they are
provided in their original source or database. Errors and defects of form, content,
or style are strictly those of the original source.}
Anonymous 1997. Reproductive toxicology. Diethylphthalate. Environ.Health Perspect.
105 Suppl 1: 245-246.
Adibi, et al. 2003. Prenatal exposures to phthalates among women in New York City and
Krakow, Poland. Environ.Health Perspect. 111(14): 1719-1722.
Experimental evidence has shown that certain phthalates can disrupt endocrine function
and induce reproductive and developmental toxicity. However, few data are available on
the extent of human exposure to phthalates during pregnancy. As part of the research
being conducted by the Columbia Center for Children's Environmental Health, we have
measured levels of phthalates in 48-hr personal air samples collected from parallel
cohorts of pregnant women in New York, New York, (n = 30) and in Krakow, Poland (n
= 30). Spot urine samples were collected during the same 48-hr period from the New
York women (n = 25). The following four phthalates or their metabolites were measured
in both personal air and urine: diethyl phthalate (DEP), dibutyl phthalate (DBP),
diethylhexyl phthalate (DEHP), and butyl benzyl phthalate (BBzP). All were present in
100% of the air and urine samples. Ranges in personal air samples were as follows: DEP
(0.26-7.12 microg/m3), DBP (0.11-14.76 microg/m3), DEHP (0.05-1.08 microg/m3), and
BBzP (0.00-0.63 microg/m3). The mean personal air concentrations of DBP, di-isobutyl
phthalate, and DEHP are higher in Krakow, whereas the mean personal air concentration
of DEP is higher in New York. Statistically significant correlations between personal air
and urinary levels were found for DEP and monoethyl phthalate (r = 0.42, p < 0.05),
DBP and monobutyl phthalate (r = 0.58, p < 0.01), and BBzP and monobenzyl
phthalate (r = 0.65, p < 0.01). These results demonstrate considerable phthalate
exposures during pregnancy among women in these two cohorts and indicate that
inhalation is an important route of exposure.
Agarwal, et al. 1985. Mutagenicity evaluation of phthalic acid esters and metabolites in
Salmonella typhimurium cultures. J.Toxicol.Environ.Health. 16(1): 61-69.
The mutagenic potential of dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl
phthalate (DBP), and di-2-ethylhexyl phthalate (DEPH), as well as metabolites of DEHP-
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
15
-i.e., mono-2-ethylhexyl phthalate (MEHP), 2-ethylhexanol (2-EH), and phthalic acid
(PA)--were tested in Salmonella typhimurium cultures using the Ames test procedure.
The compounds were tested on strains TA98, TA100, TA1535, TA1537, TA1538, and
TA2637 for base-pair substitution or frameshift-type mutations. Spot tests yielded
negative responses for all compounds with the strains tested. Each compound was tested
for a dose-effect relationship in the TA98, TA100, TA1535, and TA1538 systems. DEP
and DBP exhibited a mildly positive response in both TA100 and TA1535 cultures, and
DMP showed a similar response in TA1535. Normalization of the data for cytotoxicity of
DMP suggests TA100 has a mildly positive effect. The higher doses of these compounds
exhibited some cytotoxic effects. The mutagenic effects were apparently abolished by the
addition of S9 fraction in TA100 and TA1535 cultures, while no effect, other than
cytotoxicity, was observed in the TA98 and TA1538 systems. DEHP, MEHP, 2-EH, and
PA exhibited no mutagenicity in any of the strains of Salmonella typhimurium tested,
with or without S9 metabolic activation. MEHP and 2-EH, however, exhibited a
moderate cytotoxic effect in most cultures.
Api. 2004. Evaluation of the dermal subchronic toxicity of phenoxyethyl isobutyrate in
the rat. Food Chem.Toxicol. 42(2): 307-311.
Phenoxyethyl isobutyrate (PEIB) is a fragrance and food ingredient that has been granted
GRAS status and approved by the FDA for food use. The present studies investigated the
dermal absorption parameters and subchronic toxicity of PEIB. For the absorption,
distribution and elimination study, Sprague-Dawley rats received a dermal application of
2-[ring U 14C]-PEIB under occlusion for 6 h. PEIB was diluted in diethyl phthalate
(DEP) to administer, a total application volume of 2 ml/kg, concentrations of 0.5, 5 and
50% ( congruent with 10, 100 and 1000 mg PEIB/kgBW). Approximately 61-69% of the
applied dose was recovered from the dressing and skin surface washing procedure
performed after 6-h exposure. By 72 h post dose, systemic elimination of radioactivity
was congruent with 18 to 19% of the absorbed dose via the urine with small amounts also
found in the feces (<1.0%). Terminal (72 h) tissue analysis showed that 0.35-0.72% of
the applied dose of radioactivity was retained in the carcass with low levels
(</=0.03%) measured also in the liver, kidney and gastrointestinal tract. Plasma levels
increased in a dose-related manner, with concentrations equal to 0.02, 0.2 and 2.0 microg
equiv/ml from low to high dose, respectively. The total recovery for these studies ranged
from 92.2 to 96.2% of the dermally applied radioisotope. In a 13-week subchronic rat
toxicity study, daily dermal applications of PEIB were made under occlusion for 6 h. All
groups were dosed at a constant 2 ml/kgBW volume of PEIB in the DEP vehicle at
concentrations calculated to administer 0, 100, 300 or 1000 mg PEIB/kgBW/day. Clinical
observations, assessments of skin irritation, hematology, and blood chemistry, necropsy,
and gross and histopathologic evaluation of tissues demonstrated no treatment-related
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
16
effects. The local skin irritation and systemic toxicity no-observed-effect-levels (NOELs)
for PEIB in this study were determined to be >1000 mg/kgBW/day.
Api. 2002. Sensitization methodology and primary prevention of the research institute for
fragrance materials. Dermatology. 205(1): 84-87.
The Research Institute for Fragrance Materials Inc. (RIFM) has approached sensitization
studies with fragrance materials as primary prevention of sensitization in the healthy,
normal population. Secondary prevention, or avoidance of elicitation, most often
suggested by dermatologists for patients presenting with dermatitis, has not been part of
its program effort. Historically, RIFM evaluated the sensitization potential of fragrance
materials using the human maximization test method; no animal models were used. In
general, petrolatum was used as the vehicle. This is a harsh procedure whose main use
may provide a measure of the uppermost limits of sensitization. Treating skin with
sodium lauryl sulfate may be problematic and finding a laboratory to conduct the study
may also be difficult. In addition, using a human predictive test method for both hazard
and safety assessments is not ideal. The current practice involves a hazard assessment
using an animal model, followed by a safety assessment in a human repeated-insult patch
test (HRIPT). The animal test method is used to identify the sensitization potential and a
no-effect level. Following a review of the no-effect level and the maximum skin level, a
safety assessment in humans can be conducted. RIFM also modified the original vehicle
used in sensitization testing, since petrolatum presents two major difficulties: solubility
and inconsistent effects on skin penetration. Since the greatest exposure to fragrance
materials is considered to be from a cologne-type product, ethanol was chosen as a more
realistic vehicle. Further modification resulted in combinations of ethanol and diethyl
phthalate, due to diethyl phthalate's use in many perfume formulations as a solvent and
fluidizer. Human testing should not be conducted as a hazard assessment. If conducted as
a safety study, induction of sensitization should be a rare occurrence. Thus, follow-up
studies are not meaningful since the number of sensitized volunteers would be low.
However, following a series of the RIPTs with various concentrations of
hydroxycitronellal, RIFM identified a group of 41 individuals who became sensitized. An
extensive 3-phase use study, with 3 diagnostic patch tests and 4 whole-body
dermatological examinations showed that most subjects were able to use a bar soap, a
moisurizing lotion and cologne-type products with up to 1% hydroxycitronellal. In
subjects where sensitization was induced by predictive testing, no serious recurring
adverse dermatological conditions developed.
Api. 2001. Toxicological profile of diethyl phthalate: a vehicle for fragrance and
cosmetic ingredients. Food Chem.Toxicol. 39(2): 97-108.
Diethyl phthalate (DEP; CAS No. 84-66-2) has many industrial uses, as a solvent and
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
17
vehicle for fragrance and cosmetic ingredients and subsequent skin contact. This review
focuses on its safety in use as a solvent and vehicle for fragrance and cosmetic
ingredients. Available data are reviewed for acute toxicity, eye irritation, dermal
irritation, dermal sensitization, phototoxicity, photoallergenicity, percutaneous
absorption, kinetics, metabolism, subchronic toxicity, teratogenicity, reproductive
toxicity, estrogenic potential, genetic toxicity, chronic toxicity, carcinogenicity, in vitro
toxicity, ecotoxicity, environmental fate and potential human exposure. No toxicological
endpoints of concern have been identified. Comparison of estimated exposure (0.73
mg/kg/day) from dermal applications of fragrances and cosmetic products with other
accepted industrial (5 mg/m(3) in air) and consumer exposures (350 mg/l in water; 0.75
mg/kg/day oral exposure) indicates no significant toxic liability for the use of DEP in
fragrances and cosmetic products. .
Berg, et al. 1991. Diethyl phthalate not dangerous. Am.J.Hosp.Pharm. 48(7): 1448-1449.
Beving, et al. 1990. Increased isotransferrin ratio and reduced erythrocyte and platelet
volumes in blood from thermoplastic industry workers. Ann.Occup.Hyg. 34(4): 391-397.
Ten women (aged 31-61 years) and five men (aged 20-59 years) occupationally exposed
to welding fumes of polyacetate containing diethylphthalate in a thermoplastic industry
were studied. They had been employed 1-33 years (median: 11 years). Seven women
(aged 35-55) and eight men (aged 26-73) acted as unexposed controls. The exposed
persons showed increased isotransferrin ratio in blood serum and reduced volumes of
erythrocytes and platelets in blood.
Blount, et al. 2000. Levels of seven urinary phthalate metabolites in a human reference
population. Environ.Health Perspect. 108(10): 979-982.
Using a novel and highly selective technique, we measured monoester metabolites of
seven commonly used phthalates in urine samples from a reference population of 289
adult humans. This analytical approach allowed us to directly measure the individual
phthalate metabolites responsible for the animal reproductive and developmental toxicity
while avoiding contamination from the ubiquitous parent compounds. The monoesters
with the highest urinary levels found were monoethyl phthalate (95th percentile, 3,750
ppb, 2,610 microg/g creatinine), monobutyl phthalate (95th percentile, 294 ppb, 162
microg/g creatinine), and monobenzyl phthalate (95th percentile, 137 ppb, 92 microg/g
creatinine), reflecting exposure to diethyl phthalate, dibutyl phthalate, and benzyl butyl
phthalate. Women of reproductive age (20-40 years) were found to have significantly
higher levels of monobutyl phthalate, a reproductive and developmental toxicant in
rodents, than other age/gender groups (p < 0.005). Current scientific and regulatory
attention on phthalates has focused almost exclusively on health risks from exposure to
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
18
only two phthalates, di-(2-ethylhexyl) phthalate and di-isononyl phthalate. Our findings
strongly suggest that health-risk assessments for phthalate exposure in humans should
include diethyl, dibutyl, and benzyl butyl phthalates.
Brown, et al. 1978. Short-term oral toxicity study of diethyl phthalate in the rat. Food
Cosmet.Toxicol. 16(5): 415-422.
Cafmeyer, et al. 1991. Possible leaching of diethyl phthalate into levothyroxine sodium
tablets. Am.J.Hosp.Pharm. 48(4): 735-739.
The possible leaching of diethyl phthalate into four currently marketed brands of
levothyroxine sodium tablets was investigated. Several strengths of levothyroxine sodium
tablets and sizes of containers were used. Samples were analyzed by high-performance
liquid chromatography (HPLC) to determine the levothyroxine sodium content and to
determine if any unidentified compounds were present. The packaging for the four brands
of tablets was also analyzed by using the same HPLC system to determine if any
extractable compounds could be detected in the tablets. The potencies of the four brands
of tablets were comparable. The tablets from the 100-count container of one brand (brand
A) were the only tablets found to contain an unidentified peak in the chromatogram. The
desiccants from the bottle showed the same unidentified compound, while the bottle and
closure did not yield the peak. Thin-layer chromatography and HPLC identified the peak
as diethyl phthalate, a plasticizer in the desiccant. Tablets, bottles, closures, and
desiccants for the 1000-count brand A product and all sizes of the other brands were
negative for the presence of diethyl phthalate. The desiccants in those containers were
from a different manufacturer than the desiccant in the brand A 100-count bottle. Diethyl
phthalate in the desiccant in 100-count bottles of brand A levothyroxine sodium tablets
appeared to have leached into the tablets.
Call, et al. 2001. An assessment of the toxicity of phthalate esters to freshwater benthos.
2. Sediment exposures. Environ.Toxicol.Chem. 20(8): 1805-1815.
Seven phthalate esters were evaluated for their 10-d toxicity to the freshwater
invertebrates Hyalella azteca and Chironomus tentans in sediment. The esters were
diethyl phthalate (DEP), di-n-butyl phthalate (DBP), di-n-hexyl phthalate (DHP), di-(2-
ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), diisodecyl phthalate (DIDP),
and a commercial mixture of C7, C9, and C11 isophthalate esters (711P). All seven esters
were tested in a sediment containing 4.80% total organic carbon (TOC), and DBP alone
was tested in two additional sediments with 2.45 and 14.1% TOC. Sediment spiking
concentrations for DEP and DBP were based on LC50 (lethal concentration for 50% of
the population) values from water-only toxicity tests, sediment organic carbon
concentration, and equilibrium partitioning (EqP) theory. The five higher molecular
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weight phthalate esters (DHP, DEHP, DINP, DIDP, 711P), two of which were tested and
found to be nontoxic in water-only tests (i.e., DHP and DEHP), were tested at single
concentrations between 2,100 and 3,200 mg/kg dry weight. Preliminary spiking studies
were performed to assess phthalate ester stability under test conditions. The five higher
molecular weight phthalate esters in sediment had no effect on survival or growth of
either C. tentans or H. azteca, consistent with predictions based on water-only tests and
EqP theory. The 10-d LC50 values for DBP and H. azteca were >17,400, >29,500,
and >71,900 mg/kg dry weight for the low, medium, and high TOC sediments,
respectively. These values are more than 30x greater than predicted by EqP theory and
may reflect the fact that H. azteca is an epibenthic species and not an obligative burrower.
The 10-d LC50 values for DBP and C. tentans were 826, 1,664, and 4.730 mg/kg dry
weight for the low, medium, and high TOC sediments, respectively. These values are
within a factor of two of the values predicted by EqP theory. Pore-water 10-d LC50
values for DBP (dissolved fraction) and C. tentans in the three sediments were 0.65, 0.89,
and 0.66 of the water-only LC50 value of 2.64 mg/L, thereby agreeing with EqP theory
predictions to within a factor of 1.5. The LC50 value for DEP and C. tentans was
>3,100 mg/kg dry weight, which is approximately 10x that predicted by EqP theory. It
is postulated that test chemical loss and reduced organism exposure to pore water may
have accounted for the observed discrepancies with EqP calculations for DEP
Call, et al. 2001. An assessment of the toxicity of phthalate esters to freshwater benthos.
1. Aqueous exposures. Environ.Toxicol.Chem. 20(8): 1798-1804.
Tests were performed with the freshwater invertebrates Hyalella azteca, Chironomus
tentans, and Lumbriculus variegatus to determine the acute toxicity of six phthalate
esters, including dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate
(DBP), butylbenzyl phthalate (BBP), di-n-hexyl phthalate (DHP), and di-2-ethylhexyl
phthalate (DEHP). It was possible to derive 10-d LC50 (lethal concentration for 50% of
the population) values only for the four lower molecular weight esters (DMP, DEP, DBP,
and BBP), for which toxicity increased with increasing octanol-water partition coefficient
(Kow) and decreasing water solubility. The LC50 values for DMP, DEP, DBP, and BBP
were 28.1, 4.21, 0.63, and 0.46 mg/L for H. azteca; 68.2, 31.0, 2.64, and > 1.76 mg/L
for C. tentans; and 246, 102, 2.48, and 1.23 mg/L for L. variegatus, respectively. No
significant survival reductions were observed when the three species were exposed to
either DHP or DEHP at concentrations approximating their water solubilities.
CHEMIDplus 2004. Diethyl Phthalate. TOXNET [NLM Database].
[http://chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?objectHandle=DBMaint&actionH
andle=default&nextPage=jsp/chemidlite/ResultScreen.jsp&TXTSUPERLISTID=000084
662]
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
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Elsisi, et al. 1989. Dermal absorption of phthalate diesters in rats. Fundam.Appl.Toxicol.
12(1): 70-77.
This study examined the extent of dermal absorption of a series of phthalate diesters in
the rat. Those tested were dimethyl, diethyl, dibutyl, diisobutyl, dihexyl, di(2-ethylhexyl),
diisodecyl, and benzyl butyl phthalate. Hair from a skin area (1.3 cm in diameter) on the
back of male F344 rats was clipped, the [14C]phthalate diester was applied in a dose of
157 mumol/kg, and the area of application was covered with a perforated cap. The rat
was restrained and housed for 7 days in a metabolic cage that allowed separate collection
of urine and feces. Urine and feces were collected every 24 hr, and the amount of 14C
excreted was taken as an index of the percutaneous absorption. At 24 hr, diethyl phthalate
showed the greatest excretion (26%). As the length of the alkyl side chain increased, the
amount of 14C excreted in the first 24 hr decreased significantly. The cumulative
percentage dose excreted in 7 days was greatest for diethyl, dibutyl, and diisobutyl
phthalate, about 50-60% of the applied 14C; and intermediate (20-40%) for dimethyl,
benzyl butyl, and dihexyl phthalate. Urine was the major route of excretion of all
phthalate diesters except for diisodecyl phthalate. This compound was poorly absorbed
and showed almost no urinary excretion. After 7 days, the percentage dose for each
phthalate that remained in the body was minimal and showed no specific tissue
distribution. Most of the unexcreted dose remained in the area of application. These data
show that the structure of the phthalate diester determines the degree of dermal
absorption. Absorption maximized with diethyl phthalate and then decreased significantly
as the alkyl side chain length increased.
Field, et al. 1993. Developmental toxicity evaluation of diethyl and dimethyl phthalate in
rats. Teratology. 48(1): 33-44.
Diethyl phthalate (DEP) and dimethyl phthalate (DMP), phthalic acid ester (PAE)
plasticizers, were evaluated for developmental toxicity because of reports in the literature
that some PAE were embryotoxic and teratogenic. A previous study (Singh et al., '72)
suggested that an increased incidence of skeletal defects in rats might result from
gestational exposure to DEP (0.6-1.9 g/kg) or DMP (0.4-1.3 g/kg), ip, on gestational days
(gd) 5, 10, and 15. In the current study DEP (0, 0.25, 2.5, and 5%) or DMP (0, 0.25, 1,
and 5%) in feed (approximately 0.2-4.0 g/kg/day) were supplied to timed-mated rats from
gd 6 to 15. Treatment with 5% DMP resulted in increased relative maternal liver weight.
Also, animals exhibited reduced body weight gain during treatment (5% DEP or DMP)
and during gestation (5% DEP). Weight gain corrected for gravid uterine weight was also
reduced in animals fed 5% DEP. However, high-dose treatment with either DEP or DMP
resulted in changes in food and water consumption paralleling the body weight
reductions, suggesting that apparent toxic effects on maternal body weight may reflect
PAE/feed unpalatability. Treatment with 2.5% DEP resulted in only transient changes in
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
21
body weight during early treatment. The only maternal effects at 0.25 or 1% DMP were
minor changes in food and/or water consumption, and there were no effects at 0.25%
DEP. Thus, the NOAELs for maternal toxicity were 1% DMP and 0.25% DEP. In
contrast to the observed maternal toxicity, there was no effect of DEP or DMP treatment
on any parameter of embryo/fetal development, except an increased incidence of
supernumerary ribs (a variation) in the 5% DEP group. These results do not support the
conclusion of other investigators that DEP and DMP are potent developmental toxicants.
Rather, they suggest that the short-chain PAE are less developmentally toxic than PAE
with more complex substitution groups, e.g., di(2-ethylhexyl) phthalate, mono(2-
ethylhexyl) phthalate, and butyl benzyl phthalate.
Foster, et al. 1983. Effect of DI-n-pentyl phthalate treatment on testicular steroidogenic
enzymes and cytochrome P-450 in the rat. Toxicol.Lett. 15(2-3): 265-271.
Treatment of young male rats with dipentyl phthalate (DPP) produced significant
decreases in testicular cytochrome P-450, cytochrome P-450 dependent microsomal
steroidogenic enzymes (17 alpha-hydroxylase, 17-20 lyase) and in the maximal binding
of a natural substrate (progesterone) to testis microsomes. No effect was demonstrated by
this compound on hepatic cytochrome P-450 content. Treatment of animals with a
phthalate ester not causing testicular atrophy (diethyl phthalate; DEP) produced no
significant changes in any of the parameters measured. This effect on the enzymes
responsible for androgen production may be important as a mechanism of action involved
in the development of phthalate-induced testicular damage.
Fredricsson et al 1993. Human sperm motility is affected by plasticizers and diesel
particle extracts. Pharmacol Toxicol. 72(2):128-33.
In order to test various drugs and possibly hazardous compounds on living cells in vitro a
system with human spermatozoa was employed. A population of human spermatozoa was
transferred into a defined medium by a swim-up procedure or by separation on a Percoll
gradient. Such a population is rather homogenous with respect to motility characteristics
and was found to be useful for this purpose. Different modes of response were recorded,
indicating various effect mechanisms. Effects of various phthalates used as plastic
softeners in the production of medical equipment, and extracts from diesel particulate
material were recorded. All these compounds interfered with sperm motility in a dose-
response fashion. Immediate effects of phthalates were modest, but upon prolonged
exposure effects became more evident. Sperm motility was more affected by diethyl-
hexyl and dibutyl phthalates. Significant effects were noted for the different phthalates
with regard both to percent motility and to some of the various qualities of motility, such
as velocity, linearity and amplitude of the track. Thus, the pattern of response considering
the motion variables was not the same with the different phthalates. With regard to the
effects on sperm motion di-n-octyl phthalate seemed to be the least toxic, followed by
dibutyl phthalate. The initial effects of diesel particulate extracts were moderate and
mainly restricted to percent motile sperm but upon exposure for 18 hr the effects became
more pronounced for all the movement variables.
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
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Fromme, et al. 2004. Occurrence of phthalates and musk fragrances in indoor air and
dust from apartments and kindergartens in Berlin (Germany). Indoor Air. 14(3): 188-195.
In this study, the occurrence of persistent environmental contaminants room air samples
from 59 apartments and 74 kindergartens in Berlin were tested in 2000 and 2001 for the
presence of phthalates and musk fragrances (polycyclic musks in particular). These
substances were also measured in household dust from 30 apartments. The aim of the
study was to measure exposure levels in typical central borough apartments,
kindergartens and estimate their effects on health. Of phthalates, dibutyl phthalate had the
highest concentrations in room air, with median values of 1083 ng/m(3) in apartments
and 1188 ng/m(3) in kindergartens. With around 80% of all values, the main phthalate in
house dust was diethylhexyl phthalate, with median values of 703 mg/kg (range: 231-
1763 mg/kg). No statistically significant correlation could be found between air and dust
concentration. Musk compounds were detected in the indoor air of kindergartens with
median values of 101 ng/m(3) [1,3,4,6,7,8-hexahydro-4,6,6,7,8,8- hexamethylcyclopenta-
(g) 2-benzopyrane (HHCB)] and 44 ng/m(3) [7-acetyl-1,1,3,4,4,6-hexamethyl-tetraline
(AHTN)] and maximum concentrations of up to 299 and 107 ng/m(3) respectively. In
household dust HHCB and AHTN were detected in 63 and 83% of the samples with
median values of 0.7 and 0.9 mg/kg (Maximum: 11.4 and 3.1 mg/kg) each. On
comparing the above phthalate concentrations with presently acceptable tolerable daily
intake values (TDI), we are talking about only a small average intake [di(2-ethylhexyl)
phthalate and diethyl phthalate less than 1 and 8% of the TDI] by indoor air for children.
The dominant intake path was the ingestion of foodstuffs. For certain subsets of the
population, notably premature infants (through migration from soft polyvinyl chloride
products), children and other patients undergoing medical treatment like dialysis,
exchange transfusion, an important additional intake of phthalates must taken into
account. PRACTICAL IMPLICATIONS: The phthalate and musk compounds load in a
sample of apartments and kindergartens were low with a typical distribution pattern in air
and household dust, but without a significant correlation between air and dust
concentration. The largest source of general population exposure to phthalates is dietary.
For certain subsets of the general population non-dietary ingestion (medical and
occupational) is important.
Frosch, et al. 1995. Patch testing with fragrances: results of a multicenter study of the
European Environmental and Contact Dermatitis Research Group with 48 frequently used
constituents of perfumes. Contact Dermatitis. 33(5): 333-342.
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
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The objective of this study was to determine the frequency of reactivity to a series of
commonly used fragrances in dermatological patients. A total of 48 fragrances (FF) were
chosen, based on the publication of Fenn in 1989 in which the top 25 constituents of 3
types (1. perfumes, 2. household products, 3. soaps) of 400 commercial products on the
US market had been determined. In a pilot study on a total of 1069 patients in 11 centres,
the appropriate test concentration and vehicle were examined. For most fragrances, 1%
and 5% were chosen, and petrolatum proved to be the best vehicle in comparison to
isopropyl myristate and diethyl phthalate. In the main study, a set of 5 to 10 fragrances at
2 concentrations was patch tested in each centre on a minimum of 100 consecutive
patients seen in the patch test clinic. These patients were also patch tested to a standard
series with the 8% fragrance mix (FM) and its 8 constituents. In patients with a positive
reaction to any of the 48 FF, a careful history with regard to past or present reactions to
perfumed products was taken. A total of 1323 patients were tested in 11 centres. The 8%
FM was positive in 89 patients (8.3% of 1072 patients). Allergic reactions to the
constituents were most frequent to oak moss (24), isoeugenol (20), eugenol (13),
cinnamic aldehyde (10) and geraniol (8). Reactions read as allergic on day 3/4 were
observed only 10X to 7 materials of the new series (Iso E Super (2), Lyral (3), Cyclacet
(1), DMBCA (1), Vertofix (1), citronellol (1) and amyl salicylate (1)). The remaining 41
fragrances were negative. 28 irritant or doubtful reactions on day 3/4 were observed to a
total of 19 FF materials (more than 1 reaction: 5% citronellol (2), 1% amyl salicylate (2),
1% isononyl acetate (3), 0.1% musk xylol (2), 1% citral (2), and 1% ionone beta (2)).
Clinical relevance of positive reactions to any of the FF series was not proved in a single
case. This included the 4 reactions in patients who were negative to the 8% FM. In
conclusion, the top 25 fragrances commonly found in various products caused few
reactions in dermatological patients and these few appeared to be clinically irrelevant,
with the possible exception of Lyral. However, this data should be interpreted in the light
of the relatively small number of patients tested (only 100 in most centres).
Ghorpade, et al. 2002. Toxicity study of diethyl phthalate on freshwater fish Cirrhina
mrigala. Ecotoxicol.Environ.Saf. 53(2): 255-258.
Diethyl phthalate (DEP) is used as a plasticizer, a detergent base, in aerosol sprays, as a
perfume binder in incense sticks and after-shave lotions. It is known to be a contaminant
of freshwater and marine ecosystems. Therefore, a study was designed to determine the
toxic effects of DEP on a freshwater fish, Cirrhina mrigala. The fish was treated with 25,
50, 75, and 100 ppm (w/v) DEP dissolved in acetone to determine the LC50. Positive
controls were treated with acetone only. There was 100% mortality observed within 24 h
in 75 and 100 ppm, and 50% mortality in 50 ppm treated fish in 72 h. Those treated at 25
ppm showed only 10% mortality within 72 h and remaining fish continued to survive.
The surviving fish were treated with 25 ppm DEP once daily for 3 days with every
Contract No. IOM-2794-04-001
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change of water (Group III). One group was maintained as negative control in
dechlorinated water (Group I) and the other group received acetone once daily for 3 days
with every change of water and was used as positive control (Group II). Fish were killed
by cold narcosis on an ice block and dissected to obtain liver, muscle, and brain samples;
10% homogenates in ice-cold saline were prepared. Brain and muscle
acetylcholinesterase (AchE) activity was measured. Liver aspartate (AST) and alanine
aminotransferase (ALT), and liver and muscle succinate dehydrogenase (SDH) alkaline
and acid phosphate (ALP and ACP) were measured. There was a significant increase in
liver and muscle ACP and ALP in DEP-treated fish compared with positive and negative
controls. There was a significant increase in muscle SDH and liver ALT (ALT) in DEP-
treated fish compared with positive and negative controls. Brain AchE level was
significantly decreased in DEP-treated fish compared to positive and negative controls.
These results indicate that DEP brings about significant changes in the activity of certain
liver and muscle enzymes. These alterations in enzyme activity may have long-term
effects on that are continuously exposed to low doses of DEP in the aquatic environment.
Gollamudi, et al. 1985. Effects of phthalic acid esters on drug metabolizing enzymes of
rat liver. J.Appl.Toxicol. 5(6): 368-371.
Di(2-ethylhexyl)phthalate (DEHP) inhibited UDP-glucuronyltransferase activity of rat
liver in vitro and in vivo. Diethyl phthalate and dimethoxyethyl phthalate also inhibited
this enzyme in vitro. On the other hand, DEHP did not inhibit the activity of the cytosolic
enzyme N-acetyltransferase; it also did not alter the levels of rat liver microsomal
cytochrome P-450 in vitro. It is suggested that DEHP may alter the composition of
microsomal phospholipids.
Gray, et al. 2000. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not
DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol.Sci. 58(2):
350-365.
In mammals, exposure to antiandrogenic chemicals during sexual differentiation can
produce malformations of the reproductive tract. Perinatal administration of AR
antagonists like vinclozolin and procymidone or chemicals like di(2-ethylhexyl) phthalate
(DEHP) that inhibit fetal testicular testosterone production demasculinize the males such
that they display reduced anogenital distance (AGD), retained nipples, cleft phallus with
hypospadias, undescended testes, a vaginal pouch, epididymal agenesis, and small to
absent sex accessory glands as adults. In addition to DEHP, di-n-butyl (DBP) also has
been shown to display antiandrogenic activity and induce malformations in male rats. In
the current investigation, we examined several phthalate esters to determine if they
altered sexual differentiation in an antiandrogenic manner. We hypothesized that the
phthalate esters that altered testis function in the pubertal male rat would also alter testis
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
25
function in the fetal male and produce malformations of androgen-dependent tissues. In
this regard, we expected that benzyl butyl (BBP) and diethylhexyl (DEHP) phthalate
would alter sexual differentiation, while dioctyl tere- (DOTP or DEHT), diethyl (DEP),
and dimethyl (DMP) phthalate would not. We expected that the phthalate mixture
diisononyl phthalate (DINP) would be weakly active due to the presence of some
phthalates with a 6-7 ester group. DEHP, BBP, DINP, DEP, DMP, or DOTP were
administered orally to the dam at 0.75 g/kg from gestational day (GD) 14 to postnatal day
(PND) 3. None of the treatments induced overt maternal toxicity or reduced litter sizes.
While only DEHP treatment reduced maternal weight gain during the entire dosing
period by about 15 g, both DEHP and DINP reduced pregnancy weight gain to GD 21 by
24 g and 14 g, respectively. DEHP and BBP treatments reduced pup weight at birth
(15%). Male (but not female) pups from the DEHP and BBP groups displayed shortened
AGDs (about 30%) and reduced testis weights (about 35%). As infants, males in the
DEHP, BBP, and DINP groups displayed femalelike areolas/nipples (87, 70, and 22% (p
< 0.01), respectively, versus 0% in other groups). All three of the phthalate treatments
that induced areolas also induced a significant incidence of reproductive malformations.
The percentages of males with malformations were 82% (p < 0.0001) for DEHP, 84%
(p < 0.0001) for BBP, and 7.7% (p < 0.04) in the DINP group. In summary, DEHP,
BBP, and DINP all altered sexual differentiation, whereas DOTP, DEP, and DMP were
ineffective at this dose. Whereas DEHP and BBP were of equivalent potency, DINP was
about an order of magnitude less active.
Hansen, et al. 2001. 1H NMR of compounds with low water solubility in the presence of
erythrocytes: effects of emulsion phase separation. Eur.Biophys.J. 30(1): 69-74.
When lipophilic compounds like diethyl phthalate (DEP) were added to water, two sets of
resonances appeared in the 1H NMR spectrum, whereas when added in concentrations
above approximately 3.5 mM to erythrocytes in a high haematocrit suspension, only one
set of resonances was observed at the low-frequency position. The appearance of one set
of resonances at lower frequency was found to be common to a series of lipophilic
compounds in erythrocytes. The appearance of the NMR spectra is ascribed to the
existence of an emulsion, meaning two different phases of a compound: a
"droplet" (resonances to lower frequency) and aqueous dissolved phase
(resonances to higher frequency). The absence of the resonances from the dissolved
phase in erythrocyte solution is ascribed to exchange broadening. The absolute chemical
shift of the compound in its "droplet" phase was also measured using a
cylindrical/spherical microcell. This arrangement mimicked the geometry of the
dissolved versus the phase-separated species and thus obviated the effect of a difference
in magnetic susceptibility between the "droplet" solute and its aqueous
solution. Factors influencing the formation of emulsion phases such as erythrocytes,
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Health Effects of Diethylphthalate
26
haemoglobin and smaller proteins were investigated; they are found to be effective in the
order given.
Harris, et al. 1997. The estrogenic activity of phthalate esters in vitro. Environ.Health
Perspect. 105(8): 802-811.
A large number of phthalate esters were screened for estrogenic activity using a
recombinant yeast screen. a selection of these was also tested for mitogenic effect on
estrogen-responsive human breast cancer cells. A small number of the commercially
available phthalates tested showed extremely weak estrogenic activity. The relative
potencies of these descended in the order butyl benzyl phthalate (BBP) > dibutyl
phthalate (DBP) > diisobutyl phthalate (DIBP) > diethyl phthalate (DEP) >
diisiononyl phthalate (DINP). Potencies ranged from approximately 1 x 10(6) to 5 x
10(7) times less than 17beta-estradiol. The phthalates that were estrogenic in the yeast
screen were also mitogenic on the human breast cancer cells. Di(2-ethylhexyl) phthalate
(DEHP) showed no estrogenic activity in these in vitro assays. A number of metabolites
were tested, including mono-butyl phthalate, mono-benzyl phthalate, mono-ethylhexyl
phthalate, mon-n-octyl phthalate; all were wound to be inactive. One of the phthalates,
ditridecyl phthalate (DTDP), produced inconsistent results; one sample was weakly
estrogenic, whereas another, obtained from a different source, was inactive. analysis by
gel chromatography-mass spectometry showed that the preparation exhibiting estrogenic
activity contained 0.5% of the ortho-isomer of bisphenol A. It is likely that the presence
of this antioxidant in the phthalate standard was responsible for the generation of a dose-
response curve--which was not observed with an alternative sample that had not been
supplemented with o,p'-bisphenol A--in the yeast screen; hence, DTDP is probably not
weakly estrogenic. The activities of simple mixtures of BBP, DBP, and 17beta-estradiol
were assessed in the yeast screen. No synergism was observed, although the activities of
the mixtures were approximately additive. In summary, a small number of phthalates are
weakly estrogenic in vitro. No data has yet been published on whether these are also
estrogenic in vitro. No data has yet been published on whether these are also estrogenic in
vivo; this will require tests using different classes of vertebrates and different routes of
exposure.
Hauser, et al. 2004. Medications as a source of human exposure to phthalates.
Environ.Health Perspect. 112(6): 751-753.
Phthalates are a group of multifunctional chemicals used in consumer and personal care
products, plastics, and medical devices. Laboratory studies show that some phthalates are
reproductive and developmental toxicants. Recently, human studies have shown
measurable levels of several phthalates in most of the U.S. general population. Despite
their widespread use and the consistent toxicologic data on phthalates, information is
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
27
limited on sources and pathways of human exposure to phthalates. One potential source
of exposure is medications. The need for site-specific dosage medications has led to the
use of enteric coatings that allow the release of the active ingredients into the small
intestine or in the colon. The enteric coatings generally consist of various polymers that
contain plasticizers, including triethyl citrate, dibutyl sebacate, and phthalates such as
diethyl phthalate (DEP) and dibutyl phthalate (DBP). In this article we report on
medications as a potential source of exposure to DBP in a man who took Asacol [active
ingredient mesalamine (mesalazine)] for the treatment of ulcerative colitis. In a spot urine
sample from this man collected 3 months after he started taking Asacol, the concentration
of monobutyl phthalate, a DBP metabolite, was 16,868 ng/mL (6,180 micro g/g
creatinine). This concentration was more than two orders of magnitude higher than the
95th percentile for males reported in the 1999-2000 National Health and Nutrition
Examination Survey (NHANES). The patient's urinary concentrations of monoethyl
phthalate (443.7 ng/mL, 162.6 micro g/g creatinine), mono-2-ethylhexyl phthalate (3.0
ng/mL, 1.1 micro g/g creatinine), and monobenzyl phthalate (9.3 ng/mL, 3.4 micro g/g
creatinine) were unremarkable compared with the NHANES 1999-2000 values. Before
this report, the highest estimated human exposure to DBP was more than two orders of
magnitude lower than the no observable adverse effect level from animal studies. Further
research is necessary to determine the proportional contribution of medications, as well
as personal care and consumer products, to a person's total phthalate burden.
HSDB [Hazardous Substances Data Bank] 2004. Diethyl Phthalate. TOXNET.
[http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~qbM8dG:1].
Hu, et al. 2003. Survey of phthalate pollution in arable soils in China. J.Environ.Monit.
5(4): 649-653.
The problem of pollution by phthalates is of global concern due to their widespread
occurrence, toxicity and endocrine disruption properties. The contamination by phthalates
such as dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP)
and di(2-ethylhexyl) phthalate (DEHP) in 23 arable soils throughout China was
investigated to evaluate the present pollution situation. The survey results demonstrated
that phthalates were ubiquitous pollutants in soils in China. The total concentrations of
phthalates differed from one location to another, and ranged from 0.89 to 10.03 mg kg(-
1) with a median concentration of 3.43 mg kg(-1). Among the phthalates, DEHP was
dominant and detected in all 23 soils. DEP and DBP were also in abundance, and DMP
was rarely detected. Similar contamination patterns were observed in all 23 soils. A
distinct feature of phthalate pollution in China was that the average concentration in
northern China was higher than that in southern China. In addition, a close relationship
was observed between the concentration of phthalates in soils and the consumption of
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
28
agricultural film. The correlation showed that the application of agriculture film might be
a significant pollution source of phthalates in arable soils of China. The potential risk of
phthalates in soils was assessed on the basis of current guide values and limits.
Jones, et al. 1993. The influence of phthalate esters on Leydig cell structure and function
in vitro and in vivo. Exp.Mol.Pathol. 58(3): 179-193.
Phthalate esters are widely used in the manufacture of plastics and have been shown to
cause testicular toxicity, purportedly, by targeting the Sertoli cell alone. Recent evidence,
however, indicates that a paracrine control exists between Sertoli and Leydig cells and
the breakdown of one component of this relationship is therefore detrimental to normal
function. However, no data that explore the influence of testicular toxins on Leydig cell
structure and function have been published hitherto. The preliminary studies reported
here were initiated to test the hypothesis that phthalate intoxication may adversely alter
Leydig cell structural and functional integrity. Four phthalate esters, namely, di(2-
ethylhexyl) phthalate (DEHP, di-n-pentyl phthalate (DPP)., di-n-octyl phthalate (DOP),
and diethyl phthalate (DEP) were investigated in vivo and their monoesters (MEHP,
MPP, MOP, and MEP, respectively) in vitro for indications of Leydig cell toxicity in the
rat. Rats were dosed by oral gavage with 2 g phthalate diester/kg/day in corn oil vehicle
for 2 days, while Leydig cell primary cultures were incubated with 1,000 microM
monoester for 2 hr. Light and electron microscopy were undertaken to determine the type
and degree of any changes. Phthalate esters exerted a direct effect on Leydig cell
structure and function (as determined by testosterone output) with correlation of the in
vitro and in vivo effects of MEHP (DEHP) and MOP (DOP). No effects on Leydig cell
structure or function were seen with MPP (DPP), although Sertoli cell cytoplasmic
rarefaction and vacuolation were observed in vivo. DEP produced Leydig cell
ultrastructural alterations in vivo. We conclude that individual phthalate esters may exert
effects on both Sertoli and Leydig cells or one cell type alone.
Jonsson, et al. 2003. Toxicity of mono- and diesters of o-phthalic esters to a crustacean,
a green alga, and a bacterium. Environ.Toxicol.Chem. 22(12): 3037-3043.
The degradation of phthalic acid diesters may lead to formation of o-phthalic acid and
phthalic acid monoesters. The ecotoxic properties of the monoesters have never been
systematically investigated, and concern has been raised that these degradation products
may be more toxic than the diesters. Therefore, the aquatic toxicity of phthalic acid, six
monoesters, and five diesters of o-phthalic acid was tested in three standardized toxicity
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Health Effects of Diethylphthalate
29
tests using the bacteria Vibrio fischeri, the green algae Pseudokirchneriella subcapitata,
and the crustacean Daphnia magna. The monoesters tested were monomethyl, monoethyl,
monobutyl, monobenzyl, mono(2-ethylhexyl), and monodecyl phthalate, while the
diesters tested were dimethyl, diethyl, dibutyl, butylbentyl, and di(2-ethylhexyl)phthalate,
which were assumed to be below their water solubility. The median effective
concentration (EC50) values for the three organisms ranged from 103 mg/L to >4.710
mg/L for phthalic acid, and corresponding values for the monoesters ranged from 2.3
mg/L (monodecyl phthalate in bacteria test) to 4,130 mg/L (monomethyl phthalate in
bacteria test). Dimethyl and diethyl phthalate were found to be the least toxic of the
diesters (EC50 26.2-377 mg/L), and the toxicity of the other diesters (butylbenzyl and
dibutyl phthalate) ranged from 0.96 to 7.74 mg/L. In general, the phthalate monoesters
(degradation products) were less toxic than the corresponding diesters (mother
compounds).
Kamrin, et al. 1991. Diethyl phthalate: a perspective. J.Clin.Pharmacol. 31(5): 484-489.
Keire, et al. 2001. Diethyl phthalate, a chemotactic factor secreted by Helicobacter
pylori. J.Biol.Chem. 276(52): 48847-48853.
The structure of a small-molecule, non-peptide chemotactic factor has been determined
from activity purified to apparent homogeneity from Helicobacter pylori supernatants. H.
pylori was grown in brucella broth media until one liter of solution had 0.9 absorbance
units. The culture was centrifuged, and the bacteria re-suspended in physiological saline
and incubated at 37 degrees C for 4 h. A monocyte migration bioassay revealed the
presence of a single active chemotactic factor in the supernatant from this incubation. The
chemotactic factor was concentrated by solid phase chromatography and purified by
reverse phase high pressure liquid chromatography. The factor was shown to be
indistinguishable from diethyl phthalate (DEP) on the basis of multiple criteria including
nuclear magnetic resonance spectroscopy, electron impact mass spectroscopy, UV visible
absorption spectrometry, GC and high pressure liquid chromatography retention times,
and chemotactic activity toward monocytes. Control experiments with incubated culture
media without detectable bacteria did not yield detectable DEP, suggesting it is
bacterially derived. It is not known if the bacteria produce diethyl phthalate de novo or if
it is a metabolic product of a precursor molecule present in culture media. DEP produced
by H. pylori in addition to DEP present in man-made products may contribute to the high
levels of DEP metabolites observed in human urine. DEP represents a new class of
chemotactic factor.
Kelman, et al. 1999. Chemical components of shredded paper insulation: a preliminary
study. Appl.Occup.Environ.Hyg. 14(3): 192-197.
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Health Effects of Diethylphthalate
30
We conducted an evaluation of shredded paper insulation to identify potentially toxic
components. The study was to provide a preliminary characterization of a few samples of
insulation currently in use. The following samples were analyzed: previously produced
insulation (PPI) containing fire retardants, shredded recycled paper (PPI feedstock),
freshly produced insulation (FPI), and insulation which had been installed in a residence
(II). Volatile constituents were analyzed by GC-MS from headspace air of samples held
at room temperature or heated to 90 degrees C. Extractable constituents were sampled by
extracting with methylene chloride, and analyzing by GC-MS. Formaldehyde analysis
was done according to EPA Method TO11. Headspace air at room temperature contained
no detectable quantities of volatile constituents for any sample measured. In headspace
air at 90 degrees C, only PPI contained traces of aliphatic and aromatic hydrocarbons and
higher aldehydes, and FPI traces of toluene. Extracts of PPI contained traces of
octadecadienoic acid methyl ester and aliphatic and aromatic hydrocarbons and higher
aldehydes. Extracts of PPI feedstock contained traces of a substituted
cyclohexenecarboxylic acid. FPI contained extractable diethyl phthalate (30-50
micrograms/g). Extracts of II contained traces of methyl palmitate, an octadecenoic acid
methyl ester, and a phthalate plasticizer. No formaldehyde was detected. PPI was
composed of approximately 98 percent paper fiber and 2 percent pre-gelatinized starch.
PPI samples agglomerated together with less than 0.01 percent separating from clumps as
fine dust. Boron and sodium were expected and confirmed because they were added to
PPI and FPI as fire retardants. Chromium, copper, iron, potassium, magnesium,
manganese, phosphorus, and silicon were present at detectable concentrations. Study
calculations indicate that an occupant would have to completely consume all the fine
particles produced from 3.3 kg of insulation per day to have an intake of boron equivalent
to the EPA RfD. No other constituent appeared to be present even close to toxicologically
relevant amounts.
Kozumbo, et al. 1982. Assessment of the mutagenicity of phthalate esters.
Environ.Health Perspect. 45: 103-109.
The Ames assay was used to investigate the mutagenicity of several phthalate esters as an
approximation of their carcinogenic potential. The ortho diesters, dimethyl phthalate
(DMP) and diethyl phthalate (DEP) produced a positive dose-related mutagenic response
with Salmonella TA100, but only in the absence of S-9 liver enzymes. Dibutyl, di(2-
ethylhexyl), mono(2-ethylhexyl), and butyl benzyl phthalate as well as the dimethyl
isophthalate and terephthalates and the trimethyl ester, trimellitate, were not mutagenic
with TA100 or TA98 in the presence or absence of S-9. In a host-mediated assay, extracts
of 24-hr urines of rats injected IP with DMP (2 g/kg) were not mutagenic to TA100 at
levels up to 8 equivalent-ml of urine/plate (representing 30% of their daily urinary
output). In vitro studies revealed that S-9 associated esterase hydrolyzed DMP to the
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Health Effects of Diethylphthalate
31
monoester and methanol and eliminated its mutagenicity. Whole rat skin was shown to
have about 1.5% of the DMP-esterase activity of liver, when compared on a wet weight
basis. An in vitro binding study indicated that epidermal macromolecules bound DMP at
a severalfold greater rate than hepatic macromolecules. Thus, both the mutagenicity and
binding of DMP are inversely related to the metabolism of this compound. These results
suggest that skin could be at high risk for a mutagenic/carcinogenic insult.
Lamb, et al. 1987. Reproductive effects of four phthalic acid esters in the mouse.
Toxicol.Appl.Pharmacol. 88(2): 255-269.
These studies compared the reproductive toxicity of four phthalates by a continuous
breeding protocol. Mice were given diets with diethyl phthalate (DEP) (0.0, 0.25, 1.25, or
2.5%), di-n-butyl phthalate (DBP) (0.0, 0.03, 0.3, or 1.0%), di-n-hexyl phthalate (DHP)
(0.0, 0.3, 0.6, or 1.2%), or di(2-ethylhexyl) phthalate (DEHP) (0.0, 0.01, 0.1, or 0.3%).
Both male and female CD-1 mice were dosed for 7 days prior to and during a 98-day
cohabitation period. Reproductive function was evaluated during the cohabitation period
by measuring the numbers of litters per pair and of live pups per litter, pup weight, and
offspring survival. There was no apparent effect on reproductive function in the animals
exposed to DEP, despite significant effects on body weight gain and liver weight. DBP
exposure resulted in a reduction in the numbers of litters per pair and of live pups per
litter and in the proportion of pups born alive at the 1.0% amount, but not at lower dose
levels. A crossover mating trial demonstrated that female mice, but not males, were
affected by DBP, as shown by significant decreases in the percentage of fertile pairs, the
number of live pups per litter, the proportion of pups born alive, and live pup weight.
DHP in the diet resulted in dose-related adverse effects on the numbers of litters per pair
and of live pups per litter and proportion of pups born alive at 0.3, 0.6, and 1.2% DHP in
the diet. A crossover mating study demonstrated that both sexes were affected. DEHP (at
0.1 and 0.3%) caused dose-dependent decreases in fertility and in the number and the
proportion of pups born alive. A crossover mating trial showed that both sexes were
affected by exposure to DEHP. These data demonstrate the ability of the continuous
breeding protocol to discriminate the qualitative and quantitative reproductive effects of
the more and less active congeners as well as the large differences in reproductive
toxicity attributable to subtle changes in the alkyl substitution of phthalate esters.
Lawrence et al 1975 A toxicological investigation of some acute, short-term and chronic
effects of administering di-2-ethylhexyl phthalate (DEHP) and other phthalate esters.
Environ. Res.9:1-11.
Mallinckrodt-Baker, Inc. 2004. DIETHYL PHTHALTE. MSDS [Material Safety Data
Sheet] [http://www.jtbaker.com/msds/englishhtml/D3688.htm].
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Health Effects of Diethylphthalate
32
Mihovec-Grdic, et al. 2002. Phthalates in underground waters of the Zagreb area.
Croat.Med.J. 43(4): 493-497.
AIM: To determine whether and in what concentrations the underground waters, stream
waters, spring water, and tap water from the Zagreb area contain phthalates -- compounds
used as plastic softeners, which have recently been ascribed carcinogenic, mutagenic, and
teratogenic effects. METHOD: The presence of dimethyl phthalate (DMP), diethyl
phthalate (DEP), dibutyl phthalate (DBP), benzylbutyl phthalate (BBP), diethylhexyl
phthalate (DEHP), and dioctyl phthalate (DOP) was determined in a total of 96 samples
of underground waters, stream waters, and tap water from the Zagreb area between
February and June 1998. Identification and quantification of phthalates were performed
by the method of gas chromatography (GC-ECD), with a detection limit of 0.005
microg/L. RESULTS: The presence of one or more phthalates was demonstrated in 93
out of 96 (97%) water samples. The measured values ranged from 0.005 to 18.157
microg/L. Phthalates were detected in 76 out of 77 (98%) underground water samples.
The mean level of all phthalates present in the water samples was 4.879 microg/L.
Median test yielded a significantly increased level of phthalates in the underground
waters from Jakusevac (sampled in February 1998) and Trebe , which are Zagreb and
Samobor city waste dumps, as compared with other sites in the study (overall
median=3.785; chi-square=22.682; p<0.001). Phthalates were found at a mean
concentration of 3.363 microg/L in all 10 water samples from the Sava river, the major
source of the Zagreb alluvium underground waters. In case of drinking water, phthalates
were detected in 7 out of 9 (78%) samples, at a mean concentration of 0.887 microg/L.
As expected, DEHP was the most commonly detected phthalate, found in 78 (81%) water
samples. CONCLUSION: The highest phthalate concentrations were recorded in
underground waters directly related to the proximity of a waste dump. The levels of
phthalates recorded in this study were lower than those reported from other countries and
did not present a threat to human health. Environmental phthalate monitoring should be
continued and their maximum allowed concentrations should be prescribed by
regulations.
National Toxicology Program. 1995. NTP Toxicology and Carcinogenesis Studies of
Diethylphthalate (CAS No. 84-66-2) in F344/N Rats and B6C3F1 Mice (Dermal Studies)
with Dermal Initiation/ Promotion Study of Diethylphthalate and Dimethylphthalate
(CAS No. 131-11-3) in Male Swiss (CD-1(R)) Mice.
Natl.Toxicol.Program.Tech.Rep.Ser. 429: 1-286.
Diethylphthalate and dimethylphthalate are used as phthalate plasticizers, in an extensive
array of products. The chronic dermal toxicity of diethylphthalate was evaluated in male
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Health Effects of Diethylphthalate
33
and female F344/N rats and B6C3F1 mice in 2-year studies. In a series of special studies,
the tumor initiation or promotion potential of diethylphthalate or dimethylphthalate was
evaluated in male Swiss (CD-1(R)) mice by an initiation/promotion model of skin
carcinogenesis. The genetic toxicity of diethylphthalate and dimethylphthalate in
Salmonella typhimurium and cultured Chinese hamster ovary cells was also evaluated. 4-
WEEK STUDY IN F344/N RATS: Groups of 10 male and 10 female rats were dermally
administered diethylphthalate at volumes of 0, 37.5, 75, 150, or 300 &mgr;L (0, 46,
92, 184, or 369 &mgr;g) applied neat, 5 days per week for 4 weeks. All male and
female rats survived to the end of the study. No evidence of dermatotoxicity was
observed, with no adverse clinical signs observed and no effects on weight gain or feed
consumption. Relative liver weights of 300 &mgr;L males and females and 150
&mgr;L females were greater than those of controls. Relative kidney weights of 150
and 300 &mgr;L males and 150 &mgr;L females were greater than those of
controls. No other adverse effects were observed in this study. 4-WEEK STUDY IN
B6C3F1 MICE: Groups of 10 male and 10 female mice were dermally administered
diethylphthalate at volumes of 0, 12.5, 25, 50, or 100 &mgr;L (0, 15, 31, 62, or 123
&mgr;) applied neat, five days per week for 4 weeks. One control female died
before the end of the study; all other mice survived. No evidence of dermatotoxicity or
other adverse clinical signs were observed, and no clear adverse effects on weight gain or
feed consumption were seen. Absolute and relative liver weights of 25 and 100
&mgr;L females were greater than those of the controls. Based on these 4-week
study results, doses of 0, 35, and 100 &mgr;L diethylphthalate were recommended
for the 2-year mouse studies. A chronic study in male and female B6C3F1 mice at 0, 35,
and 100 &mgr;L (applied neat, once per day, 5 days per week) was started and
subsequently stopped after 32 weeks when significant body weight reductions were noted
in treated animals (males and females, 100 &mgr;L groups: 19% lower; males, 35
&mgr;L group: 12% lower; females, 35 &mgr;L group: 10% lower than
controls). Based on these body weight reductions, doses of 0, 7.5, 15, and 30
&mgr;L in 100 &mgr;L acetone were recommended for the restart of the 2-year
mouse study. 2-YEAR STUDY IN F344/N RATS: Based upon the results of the 4-week
study, doses of 0, 100, or 300 &mgr;L diethylphthalate (0, 123, or 369 &mgr;)
were chosen for the 2-year rat study. Groups of 60 male and 60 female rats received the
doses applied neat 5 days per week for 103 weeks and up to 10 animals per group were
evaluated after 15 months. Survival, Body Weights, and Clinical Findings: Survival of
dosed rats during the first 15 months was similar to that of controls. However, 2-year
survival was significantly reduced in all groups of male rats (survival probabilities,
males: 0 &mgr;L, 8%; 100 &mgr;L, 12%; and 300 &mgr;L, 12%). The
mean body weights of 300 &mgr;L males were slightly less than those of the
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
34
controls throughout the study. No adverse clinical signs were observed, including no
evidence of dermatotoxicity. Pathology Findings: No morphological evidence of dermal
or systemic toxicity was observed in male or female rats. Skin neoplasms were not
observed in female rats and were only rarely observed in male rats. A high incidence of
anterior pituitary adenoma occurred in all groups of male and female rats. The incidence
of anterior pituitary adenomas in the 0, 100, and 300 &mgr;L groups were: males,
39/44, 41/49, 41/49; females, 38/50, 33/49, 33/48. The incidence of this benign tumor in
control males (84%) exceeded the historical control mean incidence [feed controls,
(28.7%)] and range (12% to 60%). Anterior pituitary adenomas were considered a
primary contributing factor in the increased mortality observed in all grtor in the
increased mortality observed in all groups, regardless of treatment. A dose-related
decreasing trend in the incidence of mammary gland fibroadenomas was observed in
female rats (21/50, 12/48, 7/50). The incidence of mononuclear cell leukemia in male rats
in this study was lower than the historical incidence and may be attributable to the
shortened life span of male rats. Similarly, the incidence of interstitial cell tumors of the
testes was markedly decreased in all groups of males (4/50, 3/50, 8/50), relative to
historical control rates (90.1&percnt;; range 74&percnt;-98&percnt;). The
incidence of fatty liver degeneration was notably lower in dosed rats than in controls
(males: 26/50, 8/50, 4/51; females: 23/50, 11/50, 3/50). 2-YEAR STUDY IN B6C3F1
MICE: Groups of 60 male and 60 female mice received doses of 0, 7.5, 15, or 30
&mu;L diethylphthalate (0, 9, 18, or 37 &mu;) in 100 &mu;L acetone 5
days per week for 103 weeks with a 1 week recovery period, and up to 10 animals per
group were evaluated after 15 months. Survival, Body Weights, and Clinical Findings:
Two-year survival of dosed mice was similar to that of controls: 43/50, 41/48, 46/50, and
43/50 (males), and 41/50, 38/51, 37/49, and 36/49 (females). Mean body weights of
dosed male and female mice were similar to those of the controls throughout the study.
No adverse clinical signs were observed in mice, including no gross evidence of
dermatotoxicity. Feed consumption by male and female mice was similar to or up to 13%
greater than that by controls. Pathology Findings: No morphological evidence of dermal
toxicity was observed in male or female mice. No skin neoplasms were observed in dosed
male mice. In female mice receiving 30 &mu;L, one squamous cell carcinoma and
one basal cell carcinoma were seen at the site of application. An increased incidence of
liver neoplasms was observed in dosed male and female mice. The incidence of
hepatocellular adenoma or carcinoma (combined) in B6C3F1 mice in the 0, 7.5, 15, and
30 &mu;L groups were: (males) 9/50, 14/50, 14/50, and 18/50; (females) 7/50,
16/51, 19/50, and 12/50. The incidence of adenoma or carcinoma (combined) was
increased in 30 &mu;L male mice and the incidences of adenoma and of adenoma or
carcinoma (combined) were increased in 7.5 and 15 &mu;L females. A positive
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
35
dose-related trend in the incidence of adenoma or carcinoma (combined) was also
observed in male mice. The incidence of basophilic hepatic foci was increased in 15
&mu;L male mice (0/50, 1/50, 9/50, 3/50). The increased incidence of liver
neoplasms in this study was considered equivocal because the incidence of hepatocellular
neoplasms in control and dosed males was within the historical range and because there
was no clear dose-response relationship in females. No other treatment-related findings
were observed in this study. 1-YEAR INITIATION/PROMOTION STUDY IN MALE
SWISS (CD-1&reg;) MICE: Groups of 50 male mice were dosed dermally with
diethylphthalate or dimethylphthalate to study their effect as initiators and promoters.
Diethylphthalate and dimethylphthalate were tested as initiators with and without the
known skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Diethyl
phthalate and dimethylphthalate were tested as promoters with and without the known
skin tumor initiator 7,12-dimethylbenzanthrancene (DMBA). Comparative control groups
used during the study of diethylphthalate and dimethylphthalate included: vehicle control
(acetone/acetone); initiation/promotion control (DMBA/TPA); initiator control
(DMBA/acetone); and promoter control (acetone/TPA). Based on the incidence of skin
neoplasms diagnosed histologically and the multiplicity of skin neoplasms, there was no
suggestion that either diethylphthalate or dimethylphthalate was able to initiate skin
carcinogenesis when chronically promoted by TPA. Further, there was no evidence that
either diethylphthalate or dimethylphthalate was able to promote skin carcinogenesis in
skin previously initiated with DMBA. High incidences of both squamous cell papillomas
and squamous cell carcinomas occurred among the initiation/promotion control animals
initiated with DMBA and promoted with TPA. All TPA-dosed groups had significantly
greater incidences of dermal acanthosis, ulceration, exudation, and hyperkeratosis than
controls. GENETIC TOXICOLOGY: Neither diethylphthalate (10-10,000
&mu;/plate) nor dimethylphthalate (33-6,666 &mu;/plate) induced gene
mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with
or without rat and hamster liver S9. In cultured Chinese hamster ovary cells, both
diethylphthalate and dimethylphthalate induced sister chromatid exchanges in the
presence of S9. Neither induced sister chromatid exchanges in the absence of S9. Neither
chemical induced chromosomal aberrations, with or without S9, in cultured Chinese
hamster ovary cells. CONCLUSIONS: Under the conditions of these 2-year dermal
studies, there was no evidence of carcinogenic activity of diethylphthalate in male or
female F344/N rats receiving 100 or 300 &mu;L. The sensitivity of the male rat
study was reduced due to low survival in all groups. There was equivocal evidence of
carcinogenic activity of diethylphthalate in male and female B6C3F1 mice based on
increased incidences of hepatocellular neoplasms, primarily adenomas. In an
initiation/promotion model of skin carcinogenesis, there was no evidence of initiating
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
36
activity of diethylphthalate or dimethylphthalate in male Swiss (CD-1&reg;) mice.
Further, there was no evidence of promotion activity of diethylphthalate or
dimethylphthalate in male Swiss (CD-1&reg;) mice. The promoting activity of TPA
following DMBA initiation was confirmed in these studies. Minor dermal acanthosis was
observed following dermal application of diethylphthalate in male and female F344/N
rats dosed for 2 years and in male Swiss (CD-1&reg;) mice dosed for 1 year.
Synonyms: Diethylphthalate (CAS No. 84-66-2): 1,2-benzenedicarboxylic acid, diethyl
ester; DEP; diethyl 1,2-benzenedicarboxylate; diethyl o-phthalate; diethyl phthalate; ethyl
phthalate; o-benzenedicarboxylic acid diethyl ester; phthalic acid, diethyl ester; RCRA
U088 Dimethylphthalate (CAS No. 131-11-3): 1,2-benzenedicarboxylic acid, dimethyl
ester; dimethyl 1,2-benzenedicarboxylate; dimethyl benzene-o-dicarboxylate; dimethyl
benzeneorthodicarboxylate; dimethyl o-phthalate; dimethyl phthalate; DMP; FIFRA
028002; methyl phthalate; go-dimethyl phthalate; phthalic acid, dimethyl ester; phthalic
acid methyl ester; RCRA U102
Oliwiecki, et al. 1991. Contact dermatitis from spectacle frames and hearing aid
containing diethyl phthalate. Contact Dermatitis. 25(4): 264-265.
Olsen, et al. 1982. Nephrotoxicity of plasticizers investigated by 48 hours hypothermic
perfusion of dog kidneys. Scand.J.Urol.Nephrol. 16(2): 187-190.
The possible nephrotoxicity of the plasticizers diethyl phthalate and di-2-ethylhexyl
phthalate was tested in vitro using a 48 hours continuous pulsatile hypothermic perfusion
of canine kidneys with a human albumin perfusion medium. Since polysorbate 80 was
used to facilitate the solution of the plasticizers in the perfusion medium, this substance
was also tested. Six groups containing 9--15 kidneys were perfused with different
amounts of plasticizers and/or polysorbate 80 added. In perfusates containing polysorbate
80 either alone or with one of the two plasticizers, the LDH activity and the potassium
concentrations rose significantly higher than in the control group (p less than 0.001). The
kidney weight gain was also significantly greater in these groups. A "blind"
histological examination of needle biopsies by light microscopy revealed no differences
among the groups. Although the biochemical evidence of tissue damage was not tested by
re-implantation of the kidneys, we suggest that caution should be exercised in the use of
polysorbate 80 in organ perfusion systems.
O'Neil et al 2001. Merck Index 13th ed. (White House Station, NJ. Merck and Co.)
Otake et al 2004. Exposure to phthalate esters from indoor environment. J Expo Anal
Environ Epidemiol. Mar 24 [Epub ahead of print]
Phthalate esters and phosphate esters in samples of indoor air from 27 houses in the
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
37
Tokyo Metropolitan area were quantified using gas chromatograph/mass spectrometer
and gas chromatograph/flame photometric detector after adsorption on to charcoal and
solvent extraction. The median concentrations of diethyl phthalate, dibutyl phthalate
(DBP), butylbenzyl phthalate, dicyclohexyl phthalate and diethylhexyl phthalate were
0.10, 0.39, 0.01, 0.07 and 0.11 microg/m(3), respectively. The median concentrations of
tributyl phosphate, tris(2-chloroethyl) phosphate, triphenyl phosphate and tris(2-
butoxyethyl) phosphate were less than 0.001 microg/m(3). DBP was detected at the
highest concentration (6.18 microg/m(3)) in a new residential housing. This research
indicated that exposure to phthalate esters through inhalation of air from the indoor
environment is as important as dietary intake of phthalate esters, and can contribute to
daily intake to a much greater extent than has been assumed hitherto.Journal of Exposure
Analysis and Environmental Epidemiology advance online publication, 24 March 2004;
doi:10.1038/sj.jea.7500352
Parthasarathy, et al. 2002. Ethyl cellulose and polyethylene glycol-based sustained-
release sparfloxacin chip: an alternative therapy for advanced periodontitis. Drug
Dev.Ind.Pharm. 28(7): 849-862.
This study reports the development of a sustained-release system of sparfloxacin for use
in the treatment of periodontal disease. A sustained-release sparfloxacin device was
formulated, based on ethyl cellulose (EC) 10 cps, polyethylene glycol (PEG) 4000, and
diethyl phthalate (DEPh). It will hereafter be called the sparfloxacin chip (SRS chip). The
chip has dimensions of 10 mm length, 2 mm width, and 0.5 mm thickness. The in vitro
drug release pattern and clinical evaluation of the formulations were studied. Reports of
the short-term clinical study show that the use of the SRS chip may cause complete
eradication of the pathogenic bacteria in the periodontal pockets of patients who have
chronic generalized periodontitis. In this clinical study, the baseline and follow-up
measurements of various clinical indices, such as oral hygiene index(es), plaque index,
sulcular depth component of periodontal disease index, gingival crevicular fluid flow
measurement, and dark field microscopic examinations of oral pathogens in plaque
samples were studied. Significant improvements were observed in many parameters of
the treatment group compared with the placebo group.
Pragst, et al. 2000. Are there possibilities for the detection of chronically elevated
alcohol consumption by hair analysis? A report about the state of investigation. Forensic
Sci.Int. 107(1-3): 201-223.
The analysis of suitable ethanol markers in hair would be an advantageous tool for
chronic alcohol abuse control because of the wide diagnostic window allowed by this
specimen and the possibility of segmental investigation. Between the markers practically
used or thoroughly investigated in blood or urine, ethylglucuronide, fatty acid ethylesters,
phosphatidylethanol, acetaldehyde adducts to protein and 5-hydroxytryptophol can be
regarded as possible candidates also in hair, but preliminary data were found in the
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
38
literature only for ethylglucuronide and acetaldehyde modified proteins. By using
headspace gas chromatography and headspace solid phase microextraction in
combination with gas chromatography-mass spectrometry (SPME-GC/MS), in alkaline
hydrolysates of hair it was possible to determine between 17 and 135 ng/mg of ethanol
beside acetone and several other volatile compounds with slightly higher ethanol values
for alcoholics than for social drinkers and teetotalers. A part of this is ethanol only
absorbed in the hair matrix from the surrounding environment and consequently is not
applicable as a diagnostic criterion. By extraction with aqueous buffer, methanol or a
methanol/chloroform mixture and subsequent alkaline hydrolysis it was found that
another part is generated from ethylesters, which are preferentially deposited in the lipid
fraction of hair. In a specific search for ethylesters of 17 carboxylic acids by GC/MS-SIM
in most cases ethyl 4-hydroxybenzoate (0.1 to 5.9 ng/mg, a preservative in hair
cosmetics) and in four cases traces of indolylacetic acid ethylester were found.
Furthermore, diethyl phthalate (a softening agent, present also in many cosmetic
products) was identified in the hair of alcoholics as well as of children. As potential
markers of alcohol intake, ethyl palmitate, ethyl stearate and ethyl oleate were detected in
hair samples of alcoholics by headspace SPME-GC/MS of the chloroform/methanol
extracts.
Project 112 2004. Project SHAD Glossary. DeploymentLink [DoD].
[http://deploymentlink.osd.mil/current_issues/shad/shad_glossary.shtml]
Project 65-17 2004. Fearless Johnny. DeploymentLink [DoD].
[http://deploymentlink.osd.mil/pdfs/fearless_johnny.pdf]
RTECS [Registry of Toxic Effects of Chemical Substances] 2004. Diethyl Phthalate.
http://www.cdc.gov/niosh/rtecs/ti100590.html.
Saarma, et al. 2003. Heat shock protein synthesis is induced by diethyl phthalate but not
by di(2-ethylhexyl) phthalate in radish (Raphanus sativus). J.Plant Physiol. 160(9): 1001-
1010.
The toxicity and effects on protein synthesis of the phthalate esters diethyl phthalate
(DEP) and di(2-ethylhexyl) phthalate (DEHP) was studied in radish seedings (Raphanus
sativus cv. Koopenhaminan tori). Phthalate esters are a class of commercially important
compounds used mainly as plasticizers in high molecular-weight polymers such as many
plastics. They can enter soil through various routes and can affect plant growth and
development. First the effect of DEP and DEHP on the growth of radish seedings was
determined in an aqueous medium. It was found that DEP, but not DEHP, caused
retardation of growth in radish. A further investigation on protein synthesis during DEP-
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
39
stress was executed by in vivo protein labeling combined with two-dimensional gel
electrophoresis (2D-PAGE). For comparisons with known stress-induced proteins a
similar experiment was done with heat shock, and the induced heat shock proteins (HSPs)
were compared with those of DEP-stress. The results showed that certain HSPs can be
used as an indicator of DEP-stress, although the synthesis of most HSPs was not affected
by DEP. DEP also elicited the synthesis of numerous proteins found only in DEP-treated
roots. The toxic effect of phthalate esters and the roles of the induced proteins are
discussed.
Schulsinger, et al. 1980. Polyvinyl chloride dermatitis not caused by phthalates. Contact
Dermatitis. 6(7): 477-480.
Seven cases of contact dermatitis in children due to identification bracelets made of
polyvinyl chloride plastic are reported. Patch tests with the bracelets were negative in the
five cases tested. It is concluded that the reactions were irritant due to some unknown
chemical in the bracelets. The most widely used plasticizers in PVC, phthalates, must
have very low sensitizing properties, as only one positive patch test was found in 1532
patch tests with phthalate mix, performed as a joint study by the International Contact
Dermatitis Research Group.
Scott, et al. 1987. In vitro absorption of some o-phthalate diesters through human and rat
skin. Environ.Health Perspect. 74: 223-227.
The absorption of undiluted phthalate diesters [dimethyl phthalate (DMP),
diethylphthalate (DEP), dibutyl phthalate (DBP) and di-(2-ethylhexyl)phthalate (DEHP)]
has been measured in vitro through human and rat epidermal membranes. Epidermal
membranes were set up in glass diffusion cells and their permeability to tritiated water
measured to establish the integrity of the skin before the phthalate esters were applied to
the epidermal surface. Absorption rates for each phthalate ester were determined and a
second tritiated water permeability assessment made to quantify any irreversible
alterations in barrier function due to contact with the esters. Rat skin was consistently
more permeable to phthalate esters than the human skin. As the esters became more
lipophilic and less hydrophilic, the rate of absorption was reduced. Contact with the
esters caused little change in the barrier properties of human skin, but caused marked
increases in the permeability to water of rat skin. Although differences were noted
between species, the absolute rates of absorption measured indicate that the phthalate
esters are slowly absorbed through both human and rat skin.
Seed. 1982. Mutagenic activity of phthalate esters in bacterial liquid suspension assays.
Environ.Health Perspect. 45: 111-114.
The mutagenic activities of several phthalate esters have been evaluated in an 8-
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
40
azaguanine resistance assay in Salmonella typhimurium. Three phthalate esters were
found to be mutagenic: dimethyl phthalate, diethyl phthalate and di-n-butyl phthalate. A
number of other phthalate esters were not found to be mutagenic, including di(2-
ethylhexyl) phthalate, di-n-octyl phthalate, diallyl phthalate, diisobutyl phthalate and
diisodecyl phthalate. A metabolite of di(2-ethylhexyl) phthalate, 2-ethylhexanol, was also
noted to be mutagenic. The mutagenic activity of this agent and others in this series was
dose dependent but weak. No dose-response curve exceeded more than 3.5 times
background at maximally testable concentrations. A liquid suspension histidine reversion
assay of dimethyl phthalate showed levels of mutagenic activity similar to that observed
in the azaguanine resistance assay. The data suggest a need for further investigation of
the mutagenic potential of these agents in other assay systems.
Silva, et al. 2004. Urinary levels of seven phthalate metabolites in the U.S. population
from the National Health and Nutrition Examination Survey (NHANES) 1999-2000.
Environ.Health Perspect. 112(3): 331-338.
We measured the urinary monoester metabolites of seven commonly used phthalates in
approximately 2,540 samples collected from participants of the National Health and
Nutrition Examination Survey (NHANES), 1999-2000, who were greater than or equal to
6 years of age. We found detectable levels of metabolites monoethyl phthalate (MEP),
monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono-(2-ethylhexyl)
phthalate (MEHP) in > 75% of the samples, suggesting widespread exposure in the
United States to diethyl phthalate, dibutyl phthalate or diisobutylphthalate, benzylbutyl
phthalate, and di-(2-ethylhexyl) phthalate, respectively. We infrequently detected
monoisononyl phthalate, mono-cyclohexyl phthalate, and mono-n-octyl phthalate,
suggesting that human exposures to di-isononyl phthalate, dioctylphthalate, and
dicyclohexyl phthalate, respectively, are lower than those listed above, or the pathways,
routes of exposure, or pharmacokinetic factors such as absorption, distribution,
metabolism, and elimination are different. Non-Hispanic blacks had significantly higher
concentrations of MEP than did Mexican Americans and non-Hispanic whites. Compared
with adolescents and adults, children had significantly higher levels of MBP, MBzP, and
MEHP but had significantly lower concentrations of MEP. Females had significantly
higher concentrations of MEP and MBzP than did males, but similar MEHP levels. Of
particular interest, females of all ages had significantly higher concentrations of the
reproductive toxicant MBP than did males of all ages; however, women of reproductive
age (i.e., 20-39 years of age) had concentrations similar to adolescent girls and women 40
years of age. These population data on exposure to phthalates will serve an important role
in public health by helping to set research priorities and by establishing a nationally
representative baseline of exposure with which population levels can be compared.
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
41
Singh, et al. 1975. Maternal-fetal transfer of 14C-di-2-ethylhexyl phthalate and 14C-
diethyl phthalate in rats. J.Pharm.Sci. 64(8): 1347-1350.
14C-Di-2-ethylhexyl and 14C-diethyl phthalates were administered intraperitoneally to
pregnant rats on either Day 5 or 10 of gestation. Rats were sacrificed at 24-hr intervals
starting on Days 8 and 11, respectively; maternal blood, fetal tissue, amniotic fluid, and
placentas (whenever possible) were obtained. The 14C-activity of each sample was
determined by scintillation counting. It was found that both diesters and/or their
metabolic products were present in each of these compartments throughout the gestation
period, thus suggesting that the embryo-fetal toxicity and teratogenesis reported
previously could be the results of a direct effect of the compound (or its metabolites)
upon developing embryonic tissue. Additionally, the reduction in concentration of 14C
from these tissues as a function of time was found to fit a first-order excretion curve.
From this model curve, the half-life for both compounds was calculated; the average was
about 2.33 days for di-2-ethylhexyl phthalate and 2.22 days for diethyl phthalate.
Singh et al 1972. Teratogenicity of phthalate esters in rats. J Pharm Sci. 61(1):51-5.
Smirnov, et al. 1983. [Experience with the diagnosis and treatment of scabies]. Voen
Med.Zh. (4)(4): 60-61.
Sonde, et al. 2000. Simultaneous administration of diethylphthalate and ethyl alcohol and
its toxicity in male Sprague-Dawley rats. Toxicology. 147(1): 23-31.
Phthalate esters have been implicated as xenoestrogens. One among them is di-
ethylphthalate (DEP), which is used as plasticizer, detergent base, and binder in incense
sticks and after-shave lotions. DEP is one of the contaminants of freshwater and marine
ecosystems. Incense stick workers are occupationally exposed to DEP and some workers
are chronic alcoholics. Therefore, a study was undertaken to evaluate the interactive
toxicity of DEP with ethyl alcohol (EtOH) in young male Sprague-Dawley rats. The rats
were given 50 ppm DEP (w/v), 5% EtOH (v/v) and a combined dose of 50 ppm DEP
(w/v)+EtOH (5% v/v) in water ad libitum for a period of 120 days and were maintained
on normal diet. Control animals received normal diet and plain water. During the
treatment rats were weighed every week and water consumption per day was measured.
After the completion of treatment, liver weight/body weight, liver weight, body weight,
serum enzymes and other biochemical parameters were assessed. It was found that there
was no significant change observed in body weight, liver weight, liver weight/body
weight and water consumption. It was observed that there was a significant decrease in
liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
42
EtOH, DEP and EtOH+DEP treated rats in the order of EtOH>DEP>EtOH+DEP
as compared with control. Serum AST, ALT, acid phosphatase (ACP), alkaline
phosphatase (ALP), succinate dehydrogenase (SDH) and liver ACP showed significant
increase in DEP and EtOH+DEP treated rats in the order of DEP>EtOH+DEP as
compared with control and EtOH treated rats. On the contrary, there was no significant
change in liver ALP levels in treated rats. There was significant increase in liver SDH,
glycogen, total triglyceride, total cholesterol and lipid peroxidation in DEP and
EtOH+DEP treated rats, but no significant changes in the serum SDH, glucose and total
triglyceride levels. Serum total cholesterol levels in DEP and EtOH+DEP treated rats
were significantly high as compared to control and EtOH treated rats. These results show
that there is no interaction of DEP with EtOH but DEP alone leads to severe impairment
of lipid metabolism coupled with toxic injury to the liver as evident from significantly
altered lipid and enzyme levels in the liver and serum. Long term simultaneous exposure
to DEP and EtOH may have severe implications for humans who are occupationally
exposed to these two xenobiotics.
Sugamori, et al. 1989. Microencapsulation of pancreatic islets in a water insoluble
polyacrylate. ASAIO Trans. 35(4): 791-799.
Rat pancreatic islets were encapsulated in a water insoluble polyacrylate (Eudragit RL), a
model polymer, by coaxial extrusion and interfacial precipitation. Despite exposure to
organic solvents and nonsolvents (diethyl phthalate, corn oil, and mineral oil) and to
shear, the islets survived encapsulation. They continued to secrete insulin into the tissue
culture medium and responded to glucose in both static glucose challenges and perifusion
assays as well and as long as control islets which were not encapsulated, but were
maintained in tissue culture alongside the encapsulated islets. Unfortunately, there was a
great deal of variability in the performance of all islets studied, making unequivocal
conclusions difficult. Some encapsulated islets survived more than 140 days in vitro and
histologically appeared healthy. However, there appeared to be a general deterioration in
insulin secretion capacity following prolonged culture in all islets, with corresponding
changes (e.g., central necrosis) visible by microscopy. Although Eudragit RL is not
practical as an encapsulation polymer, this study was useful in demonstrating that islets
may be encapsulated in materials other than alginate-polylysine, and ultimately in
materials that may have a more optimum blend of the desired properties:
biocompatibility, permselectivity, and mechanical durability.
Sung, et al. 2003. Effects and toxicity of phthalate esters to hemocytes of giant
freshwater prawn, Macrobrachium rosenbergii. Aquat.Toxicol. 64(1): 25-37.
Phthalate esters (PAEs) have been considered as environmental pollutants and have been
subject to control in the United States of America and Japan. The aim of this study was to
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
43
investigate the effects and toxicity of eight PAEs to hemocytes and the defense functions
of giant freshwater prawn (Macrobrachium rosenbergii), including hemocytic adhesion,
pseudopodia formation, phenoloxidase (PO) activity, and superoxide anion (O(2)(-))
production, by means of in vitro exposure experiments. After hemocytes were treated
separately with eight PAEs at concentrations of 100 microg/ml, the results showed that
two PAEs (dipropyl phthalate, DPrP and diethyl phthalate, DEP) increased cells with
pseudopodia formation, but decreased adhesive cells; reduction in the percentages of both
pseudopodia formation and adhesive cells were detected in the dihexyl phthalate (DHP)
and diphenyl phthalate (DPP) experiment groups; and di-(2-ethyl hexyl) phthalate
(DEHP) decreased pseudopodia formation, but did not affect the adhesion. In addition,
both PO activity and O(2)(-) production were decreased after hemocytes were treated
with five PAEs (benzyl butyl phthalate (BBP), di-n-butyl phthalate (DBP), DEP, DHP
and DPrP), respectively. At the same time, microscopy showed that both DPrP and DHP
altered morphology of the cell nucleus and led to the presence of vacuoles in cytosol of
hemocytes. Using the annexin assay, and after analysis of DNA fragmentation and
transmission electron microscopy (TEM), it was found that hemocytes exposed to DHP
and DPrP for more than 10 min would primarily die via apoptosis, the fatality correlates
with increasing treatment time; and hemocytes treated with either BBP, dicyclohexyl
phthalate (DCP), DEP or DPP would primarily die via necrosis. According to these
results, we suggest that all eight PAEs examined could damage hemocytes and further
influence the defense mechanism of prawns. This study reveals an important precaution
for prawn cultivation.
Teghtsoonian, et al. 1978. Invariance of odor strength with sniff vigor: an olfactory
analogue to size constancy. J.Exp.Psychol.Hum.Percept.Perform. 4(1): 144-152.
Previous evidence has shown that detection threshold in humans and olfactory neural
discharge rate in animal preparations both depend on flow rate of odorous vapor. But no
data have been reported that show the effects of flow rate in humans on perceived odor
strength at suprathreshold intensities. Subjects learned to inspire at two flow rates, one
twice as great as the other, by adjusting (on a cathode ray tube) the transduced trace of a
sniff-produced pressure change to match either of two target contours. They then made
magnitude estimations of odor strength, while producing either weak or strong sniffs, for
odorants presented over a wide range of concentrations via a specially designed sniff-
bottle system. The odorant, diluted in diethyl phthalate, was n-butanol in two experiments
and n-amyl acetate in two others. Subject-controlled flow rate had no effect on odor
strength for either odorant. There was an apparent contradiction between these data and
those on neural discharge rate that may, however, be resolved by adopting an odor
constancy model: When sniff intensity varies during the olfactory exploration of an odor
source, information about the rate at which odorant molecules are established at the
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
44
receptor site is combined with information about sniff vigor so that the resulting percept
is of invariant odor strength.
Teranishi, et al. 1980. The effects of phthalate esters on fibroblasts in primary culture.
Toxicol.Lett. 6(1): 11-15.
The toxicity of butylbenzyl phthalate(BLP), di-n-heptyl phthalate (DNHP) and n-butyl
lauryl phthalate (BLP) to fibroblasts from newborn rat cerebellum in primary culture was
significant at concentrations of 7.0, 2.7, and 5.0 x 10(-4) M, respectively. The toxicity of
di-methoxyethyl phthalate(DMEP), butyl phthalyl butyl glycolate(BPBG), di-n-octyl
phthalate(DNOP), and di-(2-ethylhexyl) phthalate(DEHP) was not significant. Phthalic
acid and potassium hydrogen phthalate (K-phthalate) were the least toxic to fibroblasts.
Comparison of the toxicity to fibroblasts of five phthalate esters of normal series showed
that dimethyl phthalate(DMP) < diethyl phthalate(DEP) < di-n-butyl
phthalate(DNBP) > DNHP > DNOP.
US EPA. 2004 Integrated Risk Information System (IRIS) [
http://www.epa.gov/iris/subst/0226.htm]
WHO [World Health Organization] 2003 Concise International Chemical Assessment
Document 52 DIETHYL PHTHALATE .
[//www.inchem.org/documents/cicads/cicads/cicad52.htm]
Zaitsev, et al. 1990. [Health-related regulation of diethyl phthalate, di-n-hexyl phthalate
and dialkyl phthalate 810 in water]. Gig.Sanit. (9)(9): 26-28.
On the basis of studies of hygienic regulation of diethylphthalate (DEP), di-n-
hexylphthalate (DHP) and dialkylphthalate-810 (DAP-810) in the water medium) it has
been found out that the compounds are highly persistent in the water medium, are of low
toxicity (LD50 from 10.3 up to 33 g/kg and more for white rats), belong to the third and
fourth (DHP and DAP-810) classes of danger. The threshold concentrations of DEP,
DHP, DAP-810 according to the organoleptic water properties and sanitary regimen of
water reservoirs were determined on the level of 1, 0.46, 0.3 and 0.1, 1, and 1 mg/l
respectively. DEP has moderately expressed cumulative properties while in DHP and
DAP-810 they are clearly expressed. No specific effect was observed in the compounds.
MACs for DEP, DHP and DAP-810 in the water medium are recommended on the level
of 0.1, 0.5 and 0.3 mg/l according to the general toxic and organoleptic indices of
harmfulness.
Zou, et al. 1997. Effects of estrogenic xenobiotics on molting of the water flea, Daphnia
magna. Ecotoxicol.Environ.Saf. 38(3): 281-285.
Contract No. IOM-2794-04-001
Health Effects of Diethylphthalate
45
The effects of five xenobiotics, 2,4,5-trichloribiphenyl (PCB29), the polychlorinated
biphenyl (PCB) Aroclor 1242, diethyl phthalate, lindane, and 4-octylphenol, on molting
of Daphnia magna were investigated. All except PCB29 are known to have unexpected
estrogenicity in vertebrates. Daphnids exposed to PCB29, Aroclor 1242, and diethyl
phthalate took significantly more time to complete four molts than did the controls. The
inhibitory effects of these ortho-chlorinated PCBs suggest that certain structural features,
most probably including ortho-chlorination, are related to the ability of a PCB to affect
molting. Agents with multicyclic structures, such as PCBs, are more effective in
inhibiting molting than are single-ringed xenobiotics, such as diethyl phthalate, which
suggests that hydrophobicity may be a requirement for binding to the ecdysteroid
receptor. These molt-inhibiting agents with multiple rings appear to bear more structural
resemblance to the steroidal molting hormones of arthropods, the ecdysteroids, than do
the single-ringed ones. While the possibility of alternative mechanisms, such as
impairment of ecdysteroidogenesis exists, the results obtained herein support the
hypothesis that some xenobiotics which disrupt endocrine processes in vertebrates can
also interfere with the hormonally regulated molting process in arthropods through acting
as antagonists of endogenous ecdysteroids by binding to and thereby blocking the
ecdysteroid receptor.
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