Phthalates

1. Phthalates Edwin Chiang May 18, 2005 Bio 2B

2. What are Phthalates? Phthalates are a class of widely used industrial compounds used as plasticizers especially in PVC (polyvinyl chloride) Various types of phthalates Range from one carbon to seventeen carbons PVC plasticizers generally range from 4-13 carbons Examples: DINP (di-isononyl phthalate) DIDP (di-isodecyl phthalate) DBP (di-butyl phthalate)-common ingredient in nail polish DEHP (di-2-ethylhexyl phthalate)-used to make PVC

3. Chemical Properties • Insoluble in water • Soluble in most organic solvents • Colorless liquid with almost no odor • DINP: Superior anti-heat, anti-cold, and anti-volatile properties • DIDP: Low volatile properties, anti-heat and anti-aging properties, and electricity insulation properties

4. Uses of Phthalates • Accounts for 80–90 percent of the world plasticizer consumption • Used primarily as plasticizers in polyvinyl chloride (PVC) products • Child’s toys • Kitchen floor • Building materials • Medical devices: Plastic in IV, blood bags, etc. • Fixatives for perfume, slowing down evaporation and making the scent linger longer

5. Other Uses • Keep nail polish from chipping • Hair sprays • Coatings on numerous pharmaceutical products • New car smell: Partly the pungent odor of phthalates volatilizing from a hot plastic dashboard. In the evening's cool they then condense out of the inside air of the car to form an oily coating on the inside of the windshield. • Make tool handles strong and more resistant to breaking • Nail extenders • Bath soaps • Detergents • Aftershave lotions

6. Exposure • Anything plastic • Fatty items like cheese and meat from food packages • Medical tubing/bags • New car smell • Toys • Cosmetics • Leather • Cables • Products with vinyl • Study on the Levels of Seven Urinary Phthalate Metabolites in a Human Reference Population conducted by Blount, BC, MJ Silva, SP Caudill, LL Needham, JL Pirkle, EJ Sampson, GW Lucier, RJ Jackson, JW Brock in 2000 • Highest level of exposure was women of child-bearing age, • High levels of DEP, DBP, BBP • Likely sources of these exposures are through cosmetics, including hair sprays, nail polishes and perfumes, which are common applications of DBP • DEHP & DINP were not found in high concentrations

7. Exposures(DEHP) • Air • Diethyl phthalate has been measured in the indoor air of a telephone switching office and in outdoor air in Newark, USA, at concentrations ranging from 1.60 to 2.03 µg/m3 and from 0.40 to 0.52 µg/m3, respectively, during a 43-day sampling period (Shields & Weschler, 1987). • Water • Concentrations range from 0.01 µg/litre (in 6 of 10 US cities) to 1.0 µg/litre (in Miami, Florida) found in drinking-water samples from water treatment • US EPA (1989) summarized various studies (originally reported in 1980–1982) in which diethyl phthalate was detected in the groundwater of 33% of 39 public water wells in New York state; other phthalate esters were also detected. Again, it is difficult to determine whether these phthalates originated from the waterworks systems or from sample contaminations.

8. (continue…) • Food • Baked foods in the United Kingdom packaged in cardboard boxes with cellulose acetate windows (containing 16–17% w/w diethyl phthalate) had diethyl phthalate concentrations of 1.7–4.5 mg/kg. It was suggested that diethyl phthalate may volatilize from the plastic window to the food without direct contact or be adsorbed in condensate on the window, which would then fall back onto the food (Castle et al., 1988). Diethyl phthalate was quantified from retort food at concentrations of 0–0.51 mg/kg (Giam & Wong, 1987). Based on the levels of diethyl phthalate found in food by Castle et al. (1988), Kamrin & Mayor (1991) estimated a total daily dietary exposure to diethyl phthalate of 4 mg, assuming daily ingestion of 1 kg of cellulose acetate-wrapped food containing 4 mg diethyl phthalate/kg. This represents a worst-case scenario, as it assumes that most foods are packed in cardboard boxes with cellulose acetate windows containing diethyl phthalate. • Cosmetics • A 2001 survey of fragrance manufacturers in the USA provided maximum concentrations of 1–11% diethyl phthalate in perfume and up to 1.0% in deodorants and other personal cleanliness products. The products may be applied to skin, eyes, hair, and nails, and they may come in contact with mucous membranes and the respiratory tract; contact may be frequent (several times a day) and of prolonged duration (years). Diethyl phthalate is also approved for use as a component of food manufacturing equipment and packaging at unlimited concentrations (Anonymous, 1985) and in drug product containers (Kamrin & Mayor, 1991).

9. Harmful Effects • At high doses of phthalates do constitute risks in the sense of traditional toxicology, these low doses change the stakes dramatically • Male reproductive development is acutely sensitive to some phthalates • DBP & DEHP produced dramatic changes in male sexual characteristics when exposure took place in utero, at levels far beneath those of previous toxicological concern • Males • Hypospadias (anomaly of the urethra ) • Damage of Sertoli cells caused by a metabolite of DEHP, monoethylhexyl phthalate (MEHP) • Low sperm count • Reductions in semen quality • DNA damage to sperm • Females • Premature breast development • Premature birth

10. (continued…) • Carcinogenic • Damaged the liver of rats and mice at high doses • Relevant to humans: unknown

11. Research • Scientists have long known that relatively large doses of some phthalates can lead to health problems, including cancer. • Lower levels may also have negative effects. • Lowest level that produced adverse effects in the rats was 100 mg a day/kg body weight • Animal studies have shown that phthalates can disrupt the endocrine system, inhibiting male hormones and causing male infertility and birth defects • A study published in the Environmental Health Perspectives found that a group of men with DNA-damaged sperm also had higher levels of diethyl phthalate (DEP) - regarded as one of the less toxic phthalates • DINP causes liver damage in animals & constitutes 40% of plastic toys

12. More Studies • DINP can leach out at risky levels when kids suck on them • Study by the Silent Spring Institute found "significant concentrations" of phthalates including DEHP and DBP in air and house dust of 120 Massachusetts houses

13. DEHP & Male Reproductive System • In 1999 Gray, LE, C Wolf, C Lambright, P Mann, M Price, RL Cooper and J Ostby studied effects of anti-androgenic pesticides and toxic substances on male rats • Purpose: See effects on sexual differentiation in male rats • Results: diverse profiles of reproductive malformations in the male rat. • DEHP proved to be highly toxic to the reproductive system of male offspring in transgenerational studies (in which the pregnant female was exposed and effects measured in her offspring). • DEHP induced high levels of testicular and epididymal abnormalities • Atrophy and agenesis.

14. (continue…) • A striking effect of DEHP was noted in 8-day old pups • Several males from different litters displayed hemorrhagic testes that were visible by gross examination of the inguinal region • Conclusion: the testis is a direct target of DEHP during prenatal life One of the endpoints study. measured was the percentage of male pups born with hypospadias (left). Males in the control group never had hypospadias

15. (continue…) The study also determined the percentage of male pups born with areola. Males in the control group never had areolas.

16. Pre-mature Birth • Research: • Took cord blood from babies at birth in a hospital in Brindisi, Italy • Analyzed the blood for DEHP and its metabolite MEHP • Examined the relationships between several aspects of the infants' health at birth and exposure to DEHP and MEHP

17. Pre-mature Birth • Found: • Of 84 babies born consecutively • 11 were preterm • 3 had low birth weight • 4 considered small for gestational age • DEHP and/or MEHP present in 88% of the cord serum samples • Both were present in 77% of samples • Babies with MEHP had a significantly lower gestational age than those without MEHP exposures, averaging 38-39 weeks

18. Other Results from Research • Lowest level that produced adverse effects in the rats was 100 mg/day kg of body weight • About 500 times more than what a 2001 study by CDC found in the general human population • Phthalates found in largest quantities were DBP and DEP , which tend to be used in cosmetics and perfumes • Maximum exposure level w/o adverse affects: 0.1 mg / kg body weight a day (DBP & DEP) • Of 72 name-brand cosmetics - everything from shampoo to perfume to deodorant – 52 had phthalates • Word “phthalate” not on label b/c Federal laws don’t require it

19. Should We Worry ? • Issue since early 1980's • Very controversial • Some sources claim that they pose no risk to humans or environments • Carcinogenic and reproductive effects found in rodents are species specific and of little relevance to humans • Environmental impact considered to be low due to their ready biodegradability and low toxicity

20. (continued…) • European Union conducted a risk assessment on DINP, DIDP and DBP and found no risk • Assessments on DEHP and BBP by EU are still underway • FDA says phthalate-containing beauty products are safe • U.S. Consumer Product Safety Commission concluded after 4 yr study of DINP: children sucked on toys an average of 1.9 minutes per day, and would have to suck for 39 minutes to ingest risky levels • Industry argues that years of phthalate use without visible harm prove product safety.

21. But… • Contrary to EU assessment, toxicologist Paul Foster of the National Institute of Environmental Health Sciences DBP & DEHP is considered to be the most toxic phthalate. • Studies found that human health endpoints are consistent with phthalate damage found in animal experiments.

22. What’s Being Done? • In 1998, U.S. toy manufacturers voluntarily agreed to stop using phthalates in pacifiers and rattlers • The EU has banned DINP in toys for kids 3 and under, while Japan has announced a plan to get rid of DEHP and DINP in toys for kids 6 and under • Still more research

23. Credits • http://www.dcchem.co.kr • http://www.epa.gov/safewater/dwh/c-soc/phthalat.html • http://www.nsc.org/library/chemical/di(2-eth.htm • http://www.atsdr.cdc.gov/tfacts9.html