Summary of the Scientific Research on Phthalate Esters

American Chemistry Council
Phthalate Esters Panel

The Phthalate Esters Panel takes health allegations very seriously. Because of their extensive use in a variety of applications, phthalate ester plasticizers have been subject to extensive health and safety scrutiny. In fact, phthalate esters constitute some of the most studied and best understood compounds in the US from a health and environmental viewpoint. These data provide scientists with extensive knowledge about these compounds and indicates that at exposure levels likely to be encountered in everyday life, phthalate esters do not cause adverse health effects in humans or wildlife.

Some of the earliest studies of phthalate esters demonstrated that repeated exposure to extremely high doses of phthalates resulted in adverse health effects in laboratory animals. Research then focused on whether these effects would also be seen in humans, or even other species. This information has been provided to government regulators and incorporated into manufacturing and production specifications for flexible vinyl products.

• Effects are observed only at extremely high doses.

The principles of Toxicology have always been to expose rats or mice to the highest possible doses of chemicals as a means to identify the possible effect that a chemical has on the body, but once that adverse effect level is identified, to decrease the dose to the point where we cannot detect a problem. As our experience with extrapolating these effects from animals to humans grew, toxicologists and regulators began to understand that there should be reasonable limits to the highest dose tested because the relevance to human exposure was questionable otherwise. Scientists realized that if effects were only observed when the life of the animal was threatened by very high dose levels, such results were of questionable utility for predicting the impact on humans as exposure levels are much lower. Taking this into account, the dose level at which phthalate esters show adverse effects in laboratory rodents is generally extremely high.

Using exposure statistics extrapolated by ATSDR for two of the most common phthalate esters, human exposure to these compounds is 1,000-10,000 times lower than those needed to produce an effect in laboratory animals. Almost any natural or man-made compound can be toxic given the right dose. However, the levels of human exposure to phthalate esters likely to be encountered in everyday life are not comparable to those used in laboratory testing.

• Effects have only been seen in mice and rats.

Toxicologists have traditionally assumed that rats and mice are suitable models for humans. However, there are many situations where the effects observed in laboratory animals cannot be extrapolated to humans or other species. For example, researchers used other mammals that are more closely related to humans to compare or verify the reproductive effects of phthalate esters seen in mice and rats. Testing on hamsters and marmosets has consistently shown no testicular, reproductive, or toxic effect from exposure to phthalate esters. In addition, the Panel is not aware of reports of adverse human health effects from the use of products containing phthalate esters. Due to the lack of positive results in mammals that are better indicators of the human biological system, the effects observed in rats and mice are not indicative of human health effects.

• High-dose effects are not indicative of endocrine mediated effects.

Based on the reproductive effects that have been observed in high dose studies of phthalate esters, this class of compounds has been included some lists of endocrine modulators. However, the ability of a compound, at high dose levels, to cause reproductive effects does not indicate that a compound will act as an endocrine modulator. For this reason the Phthalate Esters Panel tested these compounds to determine their estrogenic activity. Testing methods include two assays using female rats, one to determine the response of the uterus to the test substance (the uterotrophic assay), and the second to determine if the compound can mimic naturally occurring estrogen in inducing the estrous cycle (the vaginal epithelial cell cornification assay). In each case, the activities of phthalate esters were compared to the activity of estradiol (the natural estrogen). The research showed that none of the phthalate esters elicited estrogenic activity.

• Liver tumors are only seen in rats and mice.

Much of the extensive research about phthalates has been conducted to identify the propensity of these compounds to cause cancer. The evidence shows that when rodents are fed high doses of some phthalates over extended periods of time, liver tumors may occur. Once again, however, the research shows that rodents appear to be uniquely sensitive to this material. Tests were conducted in hamsters and primates -- species more closely related to humans -- and bio-chemical changes that lead to tumors did not occur. As a result of this testing, producers believe phthalates do not pose any cancer risk to humans.

Plasticizer producers are not alone in their opinion, a forum of scientific experts met to evaluate compounds that caused tumors in rats and mice by way of a dose-related proliferation of liver peroxisomes. Scientists have determined that this "peroxisome proliferation" causes the tumors seen in rodents fed high doses of phthalate esters. The goal of the forum was to "determine where consensus might be reached regarding the interpretation of [peroxisome proliferation] relative to the assessment of potential human risks." Made up of government, independent and industry scientists, the forum ultimately concluded: "...that it is unlikely that peroxisome proliferators are carcinogenic to humans under anticipated conditions and levels of exposure..."

In addition, the World Health Organization recognizes that tumors caused by "peroxisome proliferation" may not be applicable to humans. The organization has gone so far as to re-classify several compounds based on cancer effects that were seen in rodents that are not relevant for humans. The Panel believes this is also the case with phthalate esters.

Based on human exposure levels and the lack of evidence showing that humans, or similar mammals, observe the effects seen in mice and rats, the Phthalate Esters Panel believes that there is no threat to humans or wildlife from the use of phthalate esters. Phthalates producers are committed to continued research and testing of these compounds and will work closely with government agencies to ensure these products can be used safely.