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Activists have released two similar "reports" in the last two years that make unsubstantiated claims about the use of dibutyl phthalate (DBP) in nail polish and other cosmetics.1 The "reports" are misleading and sometimes outright wrong. DBP has an extensive record of safety testing and safe use, and consumers can remain confident about using products that contain this important ingredient.
The activist "reports" were apparently prompted by the release of data in 2000 by the Centers for Disease Control and Prevention (CDC). The CDC measured the levels of metabolites of DBP and other phthalate esters in the urine of 289 people,2 and reported its findings in an article published in the October issue of Environmental Health Perspectives.3 The CDC measurements actually provide good news - that the measured exposures to DBP are consistent with previous estimates, are within EPA safe levels and should not pose a concern for human health. In fact, the weight of scientific evidence from the extensive safety testing of DBP supports this last conclusion.
When the CDC first released its results, the study authors expressed surprise about the urinary levels that were found, and activists have tried to raise concerns based on these early statements. However, those statements were initial reactions - before calculations were made - to translate the urinary levels into actual exposure levels. Once those calculations were made, it immediately became clear that the measured levels of DBP were not surprising, but rather were consistent with previous estimates of exposure.
DBP is readily metabolized and eliminated from the body - it does not persist or build up. Based on their knowledge of that process, the CDC and the National Institute for Environmental Health Sciences (NIEHS) calculated the actual exposures and published the results in a letter to the editor that also appeared in the October issue of Environmental Health Perspectives.4 The Phthalate Esters Panel independently calculated exposure levels and the results likewise were published in a letter to the editor.5 As shown in Table 1, the CDC/NIEHS and the Panel results are in close agreement.
Furthermore, the exposures calculated from the CDC measurements are in close agreement with previous estimates made by governmental bodies that have evaluated DBP. For example, the World Health Organization estimated average exposures to be 7.4 micrograms per kilogram per day (ug/kg/day).6 Most recently, the National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) estimated general population exposures to DBP to be in the range of 2-10 ug/kg/day.7
Table 1. Exposure to DBP, as Calculated from Measured Urinary Levels (ug/kg/day)
| Source | Average/Mediana | 95th Percentileb | Maximum |
| CDC/NIEHS | 1.5 | 7.2 | 110 |
| Panel | 1.6 | 6.9 | 117 |
a. The CDC/NIEHS provided the median value. The Panel provided the geometric mean.
b. Ninety-five percent of the values were at or below this level.
In determining whether a chemical poses a risk to human health, the question is not just whether there is exposure to the chemical, but how those exposures compare to levels at which health effects might be expected. Comparison of the CDC data to assessments by both the NTP and CERHR and the Environmental Protection Agency indicate that even the highest exposures to DBP are not a concern for human health.
1. NTP CERHR Finds Minimal to Negligible Concern for DBP Exposures
In October 2000, the CERHR published the findings of its Expert Panel on Phthalates. The Expert Panel, composed of 16 distinguished scientists from government, academia and independent research organizations, carefully reviewed over 1,000 studies on seven phthalate esters, including DBP. The Expert Panel focused its review on studies of potential reproductive and developmental toxicity. For DBP, the Expert Panel made the following conclusions:
"The Expert Panel has negligible concern for adult reproductive toxicity."
"The Expert Panel has minimal concern about effects to human development and development of the reproductive system from current estimated exposure to DBP."8
These government findings provide consumers with the good news that they can have confidence in products containing DBP. The first activist report, Beauty Secrets, ignored that good news and tried to create public alarm by claiming that the CERHR estimates of exposure were shown to be wrong when the CDC published its results. But, as explained above (Section A), the CDC measured results are in fact in very close agreement with the estimates.
The activists base their alarmist statements on the fact that the maximum values measured by the CDC were higher than the CERHR estimate. However, even these values are far below levels that have caused effects in laboratory animals. For example, the CERHR identified a no-effect dose for DBP of 50 mg/kg/day (50,000 ug/kg/day). This is a level at which no developmental toxicity was observed in rats. The maximum exposure measured by the CDC is over 400 times below this dose. In general, for this type of developmental study, a margin of safety of 100 or more is considered acceptable for protection of human health.9
2. EPA's Safe Dose (RfD) for DBP
EPA scientists have established a "reference dose" (RfD) for DBP, which is the dose to which a human can be exposed on a daily basis for a lifetime with no appreciable probability of experiencing adverse effects. In other words, EPA considers the RfD essentially
as a safe level of exposure. The EPA uses a number of conservative assumptions in deriving the RfD, so that even exposures somewhat above the RfD are not necessarily of concern.
To establish the RfD for DBP, EPA selected a study of rats in which there was increased mortality in animals that received a dose of 600 milligrams per kilogram per day (mg/kg/day).10 At 125 mg/kg/day, no effects were observed.11 EPA divided this no-effect level by a factor of 10 to account for the possibility that humans are more sensitive to DBP than are rats, a factor of 10 to account for difference in sensitivity among humans, and yet another factor of 10 to account for "deficiencies" in the study.
Thus, in total, EPA divided the no-effect level by a factor of 1,000 to derive the RfD. This gives a value of 0.125 mg/kg/day (or 125 ug/kg/day), which EPA rounded to 0.1 mg/kg/day (or 100 ug/kg/day).12
Because of the conservative assumptions used by EPA (the starting point is a dose at which no effects were observed, and this is reduced by a factor 1,000), even exposures somewhat above the RfD would not likely cause health effects.
3. Exposures At or Within EPA's Safe Dose
As shown in Table 1, the average measured exposure to DBP is 1.5 to 1.6 ug/kg/day, which is over 60 times below the RfD. And this, in turn, is 1,000 times below a level at which no effects were seen in animals.
Ninety-five percent of the exposures were at or below 6.9 to 7.2 ug/kg/day - which is more than 10 times below EPA's conservative RfD.
The maximum value was 110 to 117 ug/kg/day, which is essentially the same as the RfD of 100 ug/kg/day.13 And, it should be noted that already incorporates a safety factor of 1,000.
In short, all of the exposures measured by the CDC were at or below EPA's conservative safe dose, showing that exposures to DBP pose no health concerns.
4. An Updated RfD Would Be Higher
The study that is the basis for EPA's RfD was published in 1953. The first activist report, Beauty Secrets, pointed out that EPA gave the RfD "low" confidence. It claimed that if the RfD were "brought up to modern standards," the RfD would be lower, so that some of the CDC exposure values would be higher than the RfD (or "within the zone of concern")14. This claim is inaccurate. In all likelihood, bringing the RfD "up to modern standards" would result in a higher RfD, so that the EPA-determined margin of safety between the measured exposures and the RfD would be even greater.
The Panel agrees that better studies are available for developing an RfD than the 1953 study used by EPA.15 In fact, the Panel has often advocated that EPA revise the RfD using more recent studies on DBP. Beauty Secrets notes that a recent developmental toxicity study in rats "found a 'safe' dose" (or no-effect level) of 50 mg/kg/day.16 Under EPA's methodology, this value would be decreased by a factor of 10 to account for the possibility that humans are more sensitive than rats, and by another factor of 10 to account for potential differences among humans. Because this is a state-of-the-art study, EPA would not have the same concerns that it had for the 1953 study, and, therefore, may not apply any further safety factor.17
Thus, the RfD using modern standards probably would be 0.5 mg/kg/day, or 500 ug/kg/day. Even the maximum exposure measured by the CDC is 5 times below this value, which is itself 100 times below a level at which no effects were seen in the laboratory animals.
The misleading way in which the activists have presented the data makes DBP exposures seem alarming. A rational presentation of the data demonstrates that this ingredient is safe when formulated in nail polish and other cosmetics and used in accordance with label directions.
As shown above, there is ample evidence that the activists' claims are largely, if not totally, unfounded and alarmist. Perhaps that is why Beauty Secrets went further and alleged that DBP and other phthalates somehow contribute to alleged "disturbing trends in male reproductive health."18 While we appreciate the activists' desire to explain the perceived health trends, such an explanation should be derived through scientific and rational inquiry. There are two major flaws in the activists' assertions. First, it is not at all clear that such trends are occurring. Second, even if the trends are real, there is no scientific basis to link them to phthalates.
One of the trends that the activists claim is occurring is declining sperm count. Although they refer to an article that supports this position, what activists failed to acknowledge are the many other studies that have found no such declines.19 In fact, this issue is currently being debated in the scientific community.
Beauty Secrets also claims that there have been increases in the rates of hypospadias, undescended testicles, and testicular cancer. What increased were reports of these effects in the 70's and 80's - but that does not mean the rates of these effects have actually increased. Rather, it is quite possible that changes in medical diagnosis and reporting procedures are responsible for the apparent increases.
But even if these trends actually are occurring, it is highly speculative and unscientific to attribute them to phthalates. In fact, the available scientific evidence indicates it is most unlikely that phthalate exposures have contributed to such effects in humans. The activists base their speculation on effects in rats and mice that have been exposed to high levels of phthalates. However, the available evidence demonstrates that effects observed in rats and mice either are not relevant to humans, or would be a concern only at very high exposure levels - levels hundreds to thousands of times higher than those measured by the CDC. For example, studies in monkeys, which are much more closely related to humans than are rodents, have shown no testicular effects even at levels much higher than the doses that cause testicular effects in rats.20 The activists completely ignore these primate studies in their report.
Furthermore, as demonstrated above (Section B), actual human exposures to phthalates, as measured by the CDC, are hundreds to thousands of times below the levels at which effects have been seen in rodents treated with phthalates. (The discussion above focused on DBP, as do the activists, but the CDC's results show that exposures to other phthalates are likewise below levels of concern.21) Thus, the scientific data do not support the speculation that phthalates are contributing to alleged (but unproven) trends in male reproductive health.
Contrary to the claim in Beauty Secrets,22 DBP does not have "well recognized effects" on the immune system. In fact, researchers have noted: "Sensitization to dibutyl phthalate in cosmetics and pharmaceuticals is rare."23
There is a significant body of animal research that indicates that phthalates, including DBP, do not trigger an allergic reaction. In addition, there are data on human allergic response to phthalates. There have been some rare case reports of individuals who appeared to be sensitized to DBP. These individuals are in contrast to nearly 2000 others who failed to show any allergic response when they were tested for reaction to DBP.24
Beauty Secrets focuses on one of the rare case reports in which a patient had a severe allergic reaction after taking an oral pharmaceutical that contained a number of chemicals, including DBP. The patient tested positive for reaction to DBP.25 The study authors noted that this was the first such case in the literature, and that the other materials in the drug should be taken into consideration as potentially contributing to the patient's reaction.
The possibility of such a reaction should not be taken lightly and deserves further analysis and research. Factors such as test methods, individual characteristics, and other chemical exposures need to be considered in evaluating the responses. Until the science can determine why only a few rare individuals appear to react to DBP while the vast majority does not, the activists' claims are simply alarmist, given the available animal and human data.
By attacking the existing laws for the regulation of chemicals, the Beauty Secrets report tries to make it appear that the use of phthalates in cosmetics has not been well studied. In fact, phthalates are among the best-studied compounds in the world. As stated above, when evaluating seven phthalates, the NTP CERHR Expert Panel had over 1,000 studies to review. The Expert Panel specifically stated that it had "high confidence" in its ability to digest the "strong database" of studies about DBP26. Since the inception of the Phthalate Esters Panel 27 years ago, the Panel and its members have sponsored health and safety research on phthalate esters. This cutting-edge research follows the strictest government and scientific procedures to promote reproducibility, reliability and accuracy. Resulting data and conclusions are peer-reviewed and published in respected scientific journals such as Toxicological Sciences, Fundamental and Applied Toxicology, and Regulatory Toxicology and Pharmacology. The Panel shares its data with government agencies around the globe, such as the U.S. Environmental Protection Agency, the U.S. Food and Drug Administration, the National Toxicology Program, the Consumer Product Safety Commission, and the International Agency for Research on Cancer.
The Panel would be pleased to answer any other questions about phthalates. For additional information, please contact Marian K. Stanley, Manager of the Panel, at
(703) 741-5623 or Marian_Stanley@americanchemistry.com.
1 Houlihan, J. and Wiles, R. (2000). Beauty secrets: Does a common chemical in nail polish pose risks to human health? Environmental Working Group, Washington, DC. [hereafter "Beauty Secrets"]; Houlihan, J., Brody, C. and Schwan, B. (2002). Not too pretty: phthalates, beauty products & the FDA. Environmental Working Group, Coming Clean, Health Care Without Harm.
2 To be precise, the CDC measured the levels of a metabolite of DBP, called monobutyl phthalate, in the urine. Every molecule of monobutyl phthalate is derived from a molecule of DBP; thus, measuring the metabolite in essence measures DBP.
3 Blount, B., et al. (2000). Levels of seven urinary phthalate metabolites in a human reference population. Environmental Health Perspectives 108:979-982 (abstract available at http://ehp.niehs.nih.gov/docs/2000/108p972-982blount/abstract.html).
4 Kohn, M., et al. (2000). Human exposure estimates for phthalates. Environmental Health Perspectives 108:A440-A442 (correspondence) (available at http://ehpnet1.niehs.nih.gov/docs/2000/108-10/correspondence.html#exp).
5 David, R. (2000). Exposure to phthalate esters. Environmental Health Perspectives 108:A440 (correspondence) (available at http://ehpnet1.niehs.nih.gov/docs/2000/108-10/correspondence.html#exp).
6 International Programme on Chemical Safety (1997). Environmental Health Criteria 189: Di-n-butyl phthalate. World Health Organization, Geneva. p. 153.
7 CERHR (2000). NTP-CERHR Expert Panel report on di-n-butyl phthalate. NTP-CERHR-DBP-00. p. 36. (available at http://cerhr.niehs.nih.gov/news/index.html).
8 CERHR (2000). NTP-CERHR Expert Panel report on di-n-butyl phthalate. NTP-CERHR-DBP-00. p. 36. (available at http://cerhr.niehs.nih.gov/news/index.html).
9 EPA (1991). Final guidelines for developmental toxicity risk assessment. Federal Register 56:63798-63826 (Dec. 5, 1991).
10 Smith, C. (1953). Toxicity of butyl sterate, dibutyl sebacate, dibutyl phthalate and methoxyethyl oleate. Arch. Hyg. Occup. Med. 7:310-318.
11 Contrary to the EWG claim that the study looked only at mortality, the researchers also looked at gross pathology and hematology.
12 EPA (1990). Dibutyl phthalate, CASRN 84-74-2. Integrated Risk Information System (available at http://www.epa.gov/IRIS/subst/0038.htm).
13 As indicated in Section B.2., the RfD value without rounding would be 125 ug/kg/day. Expressed another way, if we round the maximum exposure in the same way EPA rounded the RfD, they are both 0.1mg/kg/day, or 100 ug/kg/day. And, to repeat, the RfD (and thus the maximum exposure) is 1000 times below a level at which no effects were seen in rats treated with DBP.
14 EWG Report at 17.
15 As EPA notes, the 1953 study does not indicate whether mortalities observed at 600 mg/kg/day were related to the DBP treatment. Other studies on DBP have not seen increased mortality even at higher doses. Thus, it appears the animals in the 1953 study may have been compromised by disease unrelated to the DBP treatment.
16 EWG Report at 17; Mylchreest, E. et al. (2000). Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to di(n-butyl)phthalate during late gestation. Toxicological Sciences 55:143-151.
17 See EPA (1993). Reference dose (RfD): Description and use in health risk assessments. Background Document 1A (available at http://www.epa.gov/IRIS/rfd.htm); EPA (1991). Final guidelines for developmental toxicity risk assessment. Federal Register 56:63798-63826 (Dec. 5, 1991).
18 EWG Report at 13-14.
19 For example: Saidi, J., et al. (1999). Declining sperm counts in the United States? A critical review. J Urol 161:460-462; Fisch, H., et al. (1996). Semen analyses in 1,283 men from the United States over a 25-year period: no decline in quality. Fertil Steril 65:1009-1014; Paulsen, C., et al. (1996). Data from men in greater Seattle area reveals no downward trend in semen quality: further evidence that deterioration of semen quality is not geographically uniform. Fertil Steril 65:1015-1020; Fisch, H., and Goluboff, E. (1996); Geographic variations in sperm counts: a potential cause of bias in studies of semen quality. Fertil Steril 65:1044-1046; Wittmaack, F., and Shapiro, S. (1992). Longitudinal study of semen quality in Wisconsin men over one decade. Wis Med J 91:477-479; MacLeod, J., and Wang, Y. (1979). Male fertility potential in terms of semen quality: a review of the past, a study of the present. Fertil Steril 31:103-116.
20 Pugh, G., et al. (2000). Effects of di-isononyl phthalate, di-2-ethylhexyl phthalate, and clofibrate in cynomolgus monkeys. Toxicological Sciences 56:181-188; Hall, M., Matthews, A., Webley, L., and Harling, R. (1999). Effects of di-isononyl phthalate (DINP) on peroxisomal proliferation markers in the marmoset - DINP is not a peroxisome proliferator. The Journal of Toxicological Sciences 24:237-244; Kurata, Y., et al. (1998). 13-week repeated-dose study of di(2-ethylhexyl) phthalate (DEHP) in common marmoset. Toxicol. Sci. 42:49-56; Rhodes, C., et al. (1986). Comparative pharmacokinetics and subacute Toxicity of di(2-ethylhexyl)phthalate (DEHP) in rats and marmosets: Extrapolation of effects in rodents to man. Env. Hlth. Perspect. 65:229-308.
21 David, R. (2000). Exposure to phthalate esters. Environmental Health Perspectives 108:A440 (correspondence) (available at http://ehpnet1.niehs.nih.gov/docs/2000/108-10/correspondence.html#exp).
22 EWG Report at 23.
23 Wilkinson, S., and Beck, M. (1992). Allergic contact dermatitis from dibutyl phthalate, propyl gallate and hydrocortisone in Timodine®. Contact Dermatitis 27:197 (1992).
24 Brandt, K. (1985). Final report on the safety assessment of dibutyl phthalate, dimethyl phthalate, and diethyl phthalate. J. Am. Coll. Toxicol. 4:267-303.
25 Gall, H., et al. (1999). Anaphylactic shock reaction to dibutyl-phthalate-containing capsules. Dermatology 199:169-170.
26 CERHR (2000). NTP-CERHR Expert Panel report on di-n-butyl phthalate. NTP-CERHR-DBP-00. p. 36. (available at http://cerhr.niehs.nih.gov/news/index.html).
Last Updated: August 5, 2002
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