The National Toxicology Program Board of Scientific Counselors recommended that toxicity testing be conducted on butylparaben due to the cosmetic preservative's widespread exposure to humans through personal care products, foods and pharmaceuticals.

NTP presented data on the substance, in addition to 14 other ingredients, to the Board of Scientific Counselors during an Aug. 18 meeting in Research Triangle Park, N.C. Butylparaben was one of 11 chemicals the board recommended for toxicology testing.

The agency advised toxicological characterization studies for butylparaben, including tests for genotoxicity, subchronic toxicity, chronic toxicity/carcinogencity and reproductive toxicity as determined appropriate during the study design phase.

The ingredient was nominated for testing by the National Institute of Environmental Health Sciences.

"The rationale for a study of this agent is to presume widespread exposure through personal care products," board member Scott Masten, PhD, Office of Chemical Nomination and Selection NIEHS/NTP, said.

He noted that while two Japanese studies conducted in 2001 and 2002 by Oishi et. al, found negative effects on sperm count and adverse effects on testosterone in rats and mice, neither study assessed reproductive function.

"There appears to be a lack of data on reproductive function," Masten said, adding, "There may be some other data gaps that can also be addressed by further study."

Barbara Pense, PhD, Texas Tech University Health Sciences, suggested that toxicity in children should be considered based on the high potential for exposure to butylparaben in children.

"One of the things that surprised me is all the exposure that babies will undergo with these compounds in baby lotions, in Tylenol, in children's medications and all this," she said.

Parabens have been shown to have adverse effects on the male reproductive system in rodents, as well as estrogenic activity in experimental cell systems and animal models. The Cosmetic Ingredient Review panel plans to review the ingredient during its Sept. 12-13 meeting (¹ Also see "CIR Paraben Review Delayed While Panel Examines Data" - HBW Insight, 28 March, 2005., p. 5).

Butylparaben was nominated by NIEHS for testing last year, but the Board of Scientific Counselors deferred it, citing a lack of background information.

The Cosmetic, Toiletry and Fragrance Association submitted comments to the board supporting the safety of butylparaben in cosmetics as shown in two unpublished studies.

In one in vitro study conducted by CTFA, the association measured dermal penetration of butyl and methyl paraben in a cosmetic vehicle on viable human and rat skin.

The study showed that "while penetration is significant, the skin has substantial capability to metabolize parabens, therefore limiting systemic exposure."

In a "full thickness" pilot study, metabolism of butylparaben on human donor skin was seen to be "essentially complete," according to CTFA.

The trade group also presented a study on male reproduction in rats, challenging the findings of the Japanese study by using the same experimental design but with more animals and additional endpoints.

The CTFA results showed no effects on daily sperm production at orally administered doses up to 1,000 mg/kg/day, unlike the Japanese study, which found significantly decreased sperm production at all doses.

The board expressed concern over discrepancies in the literature. "No compelling hypothesis has been set forth which...would explain the inconsistent outcomes in the literature and the additional studies provided to the NTP in conjunction with its consideration of this compound," Cheryl Walker, PhD, University of Texas, said in prepared comments presented to the board.

The CTFA results raise critical issues to be considered when designing additional studies, Masten pointed out.

"Absorption was greater for both butyl and methyl paraben in human skin preparations than in rat skin preparations, and on the flip side, the metabolism...was lower in human skin preparations than rat skin," he said.

Following Board of Scientific Counselors review, butyl paraben and other nominated ingredients will be presented to the NTP Executive Committee, which will make a final recommendation to the NTP director on whether to test, defer, or not test each of the substances.

Imidazolidinyl urea, an antimicrobial preservative often used in combination with parabens in cosmetics, is another chemical the board recommended testing.

A high production substance used in a wide range of products including baby lotion, skin cream, sunscreens, shampoos, perfumes and hair dyes, the chemical was nominated for NTP review by the National Cancer Institute.

While data on dermatitis reactions exists on the ingredient, there is limited toxicity information, which prompted the board to recommend the chemical for genotoxicity and dermal absorption testing.

The preservative should be evaluated for its possible break-down products, specifically diazolidinyl urea and formaldehyde, NTP adds.

CTFA also commented on the nomination, referencing the NTP's background document noting imidazolidinyl urea's breakdown product diazolidinyl urea was found to be mutagenic in salmonella typhimurium strains.

The association pointed out that while the report does mention a CIR finding that the ingredient is not mutagenic in salmonella typhimurium strains and does not induce micronuclei, it failed to provide technical details on the findings.

CIR had reviewed imidazolidinyl urea in 2001, but decided not to reopen a review of the ingredient (² Also see "CIR "Proactive" Approach To Seeking Controversial Ingredients Data Urged" - HBW Insight, 17 September, 2001., p. 3).

In its comments, CTFA included the three unpublished genotoxicity studies of diazolidinyl urea included in the CIR report, and encouraged NTP to contact CTFA in the future for further information on ingredient reports.

In addition to parabens and imidazolidinyl urea, the NTP board also recommended testing for several other cosmetic ingredients, including 3-dimethyl-aminopropylamine, usnic acid and usnea herb and permanent makeup inks.

NTP decided to defer four ingredients for lack of data under the review process, including 2,6-diaminopyridine, a hair dye ingredient (see ³ Also see "DMAPA Genotoxicity, Dermal Absorption Study Warranted – NTP Board" - HBW Insight, 29 August, 2005. ).

Butylparaben Toxicity Testing Recommended By NTP Board

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