Newly released documents that supported the FDA’s 1997 approval of Colgate Total toothpaste include indications that its active ingredient, triclosan, may disrupt hormone functions, say three scientists who reviewed the pages. Total’s maker, Colgate-Palmolive, says the FDA’s approval and annual product-safety updates establish that triclosan is safe and effective in toothpaste. Photographer: Susana Gonzalez/Bloomberg
The chemical triclosan has been linked to cancer-cell growth and disrupted development in animals. Regulators are reviewing whether it’s safe to put in soap, cutting boards and toys. Consumer companies are phasing it out. Minnesota voted in May to ban it in many products.
At the same time, millions of Americans are putting it in their mouths every day, by way of a top-selling toothpaste that uses the antibacterial chemical to head off gum disease — Colgate-Palmolive Co.’s Total.
Total is safe, Colgate says, citing the rigorous Food and Drug Administration process that led to the toothpaste’s 1997 approval as an over-the-counter drug. A closer look at that application process, however, reveals that some of the scientific findings Colgate put forward to establish triclosan’s safety in toothpaste weren’t black and white — and weren’t, until this year, available to the public.
The pages show how even with one of the U.S.’s most stringent regulatory processes — FDA approval of a new drug — the government relies on company-backed science to show products are safe and effective. The recently released pages, taken alongside new research on triclosan, raise questions about whether the agency did appropriate due diligence in approving Total 17 years ago, and whether its approval should stand in light of new research, said three scientists who reviewed the pages at Bloomberg News’s request.
Among the pages were studies showing fetal bone malformations in mice and rats. Colgate said the findings weren’t relevant. Viewed through the prism of today’s science, such malformations look more like a signal that triclosan is disrupting the endocrine system and throwing off hormonal functioning, according to the three scientists.
Colgate’s application materials also show that the FDA asked questions about the thoroughness of cancer studies, which are partly addressed in recently released documents.
“We have created a system where we are testing these chemicals out on the human population. I love the idea they are all safe,” Zoeller said. “But when we have studies on animals that suggest otherwise, I think we’re taking a huge risk.”
New York-based Colgate isn’t accused of wrongdoing, and the 35 pages don’t prove triclosan is harmful. It was the FDA’s decision to keep the documents off of its website, Colgate said.
The FDA followed standard procedure by redacting information that had come from a third party, said spokeswoman Andrea Fischer. Some studies were done in the labs of Ciba-Geigy, the first triclosan maker and a predecessor to its current primary maker, BASF SE, according to the documents. The pages didn’t denote which studies were done by an outside party, or who the party was. Fischer declined to identify them.
Colgate said Total’s effectiveness and safety are supported by more than 80 clinical studies involving 19,000 people, and that it gave the FDA 98 volumes, numbering hundreds of pages each, in support of Total. Colgate submits annual reports to the FDA reviewing new science and safety findings, said Colgate spokesman Thomas DiPiazza.
“In the nearly 18 years that Colgate Total has been on the market in the U.S., there has been no signal of a safety issue from adverse-event reports,” DiPiazza said. Colgate also pointed to an independent 2013 review by the Cochrane Oral Health Group, a network of doctors, researchers and health advocates, which found no evidence of harmful effects associated with using Colgate Total.
Total has an important health benefit because it fights plaque and gingivitis, DiPiazza said. Gingivitis can progress to periodontal disease, which affects almost half of Americans 30 and over, according to a 2012 study by the Centers for Disease Control and Prevention.
The FDA reviews all new safety information on ingredients to determine whether a reassessment is necessary, said Jeff Ventura, a spokesman. The agency is revisiting triclosan in hand soaps though not in Total, said Sandra Kweder, deputy director of the agency’s Office of New Drugs. That’s because while triclosan hasn’t been proven superior to soap and water at washing hands, she said, its benefit as an active ingredient in toothpaste was made clear through its FDA approval process.
Colgate removed triclosan from its Softsoap liquid handsoaps and Palmolive antibacterial dish liquid in 2011, citing changing consumer preferences and superior formulations. It said it has no plans to reformulate Total, which is the only triclosan toothpaste approved for U.S. sale.
This article is based on interviews with Colgate, former and current FDA staff and oral biology experts, transcripts of FDA meetings, as well as on the 35 pages, which the FDA shared in January with the Natural Resources Defense Council, a public-health advocate that sued for them. The scientists who examined the pages included Zoeller, a second university-affiliated endocrine specialist, and an environmental toxicologist affiliated with the Environmental Working Group, a public health advocacy.
Of the more than 84,000 chemicals sold in the U.S., few are attracting more scrutiny than triclosan. Used for decades in handsoaps, it is now part of almost 200 products including rugs and pet-food dispensers. Companies including Johnson & Johnson and Procter & Gamble Co. have vowed to remove it from their lineups. In May, Avon Products Inc. announced its plans to go triclosan-free.
Those moves are coming in part as consumers, armed with toxicity ranking systems such as the Environmental Working Group’s Skin Deep Database, have turned away from chemicals including Bisphenol A and phthalates, even in the absence of firm scientific or regulatory conclusions.
Wariness is mounting as factors from environment to diet are blamed for a global rise in endocrine-related diseases. Breast, ovarian, prostate and testicular cancer rates have increased over the past 40 to 50 years, according to a 2012 report from the World Health Organization and the United Nations Environment Programme. A rise in preterm and low birthweight babies, early breast development in girls and undescended testicles in boys may be linked to endocrine-disrupting chemicals, the report says.
Zoeller, the endocrine specialist, said that while an estimated 800 to 1,000 chemicals are believed to disrupt the endocrine system, triclosan is one of about 10 to which people are regularly exposed. “We may not have to change very much to have a big impact,” he said.
Total, the No. 3 selling brand in the U.S., lost 2 percent of its market share last year, with $189.8 million in sales for the year that ended on Jan. 26, according to market research firm Mintel Group Ltd. Colgate’s Tom’s of Maine line grew 14 percent, to $38.9 million, suggesting shoppers are gravitating toward more natural options, the report said.
Procter & Gamble, which makes Crest 3D White and Crest Pro-Health — the top two U.S. toothpastes according to Mintel — has sought to capitalize. A Google search for “triclosan” and “toothpaste” brings up an advertisement linked to a Procter & Gamble site touting Crest products as “100% triclosan free.”
P&G’s oral-care products have been triclosan-free in the U.S. and several other markets “for a number of years,” said Kristopher Parlett, a spokesman for the Cincinnati-based company. P&G doesn’t produce or market triclosan-containing oral care products anywhere, he added.
GlaxoSmithKline Plc, which once had triclosan in some Aquafresh and Sensodyne toothpastes, has reformulated all of its oral care products that previously contained it, said spokeswoman Joanmarie Goddard. She couldn’t say what year they had been reformulated or whether triclosan versions had been sold in the U.S. The decision was a response to consumer concern that triclosan across a range of products “may have a negative environmental impact in the future,” she said.
From its beginnings as an ingredient in surgical hand scrubs, triclosan — also identified as 5-Chloro-2-(2,4-dichlorophenoxy)phenol — has grown to a $100 million a year chemical globally, according to statistics from the Kline Group. BASF, based in Ludwigshafen, Germany, sells it under the trade names Irgasan and Irgacare. India-based Kumar Organic Products Ltd. and Vivimed Labs Ltd. also make it.
BASF says that 40 years of global studies and publications prove triclosan’s efficacy in oral care and cosmetic products, as well as in hand disinfectants and other health-care applications, according to Thomas Nonnast, a spokesman. Klaus Nussbaum, a spokesman for Kumar, said studies have established triclosan’s safety. Vivimed didn’t respond to requests for comment.
While company-sponsored safety tests on triclosan that would become part of Colgate’s FDA application for Total began as early as 1968, U.S. agencies have yet to comprehensively review it for other uses.
In 1974, the FDA proposed issuing a so-called monograph that would determine whether antibacterial ingredients such as triclosan were considered safe and effective for hand soaps. Two years later, the U.S. Toxic Substances Control Act of 1976, which aimed to comprehensively regulate chemicals, grandfathered in existing substances with no safety testing.
The law gave the EPA — which oversees triclosan’s use in durable goods including fabrics and sealants — the power to restrict or test substances. It excluded food, drugs and cosmetics, which fall under the FDA’s mandate. The FDA, four decades after its first promise, has yet to issue a ruling on whether triclosan is safe or effective in soaps.
In the meantime, triclosan made its way into toothpaste.
Colgate spent 10 years and $38 million developing Colgate Total, according to Mintel. Introduced in 1992, it was marketed in almost 100 countries before gaining U.S. approval, according to transcripts of FDA meetings.
Colgate applied to the U.S. starting in 1992, according to FDA records, before gaining the FDA’s blessing on July 11, 1997. In a statement at the time, Colgate called Total “the most significant advancement in home dental care since the introduction of fluoride.”
In the early 2000’s, Caren Helbing, a professor at the University of Victoria in Canada, noticed the SARS outbreak in China had led to a germ-killing frenzy. Seeing triclosan listed as an active ingredient in many antibacterial products, she looked up its chemical structure. It was similar to both thyroid hormones and to polychlorinated biphenyls, or PCBs, she said. Such a structure, she and other scientists have said, allow the chemicals to become active on hormone receptors.
Helbing, who has a Ph.D. in biochemistry and microbiology, found that tadpoles exposed to triclosan developed into smaller froglets and had malformed legs — results that she and other scientists published in the peer-reviewed Aquatic Toxicology journal in 2006.
Other studies found no such links between the chemical and hormone function. A 2011 paper published in Science of the Total Environment found that over four years, the use of triclosan toothpaste had no detectable effect on thyroid function in humans. Three of that study’s five authors received a grant from Colgate. One, Greg Seymour, a professor at the School of Medicine at the University of Queensland, said Colgate requested the analysis of thyroid hormones after it granted them money for a separate study on gingivitis. Colgate had no input on data collection or analysis, he said.
The Cochrane paper, which Colgate cited in its favor, comes to a more complex conclusion. The review of more than 30 studies published from 1990 to 2012 found “moderate quality evidence” that Total is more effective than other toothpastes at fighting gum bleeding and inflammation. On the topic of safety, authors Philip Riley and Thomas Lamont, speaking about the review in a podcast, said the studies didn’t cover enough years to allow them to investigate any long-term ill effects.
“What I would be concerned about is the amount people are exposed to over time,” said William Bowen, a professor emeritus at the University of Rochester Medical Center, who specializes in oral biology and also served on a subcommittee at the FDA that evaluated dental products in the 1990s.
Meanwhile, triclosan is showing up in humans and the environment. It was found in the urine of 75 percent of 2,517 Americans tested, including children, according to a 2003 study by the Centers for Disease Control and Prevention. It and a related chemical, triclocarban, were detected in 90 percent of surface water samples from the Great Lakes and in many fish species, according to a July 2014 study by the Canadian Environmental Law Association.
Scientific studies that have raised health concerns include one 2012 study linking triclosan to reduced fertility in mice, and another that year suggesting it could impair muscle function. A study last year linked it to lowered sperm production and changed sperm shape in rats. Triclosan’s core credentials have also come under scrutiny: While some studies have supported its benefit in killing bacteria, others have found it no more effective than soap and water — and in some cases suggested it could support growth of bacteria including the type that causes staph infections.
In 2010, the European Union banned triclosan in materials that come into contact with food. Three years later, the EPA, which reviewed the chemical in 2008, began another review, 10 years earlier than planned. It cited the “rapidly developing scientific database” on the chemical, which includes studies on thyroid effects, according to its website.
Amid these debates, the Natural Resources Defense Council turned its attention to one of triclosan’s main regulators. In 2013, it sued the FDA for the toxicology data the agency had relied on in approving Colgate Total. In January, the FDA handed the NRDC the 35 pages and later put them online along with a previously unreleased cancer study and other information.
The pages included a summary of a 1992 study showing that pregnant mice receiving higher doses of triclosan had lower-weight fetuses and increased incidence of irregular bone formation in their skulls and paw bones. Five of the 120 mice delivered prematurely. A study on pregnant rats the same year found that at higher doses, rat litters had increased incidence of delayed bone formation in areas including the skull, vertebrae and pelvis.
The application dismissed both results — saying the premature births weren’t dose related and were therefore “incidental.” The bone-formation issues were due to toxic effects on the mother, not the fetus, the summary said.
Not Enough Detail
The summaries didn’t provide enough detail to justify those dismissals, according to the scientists reviewing them.
“Wow. They kept that private?” said Zoeller of the University of Massachusetts. “The distinction between maternal and fetal toxicity is an excuse to do nothing. And it’s not scientifically justifiable.”
Such results could have served as clues for later scientists if they had been made public, said the third reviewer, Johanna Congleton, a scientist at the EWG who has a PhD in Environmental Toxicology from Cornell University.
Since Total’s approval, researchers have gained new insights into chemicals that disrupt the endocrine system. The Total studies focused on whether triclosan had an amplified effect as exposure levels rose — a model consistent with a longstanding belief that the bigger the dose, the greater the poison.
Newer science has shown that even small doses of certain chemicals can significantly affect hormone functions, if they are delivered at the wrong moment — and that rising doses may cause new unpredictable effects, rather than a rising incidence of the same issue. Some of the data Colgate dismissed in the non-public pages are “almost a hallmark of endocrine disruption,” said Helbing, who conducted the study on frogs.
The effects Helbing had documented — smaller froglets and malformed legs — could be seen with doses equivalent to 1/10 of what a person would use in squeezing a pea-sized amount of Total onto a toothbrush twice a day, Helbing said.
The 35 pages of recently released documents also include a cancer study in which triclosan was fed to rats for as long as two years. FDA reviewers deemed the study inadequate, according to the recently released document, and called for another.
Shortly after, in February 1996, an FDA dental-products panel said the agency was working closely on a new cancer study with the Triclosan Industry Alliance — a trade group whose members, according to documents on the FDA’s website, included Colgate, Procter & Gamble and Ciba Specialty Chemicals. Colgate said it believes the alliance no longer exists.
According to the minutes of the meeting obtained through a Freedom of Information Act request, the study was expected in 18 months. Total was approved 17 months later.
An industry group’s study was submitted to the FDA in 1999, said Colgate’s DiPiazza. Both Colgate and the FDA declined to make that study available.
The FDA, in response to a Bloomberg News inquiry, said the agency’s concerns about carcinogenicity had been resolved by a cancer study that was submitted in January 1997. The study, which the FDA put on its website following a Bloomberg News inquiry, “supports the FDA’s conclusion that triclosan does not pose a cancer risk for humans,” DiPiazza said.
David Kessler, a former commissioner of the FDA from 1990 to 1997, just prior to when Colgate Total was approved, said he couldn’t comment on the thoroughness of the agency’s review. Typically, he said, only confidential commercial information is redacted from public documents. It’s the manufacturer’s responsibility, he said, to assure its product is safe and that relevant information is made public.
“The real question is did Colgate do a good job,” Kessler said.
Colgate continues to reference its FDA bona fides. This spring, Minnesota became the first state to pass a triclosan ban. Effective 2017, the state will prohibit the sale of triclosan-based cleaning products for the hands and body — except those with FDA approval, such as Total.
“Colgate came in and lobbied, and said it’s a good product,” said John Marty, a state senator who sponsored the bill.
The FDA, meanwhile, has vowed to deliver the monograph covering triclosan in handsoaps — the one it promised for the first time four decades ago — by 2016.
As part of that review, the agency will look at recent safety data on triclosan, said Kweder, the deputy director of the new drugs office. Kweder said the FDA doesn’t plan to revisit its Total decision but that if it finds concern in its broader review, it could look back into Total’s 1997 approval.
“But we would have to have a good reason to do that,” Kweder said.