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ALKYLPHENOLS AND ALKYLPHENOL ETHOXYLATES
AN OVERVIEW OF SAFETY ISSUES
January 1999
TABLE OF CONTENTS
ALKYLPHENOLS & ETHOXYLATES RESEARCH COUNCIL
Alkylphenols and Alkyphenol EthoxylatesEXECUTIVE SUMMARY
What happens to alkylphenols and alkylphenol ethoxylates if they reach the environment? Do they pose a significant ecological risk? Do they affect the endocrine system and thereby pose potential health risks? This paper outlines the extensive research on alkylphenols and alkylphenol ethoxylates in the areas of biodegradability, environmental monitoring, aquatic effects and recent hypotheses related to the endocrine system.
Alkylphenols (APs) are a class of chemicals used to manufacture derivatives, mainly alkylphenol ethoxylate (APE) surfactants. APEs, most often nonylphenol ethoxylates (NPEs), are used in many industrial applications and institutional and household cleaning products.
Biodegradability APs and APEs are biodegradable. Field studies and laboratory tests show that APs and APEs biodegrade in the presence of oxygen (oxic conditions).
Environmental Monitoring Studies demonstrate that 92% to 99% of NPEs are removed in well-functioning wastewater treatment plants. Comprehensive monitoring of U.S. rivers receiving wastewater found no nonylphenol (NP) or NPEs in over two-thirds of the samples and only trace levels in remaining samples.
Aquatic Effects U.S. studies indicate that AP and APE concentrations in rivers and lakes are below those which may harm fish and other aquatic organisms. Similar low concentrations were observed in a Canadian study of the St. Lawrence River and the Great Lakes.
Studies also demonstrate that APs and APEs do not build up in the food chain. Fish and other aquatic organisms and laboratory animals rapidly metabolize and excrete APs and APEs.
Endocrine System Effects
Commercial APEs have not demonstrated estrogenic activity in animal tests. While some APE degradation intermediates exhibit weak estrogenic activity, these compounds are thousands of times less potent than natural estrogen. The low environmental concentrations of these substances are not likely to cause a hormonal (or endocrine) response. Recent studies show no effect on reproduction or development in laboratory animals from exposure to nonylphenol at levels hundreds of times higher than potential daily human exposure.In addition, no direct link has been established between a specific environmental substance and any adverse human health effect based on endocrine disruption.
Conclusions
Extensive research demonstrates that APs and APEs are biodegradable and that concentrations in rivers and lakes in the U.S. and Canada are below levels that could have adverse effects on aquatic organisms. The low environmental concentrations of nonylphenol have not been shown to cause reproductive effects. Based on this research, these chemicals do not appear to pose a significant ecological risk or to cause adverse, endocrine-related human health effects.The APE Research Council is working with government and academic scientists in the U.S., Canada and Europe to further the understanding of the health and environmental profile of APs and APEs.
ALKYLPHENOLS AND ALKYPHENOL ETHOXYLATES
AN OVERVIEW OF SAFETY ISSUESINTRODUCTION
Note: This paper focuses primarily on research on nonylphenol, octylphenol and their ethoxylates, which are the most commonly used alkylphenols and alkylphenol ethoxylates. It is intended to answer general questions regarding environmental effects and recent hypotheses related to "endocrine disruption." For further information on the research on alklyphenols and alkylphenol ethoxylates, please contact the APE Research Council.
The APE Research Council is composed of manufacturers, processors, users and raw material suppliers whose purpose is to further an accurate and scientifically sound understanding of the human health and environmental profile of alkylphenols (APs) and alkylphenol ethoxylates (APEs).
This document summarizes the extensive research on these substances in an effort to answer the questions: "What happens to alkylphenols and alkylphenol ethoxylates if they reach the environment?" "Do they pose a significant ecological risk?" "Do they affect the endocrine system and thereby pose potential health risks?" This paper will review the areas of biodegradation, environmental monitoring, aquatic effects and recent hypotheses related to the endocrine system.
Scientists determine the potential environmental and health risks of a substance by identifying and measuring its hazard (the adverse effect it can cause), its potency (the strength of this effect at various doses) and its actual exposure to the environment or to humans. There has been extensive research on APs and APEs in these areas. Based on a thorough review of this research, these chemicals do not appear to pose a significant ecological risk or to cause adverse, endocrine-related human health effects.
A. Description
APEs are surface active agents (surfactants) which are manufactured by reacting alkylphenols with ethylene oxide. An APE molecule consists of two parts (Figure 1). The alkylphenol portion of an APE molecule consists of a hydrocarbon chain attached to phenol. The alkylphenol portion gives APEs the ability to dissolve grease and other substances that are not soluble in water. The ethoxylate portion of an APE is a long chain of two-carbon units connected by oxygen atoms. This structure makes APEs soluble in water and helps remove dirt and grease from soiled surfaces into water.The most widely used APEs in commerce are nonylphenol ethoxylates (NPEs), in which the alkylphenol portion of the structure consists of a 9-carbon side chain. NPEs account for approximately 80% of total APE use with total U.S. production exceeding 500 million pounds per year. Octylphenol ethoxylates (OPEs), which contain an 8-carbon side chain, comprise most of the remaining production.
Most NPEs are clear liquids with varying water solubility, depending on the number of ethoxylate groups present. NPEs containing up to six ethoxylate groups are only slightly soluble in water, while NPEs with more ethoxylate groups are readily soluble in water. The most widely used NPEs have 9 or 10 ethoxylate groups, so the great majority of NPEs in use are easily dissolved by water.
B. Applications & Markets
The major use for APEs is as surfactants which can function as detergents, wetting agents, dispersants, emulsifiers, solubilizers and foaming agents. APEs are important to a number of industrial applications, including pulp and paper, textiles, coatings, agricultural pesticides, lube oils and fuels, metals and plastics. Industrial applications comprise 55% of the APE market. The remaining uses include industrial and institutional cleaning products (30%), household cleaning products (15%) and other uses (<1%). In addition to their role as a raw material for APEs, alkylphenols are used in the preparation of phenolic resins, polymers, heat stabilizers, anti-oxidants and curing agents.
II. BIODEGRADABILITY AND ENVIRONMENTAL MONITORING
A. APE Biodegradation in the Environment
Biodegradation studies primarily have examined the behavior of APEs in wastewater treatment facilities, where most of the products which contain APEs are treated after use.Biodegradation initially results in the conversion of APEs to partially degraded intermediate substances. This "primary biodegradation" rapidly transforms APEs to lower molecular weight substances that can no longer act as surfactants. Under oxic (oxygen-containing) conditions in treatment plants and the environment, APEs break down further into carbon dioxide and water, although this final process (called "mineralization" or "ultimate biodegradation") takes place more slowly.
During APE biodegradation, microbial organisms remove ethoxylate groups from the end of the ethoxylate chain. This may be accomplished by conversion of the end of the ethoxylate chain to a carboxylic acid known as an alkylphenol ether carboxylate (APEC), which then is further degraded. The process of ethoxylate chain degradation continues until one or two ethoxylate units remain. At this stage in the biodegradation process, the phenol "ring" of the APEs and APECs is degraded.
As nonylphenol ethoxylates degrade, nonylphenol (NP) does not appear to be a significant degradation by-product of aerobic processes, and only trace quantities of NP are found in treatment plant discharges (as noted in the next section). Questions regarding NP's resistance to further degradation have arisen because it has low solubility in water and can cling to solid organic matter, such as sewage sludge and river sediment. However, studies using radioactive tracers have demonstrated that the phenol portion of NP is degraded or mineralized in both river water and seawater. NP also passed the standard laboratory test for "inherent biodegradability." Studies also demonstrate that the NP remaining in river and lake sediments and in sewage sludge applied to land continues to biodegrade.
These and other studies show that APs, APEs and APECs are biodegradable in the presence of oxygen.
B. Monitoring Studies
APEs are highly treatable in well-functioning wastewater treatment plants, meaning they are removed or broken down within the time that wastewater resides in the facilities. For example, studies in the U.S. show NPE removal from wastewater ranging from 92% to over 99%, with minor seasonal variations. NPE concentrations in discharges after treatment are low, varying between 50 ppb (parts per billion) and 200 ppb. NP is not released in significant amounts (usually less than 10 ppb) in discharges from well-functioning sewage treatment plants.A comprehensive monitoring study of levels of NP and NPEs in U.S. rivers reviewed samples from 30 randomly selected river locations below effluent discharges from wastewater treatment plants and from industries which likely used NPEs. The researchers designed the study to detect very low concentrations of NP and NPEs and to help determine how many U.S. rivers might have high levels of NPEs and their degradation products in water or sediment.
NP and NPEs were not detected in more than two-thirds of the river water samples. The highest levels found were 1 ppb for NP and the NPEs with one or two ethoxylate groups, 15 ppb for the other NPEs and 6 ppb for NPECs (in a survey of six of the 30 rivers). NP concentrations in river sediment samples averaged a fraction of a ppm (part per million) and ranged from non-detected to 3 ppm. The highest concentrations in water and sediment were associated with polluted rivers, likely due to inadequate wastewater treatment.
A more intensive study of NPE levels was conducted on the lower Fox River, a river in Wisconsin which receives wastewater discharges from many paper manufacturing plants and municipal treatment plants. Concentrations of NP and NPEs in river water were comparable to the 30 Rivers Study. Concentrations of NPECs ranged from non-detected to 13 ppb in the river.
In Canada, an environmental monitoring study conducted on 35 sites in the Great Lakes basin and the upper St. Lawrence river showed results similar to the 30 Rivers Study.
These and other monitoring studies demonstrate that levels of NP, NPEs and NPECs in rivers and lakes in the U.S. and Canada are well below the threshold levels for environmental effects (which are discussed in the next section).
III. AQUATIC EFFECTS
A. Acute and Chronic Toxicity
APs, APEs and APECs have been studied to determine effects in fish, algae and invertebrates from acute (short-term) and chronic (long-term) exposures. This research is used to determine whether environmental levels of these substances can cause adverse effects. These studies have found:The lowest concentration of NP which can cause acute toxicity in invertebrates is 20 ppb. Chronic toxicity in rainbow trout, one of the most sensitive organisms, can occur at about 6 ppb of NP. Monitoring studies of rivers and lakes in the U.S. and Canada either did not detect NP or reported levels of less than 1 ppb, well below the threshold of potential toxic effects.
For OP, the threshold for chronic toxicity is about 6 ppb. Studies of rivers and lakes in Canada either did not detect OP or reported levels less than 0.1 ppb, well below the threshold of potential toxic effects.
For NPEs with one or two ethoxylate groups, the threshold for chronic toxicity is about 280 ppb. Studies of rivers and lakes in the U.S. and Canada either did not detect these NPEs or reported levels of 10 ppb or less, well below the threshold of potential toxic effects.
For other NPEs, such as NPE with nine ethoxylate groups, the threshold of chronic toxicity is about 1000 ppb. For NPECs, the threshold of chronic toxicity is higher, about 2200 ppb. Monitoring studies in the U.S. either did not detect these compounds or reported levels well below the thresholds of potential toxic effects.
For organisms living in sediments, the threshold of chronic toxicity is about 0.6 to 2.0 ppm of NP and about 0.9 to 3.0 ppm of NPEs with one or two ethoxylate groups. Monitoring studies in the U.S. and Canada either did not detect these substances in sediments or generally reported concentrations below these levels. The highest levels in sediment were detected near sewage treatment plant discharge pipes and at a Superfund site on the Grand Calumet River.
These toxicity tests, coupled with the monitoring studies, indicate that concentrations of APEs and their intermediates in river and lake water are below levels that could have adverse effects on aquatic organisms and that concentrations in sediments are generally below levels that could have adverse effects on sediment organisms.
B. Bioaccumulation
Some substances found in the environment can accumulate in the fatty tissues of fish or other aquatic organisms. Significant "bioaccumulation" can increase the concentration of a substance to which wildlife and other animals higher on the food chain may be exposed.Bioconcentration factor (BCF), the ratio of the concentration of the substance in fish or other aquatic organisms to the concentration in water or feed items, is used to measure the potential of chemicals to bioaccumulate. BCF values greater than 1000 generally are considered of concern due to the potential for concentrations of the substance to increase while moving up the food chain.
The BCFs for NP in fish and other aquatic organisms measured in field studies range from 6 to about 500, with most values less than 100. These low to moderate BCF values indicate that NP would not be expected to build up in the food chain to any significant extent. In addition, accumulation of NP in fish was readily reversed when exposure ended. APEs also would not be expected to build up in the food chain because they are more water soluble than NP.
IV. ENDOCRINE SYSTEM EFFECTS
Certain natural and synthetic substances have some characteristics similar to estrogen and other hormones. Over the past several years, a number of new methods have been developed to test compounds for estrogenic (or other hormonal) activity. Scientists are exploring the theory that these substances may impact the endocrine (hormone) system and thereby affect the reproductive and developmental health of wildlife or humans.In recent years studies have examined the potential of many substances, including APs, APEs and APECs, to cause estrogenic activity in mammals and aquatic organisms. Based on the available findings to date, a causal link has not been established between exposure to any of these materials in the environment and endocrine-related human health effects.
The "endocrine disruption" theory itself remains under review. In February 1997, the United States Environmental Protection Agency issued an interim report which concluded that, aside from a few exceptions such as DES (a therapeutic drug which has been taken off the market), "a causal relationship between exposure to a specific environmental agent and an adverse effect on human health operating via an endocrine disruption mechanism has not been established." A similar conclusion was reached at a December 1996 international science workshop in Weybridge, United Kingdom: "The existing exposure information was considered generally insufficient to definitely associate the health effects seen in humans with chemical exposure."
A. Test-Tube (In Vitro) Studies
Like other hormones, estrogens bind to a specific cellular receptor as a first step in hormone action. In vitro studies (tests done in test tubes) show that OP, NP and an NPEC can bind to the estrogen receptor, a characteristic of the natural human estrogen, 17 -estradiol. However, 17 -estradiol is orders of magnitude more potent than these compounds.Other in vitro tests use cells that contain an estrogen receptor to study the estrogenic activity of a substance. When a substance binds to the receptor in the cell system, a sequence of events occurs in the cell that ends with the production of a measurable endpoint. Studies using these various endpoints also show that OP, NP and NPEs and NPECs with one or two ethoxylate groups are weakly estrogenic. Like the estrogen receptor binding studies, these cell systems typically require concentrations of these substances that are two to four orders of magnitude (one hundred to ten thousand times) higher than 17 -estradiol to elicit estrogenic activity.
B. Fish (In Vivo) Studies
While in vitro tests are useful for examining theoretical hormonal action, in vivo (live animal) studies are needed to understand the actual response of fish and aquatic organisms in the environment.In one type of in vivo study, male fish are exposed to substances which can stimulate the production and secretion of vitellogenin, a liver protein produced in sexually mature female fish. This type of study has been used to determine if there are estrogenically active compounds in rivers or lakes. Another type of study looks for reduced growth of male reproductive organs in fish exposed to estrogenically active substances.
For example, in the United Kingdom, researchers placed male rainbow trout in cages at various locations in rivers receiving outflows from sewage treatment plants. The trout downstream of these outflows showed an increased vitellogenin response compared to trout upstream.
Studies to isolate the source of the estrogenic activity in these and other sewage outflows showed that natural estrogens and the synthetic estrogens used in birth control pills were the primary active estrogenic substances in U.K. rivers. Similar results have been found in U.S. rivers. For example, in one U.S. river (the Las Vegas Wash) where vitellogenin production by male fish was observed, the flow of the river is dominated by the outflow of a domestic sewage treatment plant. Natural estrogens and the synthetic estrogen used in birth control pills were identified as the only sources of estrogenic activity in the river water.
In the U.K. rainbow trout study, concentrations of NP in two of the three rivers ranged from less than 0.2 to 2.9 ppb, well below the concentrations of NP (about 20 ppb) which could increase vitellogenin production in fish or show effects on the growth of male reproductive organs. U.S. and Canadian studies show similar or lower concentrations. The exception was the River Aire in Yorkshire, U.K., where NP concentrations reached 180 ppb (a level comparable to raw sewage), in part due to poor treatment of the discharge from a wool scouring mill which used NPEs. Fish showed an estrogenic response above and below the outflow of the treatment works on the River Aire, so the extent of NP's contribution to the vitellogenin response is unclear.
C. Laboratory Animal Studies
While in vitro studies of estrogenic activity and studies of vitellogenin production in male fish indicate the ability of a substance to interact with the estrogen receptor and related processes, these studies do not address many important questions related to the potential of a substance to affect human health. For example, absorption across the intestine or skin, breakdown by metabolic processes, excretion, feedback control and other activities can increase or decrease the biological activity of a molecule. These factors can only be fully assessed with laboratory animal studies.Studies in laboratory animals demonstrate that NP ingested by animals is either poorly absorbed from the gastrointestinal system, rapidly excreted from the body or both. Also, NP does not accumulate - only 0.4% remains in animal bodies 7 days after administration.
One of the most predictive laboratory animal tests for estrogenic activity is the uterotrophic assay in mice or rats. OP did not produce an estrogenic response in the standard uterotrophic assay when given to the animals orally. NP did not show estrogenic activity at low doses in this test and showed very weak estrogenic activity at high exposure levels. The estrogenic activity of NP was characterized as "weak" in this assay since NP produced markedly less of an estrogenic response than 17 -estradiol and since a 475-fold higher dose of NP than 17 -estradiol was required to produce an estrogenic effect. Based on these assays, the estrogenic activity of APs in animals appears low.
Commercial APEs have demonstrated no estrogenic activity in the uterotrophic assay.
Less conventional laboratory animal studies have analyzed substances for responses which may be related to estrogenic activity. These studies have reported various responses in laboratory animals following exposure to OP, including reduced sperm production and changes in the body weight and testis weight. However, the researchers subsequently reported that they could not replicate their results.
Two major studies in laboratory animals found no estrogenic activity from nonylphenol at levels significantly higher than those found in the environment. A 90-day study of rats which ingested NP at 200, 650 or 2000 ppm (parts per million, much higher than the low parts per billion in the environment) in the diet showed no estrogenic activity. Specifically, no effects at any dose level were observed on estrus cycling, sperm evaluations or endocrine glands in this study.
In addition, a U.S. government study of three generations of rats concluded that NP is not a reproductive or developmental toxicant. There was some estrogenic activity at the two higher concentrations (650 and 2000 ppm) in the study and no activity at the lower level (200 ppm). This lower dose is several orders of magnitude higher than an estimated, maximal daily human intake. There were no adverse effects on fertility even at doses of 2000 ppm, the highest dose tested.
V. CONCLUSIONS
Reviewing the extensive research on APs and APEs helps answer the question posed in the beginning of this overview: "What happens to alkylphenols and alkylphenol ethoxylates if they reach the environment?" "Do they pose a significant ecological risk?" "Do they affect the endocrine system and thereby pose potential health risks?"Studies demonstrate that APs and APEs are biodegradable. Monitoring studies in the U.S. and Canada have shown that concentrations of NP, NPEs and NPECs in rivers and lakes are well below those that could have adverse effects on aquatic organisms when well-functioning sewage treatment is present.
Commercial APEs have not demonstrated estrogenic activity in animal tests. While APs and some APEs and APECs with one or two ethoxylate groups exhibit weak estrogenic activity, these compounds are typically two to four orders of magnitude less potent than the natural estrogen, estradiol. The low environmental concentrations of these substances observed when well-functioning sewage treatment is present are not likely to cause a hormonal (or endocrine) response in fish or humans.
Based on these findings, APs and APEs do not appear to present a significant ecological risk or to cause adverse, endocrine-related human health effects.
FOR FURTHER READING
The Alkylphenols and Alkylphenols Ethoxylates Review, published in February, 1998, provides an overview of key studies on APs and APEs. The Review includes selected studies from each aspect of an environmental and health assessment: biodegradation, removal in sewage treatment, environmental monitoring, risk assessment, estrogenic activity and mammalian toxicity. It also includes a list of additional studies.To receive a copy of the Review, or additional information on studies on APs and APEs, please contact the APE Research Council at 202.419.1506.
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