High Production Volume Chemicals Research Articles

Industry's Commitment

It was a remarkable scene: Vice President Al Gore, Environmental Defense Fund Executive Director Fred Krupp, Environmental Protection Agency Administrator Carol Browner, and me sharing a podium in Boston to announce a plan to voluntarily test high-production-volume (HPV) chemicals. It marked the conclusion of a six-month collaborative effort to find the best way to increase the pace of testing. It also marks the beginning of what I hope will become a better, faster approach to how environmental policy decisions are made and implemented. For those who have not closely followed the testing issue, the $500 million to $700 million that industry will spend to test HPV chemicals in the coming years is only one part of the commitment companies are making to ensure chemical effects are well understood. Along with the voluntary HPV chemical program, the chemical industry also is participating in the development of two other EPA regulatory testing programs—endocrine screening and testing, and ...

Chemical industry pressured to test high-production volume chemicals

Chemical industry pressured to test high-production volume chemicals

Classification of Environmentally Occurring Chemicals Using Structural Fragments and PLS Discriminant Analysis

Chemicals were classified according to one of the four classes as described by Verhaar et al. (Chemosphere 1992, 25, 471−491) based on the structural information present in fragments of these chemicals. A PLS discriminant analysis method with the classes as the response variables and the screens as the predictor variables was used. The data were modeled in two different ways. The response variables were either modeled individually (PLS1), resulting in one model for each class, or together in a unified PLS2 model. This method resulted in some good models and a few moderate ones. The inert and less inert chemicals are concentrated in a relatively small region, whereas the reactive and specifically acting chemicals were more spread out. The reactive chemicals showed some diffuse border with the inert chemicals. Distinction between reactive and specifically acting chemicals is not straightforward. Prediction of class membership for a set of high production volume chemicals (HPVCs), not formerly classified, wa...

Assessment of the in vivo mutagenic potential of methyl tertiary-butyl ether.

Methyl tertiary-butyl ether (MTBE) is one of the highest production volume chemicals in the USA. Previous results from in vitro genetic toxicity studies suggested that it was not mutagenic. However, chronic exposure at high levels resulted in liver tumors in female mice and kidney tumors in male rats. The current program assessed in vivo genotoxicity and also explored the possibility that a mutagenic mechanism was involved in the carcinogenic process. The specific tests used included the Drosophila sex-linked-recessive-lethal test, the rat bone marrow cytogenetics test, the mouse bone marrow micronucleus test and the in vivo-in vitro hepatocyte unscheduled DNA synthesis test in the mouse. All tests produced negative results, indicating that the potential for in vivo mutagenic activity was low. These data also suggest that the tumorigenic activity was probably the result of a non-genotoxic process.

Monitoring and prioritisation of organic contaminants in sewage sludges using specific chemical analysis and predictive, non-analytical methods

Municipal sludge application on agricultural land (land utilization) is practised widely and accounts for between 30–40% of production in Canada and the UK. Land utilization is subject to public concerns over the potential for deleterious effects of organic contaminants on agricultural productivity and uptake into the foodchain. Consequently, reliable data on the concentrations of organic contaminants in sludge are required to assess risks associated with land use. A detailed monitoring survey has been carried out by WTC to determine the concentrations of a range of industrial organic contaminants in 11 Canadian sewage sludges and one sludge compost. Volatile, base-neutral and acid extractable contaminants seldom exceeded 5 mg kg−1 dry wt., organochlorine pesticides and polychlorinated biphenyls did not exceed 1 mg kg−1 dry wt. and toxaphene and N-nitrosodimethylamine were not detected in the materials analyzed. Mean total PCDD and PCDF concentrations were ≤ 36 μg kg−1 dry wt. (median 6.7 μg kg−1 dry wt.) and mean toxic equivalents were ≤ 0.12 μg kg−1 dry wt. (median 0.02 μg kg−1 dry wt.). It was concluded that in many Canadian sludges the aforementioned organic contaminants represent no significant risk to agriculture and the environment. However, other organic contaminants potentially present in sewage sludge may not be amenable to analysis by the target compound techniques widely used. Consequently, WRc have applied a non-analytical approach to assess which contaminants may occur in sewage sludges and persist in treated soils. Predictions of physicochemical properties using quantitive structure activity relationships (QSARs) have been used to aid the screening and prioritisation of a range of high production volume chemicals (HPVCs) that may enter sewage treatment works. Analytical surveys for organic residues are expensive and this type of approach may assist in identifying further contaminants which should be analyzed in sewage sludges and treated soils.

IUCLID: A Database on Chemical Substances Information as a Tool for the EU-Risk-Assessment Program

A database on so-called “Existing Chemicals” is being developed at the European Chemicals Bureau (ECB). The database IUCLID contains all data sets submitted by Industry following Council Regulation (EEC) 793/931 on the “Evaluation and Control of the Risks of Existing Substances”. The Regulation obliges Industry to submit all readily available data on “High Production Volume Chemicals”, using the HEDSET software package, to the ECB. Copies of the database are being used by the European Commission and in the EU-Member States Authorities as the data source for selecting priority substances and for carrying out the risk assessment on them. The outcome of the risk assessment process will be a validated IUCLID data sheet which includes a summary risk assessment report for each priority substance. The multilingual database is available from the ECB, in IUCLID format or as an easy to use CD-ROM version, including the original data submitted by Industry and later the validated data and the risk assessment reports.

Predictions for Existing Chemicals-A Multilateral QSAR Project

Abstract Following a previous collaborative EU/EPA project focussed on QSAR predictions for a selection of new chemicals which had been notified in the EU, a similar exercise was started in 1993 on existing chemicals. In a first phase, the project addresses the High Production Volume (HPV) chemicals which are produced or imported at levels above a 1000t/year in the EU and 454t/year in the US. The relevant EU (Annex 1 of Existing Chemicals Regulation No. 793/93) and US-EPA lists contain 1036 and 2881 organic substances respectively of which HPV 749 chemicals are in common. The joint project aims at an estimation through validated QSAR models of the physical-chemical, ecotoxicity and toxicity endpoints which are included in the regulation and where experimental data will become available in IUCLID (International Unified Chemicals Information Database). Next to EC-JRC (ECB) and US-EPA, various laboratories in the EU are contributing to the project and recently, two institutes in Japan have joined in this project.

The application of structure-activity relationships (SARs) in the aquatic toxicity evaluation of discrete organic chemicals.

The Office of Pollution Prevention and Toxics (OPPT), United States Environmental Protection Agency (USEPA) routinely uses structure-activity relationships (SAR) for the aquatic hazard assessment of new chemicals submitted under Section 5 of the Toxic Substances Control Act (TSCA). With 15 years of experience and the general acceptance of toxicity predictions based on SARs, OPPT has expanded the use and application of the methodology to include existing chemicals used in printing, dry cleaning, and paint stripping. SAR analysis has also been used in the hazard evaluation of the U.S. and EU/OECD high production volume (HPV) chemicals. This paper describes the assumptions, limitations, and methodology for the use of SARs to evaluate large sets of discrete organic chemicals.

Application of QSARs in Risk Management of Existing Chemicals

QSAR-estimates of aquatic toxicity of relatively unreactive (narcosis-type) organic chemicals for 19 species were used to predict "no-effect-levels" (NELs) at the ecosystem level by means of several extrapolation models which were recently discussed by the Organisation for Economic Cooperation and Development (OECD). It appeared that the differences between the numerical results of these extrapolation methods, despite their different statistical assumptions, were small. Equilibrium-partitioning theory for sediment and water as well as biota and water was used to derive NELs for aquatic sediments and whole-body residues. Simple equations are given, from which NELs for water, and subsequently for sediments and whole-body residues, can be predicted on the basis of only the octanol-water partition coefficient. Actual application of the models presented absolutely requires the availability of methods to recognize chemicals that act by the unspecific mechanism of narcosis. To this end, a classification scheme, based on molecular structure, was developed. This classification scheme was applied to the approximately 2000 so-called High Production Volume Chemicals (HPVCs) listed in Annex 1 of the Council Regulation on the Evaluation and the Control of the Environmental Risks of Existing Chemicals of the European Communities. From the classification of these 2000 HPVCs it is concluded that, for a large portion of all existing chemicals, reliable QSAR estimates of aquatic toxicity can be made; this considerably speeds up the process of priority setting and risk assessment of existing chemicals. The validity of this (dual) approach was tested by a comparison of estimated NELs with actual FCC values for all compounds from the US-EPA Water Quality Guidelines list that classify as narcosis-type compounds. This comparison shows that for many existing chemicals QSARs may be used to derive quality guidelines for water, aquatic sediments and residues in aquatic biota.

Confirmation study, using nitrobenzene, of the Combined Repeat Dose and Reproductive/Developmental Toxicity Test protocol proposed by the Organization for Economic Cooperation and Development (OECD).

A confirmatory familiarization study of the Combined Repeat Dose and Reproductive/Developmental Toxicity Screening (ReproTox) test protocol proposed by the Organization for Economic Cooperation and Development (OECD) was performed using nitrobenzene, a testicular toxicant. The agent was given daily by gavage to groups of 10 male and 10 female Sprague-Dawley rats at doses of 100, 60, 20 and 0 mg/kg body weight. Some of the high dose animals exhibited neurological signs, and two males and 9 females died. Hemolytic anemia due to methemoglobin formation was evident in treated males. Histopathologically, treated males showed atrophy of seminiferous tubules of the testis, reactive changes secondary to hemolytic anemia in the hematopoietic organs, and hepatocellular swelling. Cerebral gliosis was observed in middle and high dose males. Male fertility was not affected. The body weights of pups from treated dams were lowered, and their postnatal loss was increased. Most of the known toxicological properties of this chemical was demonstrated in the present study, with the exception of reduced fertility. Therefore, the ReproTox protocol was concluded as being useful as a screening test of existing high production volume chemicals. It should be noted that while the reproductive toxicity test alone is insensitive for detection of male fertility disturbances associated with testicular toxicity, the latter easily be distinguished on morphological grounds.

Impact of the environment on reproduction from conception to parturition.

Consideration of environmental influences on human reproduction must include an investigation of the socioeconomic factors that play an important role in embryo-fetal development. Nutritional factors are of prime importance, and modern methods of food production and supply have led to new hazards for pregnant women. For example, pregnant women have been advised in a number of European countries not to eat liver due to the very high concentration (frequently exceeding 100,000 IU per 100 g) of vitamin A. The clear demonstration that periconceptional vitamin supplementation can dramatically reduce the recurrence rate of neural tube defects suggests that folic acid deficiency may be common even in otherwise well-nourished women. Modern methods of food production manufacture and sale have increased the risks of Salmonella and Listeria infections in pregnancy. The dangers of social drug use, especially alcohol and tobacco, are discussed. The types of adverse effect that can result from chemical exposure during the different stages of pregnancy is reviewed with a discussion of some of the problems of epidemiological studies in attempting to identify toxic chemicals. The extent of the ignorance concerning the reproductive toxicity of industrial and environmental chemicals is emphasized by the fact that data are available on only a small percentage of even the high-production volume (1000 tons/year) chemicals. The evidence of reproductive toxicity from exposure to lead, methyl mercury, polychlorinated biphenyls, polychlorinated dibenzofurans, and hexachlorobenzene are briefly reviewed. Some areas of research needs are discussed with emphasis on nutrition, food production, preparation, and storage and the new problems that may be introduced by genetic manipulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhalation toxicity of 1,6-Hexanediamine dihydrochloride in F344/N rats and B6C3F 1 mice

1,6-Hexanediamine (HDA) is a high production volume chemical which is used as an intermediate in the synthesis of paints, resins, inks, and textiles and as a corrosion inhibitor in lubricants. Two- and 13-week studies of the toxicity of the dihydrochloride salt of HDA (HDDC) were conducted in male and female Fischer 344/N rats and B6C3F1 mice using whole-body inhalation exposure. Both species were evaluated for histopathologic and reproductive effects, and rats were examined for clinical chemistry and hematologic changes. In the 2-week inhalation studies, animals were exposed to 10-800 mg HDDC/m3, 6 hr per day. All rats, all female mice, and two of five male mice in the high-exposure group died before the end of the study. Surviving mice in this group had a dose-dependent depression in body weight gain. Clinical signs were primarily related to upper respiratory tract irritation and included dyspnea and nasal discharge in both species. Treatment-related histopathologic lesions included inflammation and necrosis of the laryngeal epithelium of both species and the tracheal epithelium of mice, as well as focal inflammation and ulceration of the respiratory and olfactory nasal mucosa. In the 13-week inhalation studies, animals were exposed to HDDC at concentrations of 1.6-160 mg/m3 for 6 hr per day, 5 days per week. In addition to the base study groups, a supplemental group of rats at each exposure level was included to assess the effect of HDDC on reproduction. No treatment-related changes in organ weights or organ-to-body-weight ratios occurred in rats, and no treatment-related clinical signs or gross lesions were seen in either species. Chemical-related microscopic lesions were limited to the upper respiratory tract (larynx and nasal passages) in the two highest exposure groups and were similar in both species. These lesions included minimal to mild focal erosion, ulceration, inflammation, and hyperplasia of the laryngeal epithelium, in addition to degeneration of the olfactory and respiratory nasal epithelium. HDDC caused no significant changes in sperm morphology or vaginal cytology and no significant adverse effects on reproduction in rats or mice. Hematologic and clinical chemistry changes in rats were minor and sporadic and were not accompanied by related histologic findings. HDDC did not increase the frequency of micronucleated erythrocytes in mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Environmental hazard assessment of existing chemicals

The environmental hazard assessment of existing chemicals in Germany consists of the following steps: 1. Collection of all available data on effects and exposure for high production volume chemicals. 2. Validation of this information. 3. Exposure assessment using information on the manufacturing process, emission factors, and use pattern and by applying the distribution model of Mackay (Level 1). Predicted environmental concentrations (PEC) are determined by applying special scenarios which differ according to the compartment and the kind of exposure. 4. For those compartments which have been identified in the exposure analysis as being of relevance, an effect assessment is performed. 5. A safety factor F is derived depending on the quality and the density of data, as well as on information on biodegradability and bioaccumulation. F is compared to the ratio Q of LC 50 (EC 50) or NOEC of the most sensitive species and PEC. The values of F and Q can be changed by further information or tests. 6. If Q remains below F, emissions need to be reduced.

An abbreviated repeat dose and reproductive/developmental toxicity test for high production volume chemicals

A novel protocol is described for obtaining preliminary data on repeated dose systemic effects and reproductive/developmental toxicity. The test protocol was developed by a group of experts at the request of the U.S. Environmental Protection Agency (EPA) for use as part of a Screening Information Data Set on high production volume chemicals. Interest in this protocol is shared by several regulatory agencies, including the Organization for Economic Cooperation, the European Community, and the EPA. To validate the study protocol, ethylene glycol monomethyl ether (EGME) was used. After a dosing period of approximately 6 weeks, EGME showed both systemic and reproductive/developmental effects similar to those previously reported using standard protocols. Thus, this test protocol may be used as a screening tool for high production volume chemicals.

Identification and Mutagenicity of the Urinary Metabolites of the Mutagenic Noncarcinogen 2,6-Diaminotoluene

Abstract 2,6-Diaminotoluene (2,6-DAT) is a high production volume chemical; approximately 100 million pounds are produced annually in the synthesis of several dyes for furs and textiles and in the manufacture of 2,6-toluenediisocyanate for the manufacture of flexible polyurethane foams and elastomers. 2,6-DAT is mutagenic in the Ames/Salmonella test requiring metabolic activation, but was not carcinogenic to male or female rats or mice in 2-year bioassays. Following oral administration of 14C-labeled 2,6-DAT, 85% of the radioactivity was excreted in the urine within 24 hours. Resolution of the urine by reversed phase HPLC identified 4 metabolites, and no parent compound was excreted. Analysis by mass spectroscopy and nuclear magnetic resonance spectroscopy identified the metabolites as a) 3-hydroxy-2,6-DAT, b) 5-hydroxy-2-acetylamino-6-aminotoluene, c) 2-acetylamino-6-aminotoluene, and d) 2,6-di(acetylamino)-toluene. Metabolites b and d were found to be mutagenic in the presence of an activation system. T...

Epoxidation of 3-chlorobutene-1 by tert-butyl hydroperoxide: Ye. Mil'khert, Neftekhimiya 29, No. 5, 693–696, 1989

Bisphenol A (BPA), 4-cumylphenol (4-CP) and 2,4-bis-(dimethylbenzyl)phenol (2,4-DCP) are all high production volume chemicals and widely used in plastic and other consumer products. During the past two decades, BPA has attracted a great deal of scientific and public attention due to its presence in the environment and estrogenic property. Although 4-CP and 2,4-DCP are much more estrogenic and toxic than BPA, little information is available about their occurrence and fate in the environment. In this study, a rapid, selective, accurate and reliable analytical method was developed for the simultaneous determination of 4-CP, 2,4-DCP and BPA in prawn Macrobrachium rosenbergii. The method comprises an ultrasound-accelerated extraction followed by capillary gas chromatographic (GC) separation. The detection limits range from 1.50 to 36.4 ng kg−1 for the three alkylphenols. The calibration curves are linear over the concentration range tested with the coefficients of determination, R2, greater than 0.994. The developed method was successfully applied to the simultaneous determination of 4-CP, 2,4-DCP and BPA in prawn samples. The peak identification was confirmed using GC–MS. Bisphenol A, 2,4-bis-(dimethylbenzyl)phenol and 4-cumylphenol were found in prawn samples in the concentration ranges of 0.67–5.51, 0.36–1.61, and 0.00–1.96 ng g−1 (wet weight), respectively. All relative standard deviations are less than 4.8%. At these environmentally relevant concentration levels, 4-CP, 2,4-DCP and BPA may affect the reproduction and development of aquatic organisms, including negative influence on crustaceans’ larval survival, molting, metamorphosis and shell hardening. This is the first study reported on the occurrence of 4-CP, 2,4-DCP and BPA in prawn M. rosenbergii.

High Resolution Gas Chromatography of Chlorinated Benzenes

Abstract Chlorinated benzenes have been found as contaminants in foods and water. These high production volume chemicals may enter the environment and food chain through improper waste disposal, use as solvents and odor control agents, or as impurities in other industrial chemicals. Because of differences in the electron capture responses of the isomers at each chlorination level, residue quantitation requires the separation of all 12 chlorobenzenes. Resolution studies were made on packed and capillary columns coated with Kovats’ C87H176 hydrocarbon, OV-101, OV-210, OV-17, and Carbowax 20M. Satisfactory resolution of all 12 chlorobenzenes was obtained with a Carbowax 20M-coated 20 m × 0.25 mm id capillary column operated isothermally at 120°C.