Toxicological Assessment of Higher Olefins in OECD TG 422 Repeated Dose and Reproductive /Developmental Toxicity Screening Tests in Han Wistar Rats.

Higher olefins (HO) are used primarily as intermediates in the production of other chemicals, such as polymers, fatty acids, plasticizer alcohols, surfactants, lubricants, amine oxides, and detergent alcohols. The potential toxicity of five HO (i.e., 1-Octene, Nonene, Decene, Hexadecene, and 1-Octadecene) with carbon ranging from C8 to C18 was examined in a combined repeated dose and reproduction/developmental toxicity screening study (OECD TG 422). These five HO were administered to Han Wistar rats by gavage at 0 (controls), 100, 300, and 1000 mg/kg bw/day. As a group of substances, adaptive changes in the liver (liver weight increase without pathological evidence), as well as increased kidney weight in male rats, were observed in HO with carbon numbers from C8 to C10. The overall systemic no observed adverse effect level (NOAEL) for all HO was determined at 1000 mg/kg bw/day. In the reproductive/developmental toxicity assessment, offspring viability, size, and weights were reduced in litters from females treated with Nonene at 1000 mg/kg bw/day. The overall no observed effects level (NOEL) for reproductive toxicity was considered to be 300 mg/kg bw/day for Nonene and 1000 mg/kg bw/day for the other four HO, respectively. These data significantly enrich the database on the toxicity of linear and branched HO, allowing comparison with similar data published on a range of linear and branched HO. Comparisons between structural class and study outcome provide further supportive data in order to validate the read-across hypothesis as part of an overall holistic testing strategy.

Application of physiologically-based pharmacokinetic modeled toluene blood concentration in the assessment of short term exposure limits.

Toluene is a volatile hydrocarbon with solvent applications in several industries. Acute neurological effects in workers exposed to toluene have been reported in various publications. To inform the basis for a toluene Short Term Exposure Limit (STEL), studies of toluene-exposed workers were modeled using customized exposure scenarios within an existing physiologically-based pharmacokinetic (PBPK) model to simulate blood concentrations during individual studies. Maximum simulated blood concentration ranged from 0.3 to 1.7 (mean = 0.74 mg/L, median = 0.73, upper 95th percentile = 1.07) at the studies identified No Observed Adverse Effect Concentration (NOAEC). Maximum simulated blood concentration ranged from 0.7 to 4.1 mg/L (mean = 1.81, median = 1.63, lower 95th percentile = 0.92) at the studies identified Lowest Observed Adverse Effect Concentration (LOAEC). The maximum blood concentration for a 100 ppm STEL-like simulation was 0.4 mg/L, at the lower end of the NOAEC range and below the 95th percentile of the LOAEC. Therefore, it appears that a STEL <100 ppm would be unnecessary to protect workers due to peak occupational exposures to toluene.

Selection of Representative Constituents for Unknown, Variable, Complex, or Biological Origin Substance Assessment Based on Hierarchical Clustering.

Many of the newly produced and registered substances are complex mixtures or substances of unknown or variable composition, complex reaction products, and biological materials (UVCBs). The latter often consist of a large number of constituents, some of them difficult-to-identify constituents, which complicates their (eco)toxicological assessment. In the present study, through a series of examples, different scenarios for selection of representatives via hierarchical clustering of UVCB constituents are exemplified. Hierarchical clustering allows grouping of the individual chemicals into small sets, where the constituents are similar to each other with respect to more than one criterion. To this end, various similarity criteria and approaches for selection of representatives are developed and analyzed. Two types of selection are addressed: (1) selection of the most "conservative" constituents, which could be also used to support prioritization of UVCBs for evaluation, and (2) obtaining of a small set of chemical representatives that covers the structural and metabolic diversity of the whole target UVCBs or a mixture that can then be evaluated for their environmental and (eco)toxicological properties. The first step is to generate all plausible UVCB or mixture constituents. It was found that the appropriate approach for selecting representative constituents depends on the target endpoint and physicochemical parameters affecting the endpoint of interest. Environ Toxicol Chem 2021;40:3205-3218. © 2021 SETAC.

Derivation of an occupational exposure limit for benzene using epidemiological study quality assessment tools.

This paper derives an occupational exposure limit for benzene using quality assessed data. Seventy-seven genotoxicity and 36 haematotoxicity studies in workers were scored for study quality with an adapted tool based on that of Vlaanderen et al., 2008 (Environ Health. Perspect. 116 1700-5). These endpoints were selected as they are the most sensitive and relevant to the proposed mode of action (MOA) and protecting against these will protect against benzene carcinogenicity. Lowest and No- Adverse Effect Concentrations (LOAECs and NOAECs) were derived from the highest quality studies (i.e. those ranked in the top tertile or top half) and further assessed as being "more certain" or "less certain". Several sensitivity analyses were conducted to assess whether alternative "high quality" constructs affected conclusions. The lowest haematotoxicity LOAECs showed effects near 2 ppm (8 h TWA), and no effects at 0.59 ppm. For genotoxicity, studies also showed effects near 2 ppm and showed no effects at about 0.69 ppm. Several sensitivity analyses supported these observations. These data define a benzene LOAEC of 2 ppm (8 h TWA) and a NOAEC of 0.5 ppm (8 h TWA). Allowing for possible subclinical effects in bone marrow not apparent in studies of peripheral blood endpoints, an OEL of 0.25 ppm (8 h TWA) is proposed.

Guidance on the selection of cohorts for the extended one-generation reproduction toxicity study (OECD test guideline 443).

The extended one-generation reproduction toxicity study (EOGRTS; OECD test guideline 433) is a new and technically complex design to evaluate the putative effects of chemicals on fertility and development, including effects upon the developing nervous and immune systems. In addition to offering a more comprehensive assessment of developmental toxicity, the EOGRTS offers important improvements in animal welfare through reduction and refinement in a modular study design. The challenge to the practitioner is to know how the modular aspects of the study should be triggered on the basis of prior knowledge of a particular chemical, or on earlier findings in the EOGRTS itself, requirements of specific regulatory frameworks notwithstanding. The purpose of this document is to offer guidance on science-based triggers for these extended evaluations.

Toxicological assessment of refined naphthenic acids in a repeated dose/developmental toxicity screening test.

Naphthenic acids (NAs) are primarily cycloaliphatic carboxylic acids with 10 to 16 carbons. To characterize the potential of refined NAs (>70% purity) to cause reproductive and/or developmental effects, Sprague-Dawley rats (12/group) were given oral doses of 100, 300, or 900 mg/kg/d, beginning 14 days prior to mating, then an additional 14 days for males or through lactation day 3 for females (up to 53 days) in a repeated dose/reproductive toxicity test (Organization for Economic Cooperation and Development [OECD] 422). Potential mutagenic effects were assessed using Salmonella (OECD 471) and in in vivo micronucleus tests (OECD 474) using bone marrow taken from treated animals in the screening study described previously. Systemic effects included reduced terminal body weights, increased liver weights, and changes in a number of blood cell parameters. The overall no effect level for all target organ effects was 100 mg/kg/d. In the reproductive/developmental toxicity assessment, there were significant reductions in numbers of live born offspring in groups exposed to 300 and 900 mg/kg/d. The overall no effect level for developmental effects was 100 mg/kg/d. The data from the Salmonella and micronucleus tests provide evidence that refined NAs are not genotoxic.