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.

Assessment of the Intestinal Absorption of Higher Olefins by the Everted Gut Sac Model in Combination with In Silico New Approach Methodologies.

To reduce the number of animals and studies needed to fulfill the information requirements as required by Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) (EC no. 1907/2006), a read-across approach was used to support approximately 30 higher olefins. This study aimed to assess the absorption potential of higher olefins through the gut wall as the experimentally determined bioavailability which would strengthen the read-across hypothesis and justification, reducing the need for toxicity studies on all of the higher olefins. The absorption potential of a series of higher olefins (carbon range from 6 to 28, with five configurations of the double bond) was determined in the in vitro everted rat small intestinal sac model and subsequently ranked. In addition, in silico approaches were applied to predict the reactivity, lipophilicity, and permeability of higher olefins. In the in vitro model, everted sacs were incubated in "fed-state simulated small intestinal fluid" saturated with individual higher olefins. The sac contents were then collected, extracted, and analyzed for olefin content using gas chromatography with a flame ionization detector. The C6 to C10 molecules were readily absorbed into the intestinal sacs. Marked inter-compound differences were observed, with the amount of absorption generally decreasing with the increase in carbon number. Higher olefins with ≥C14 carbons were either not absorbed or very poorly absorbed. In the reactivity simulation study, the reactivity is well described by the position of the double bond rather than the number of carbon atoms. In the lipophilicity and permeability analysis, both parameter descriptors depend mainly on the number of carbon atoms and less on the position of the double bond. In conclusion, these new approach methodologies provide supporting information on any trends or breakpoints in intestinal uptake and a hazard matrix based on carbon number and position of the double bond. This matrix will further assist in the selection of substances for inclusion in the mammalian toxicity testing programme.

Analysis of polycyclic aromatic hydrocarbons (PAHs) in surface sediments and edible aquatic species in an oil-contaminated mangrove ecosystem in Bodo, Niger Delta, Nigeria: Bioaccumulation and human health risk assessment.

This work investigated the occurrence and risks associated with polycyclic aromatic hydrocarbons (PAHs) in tissues from five commonly consumed aquatic species (swimming crabs, estuarine shrimp, tiger prawns, periwinkles, and tilapia) and sediment across six sites in the area around Bodo town, in the Niger Delta region of Nigeria. We aimed to establish a relationship between PAH concentrations in sediment and biota, and to derive biota-sediment accumulation factors (BSAFs). Risks to human health associated with consumption of impacted food sources were assessed based on measured biotic concentrations of PAHs. The average concentration of PAHs and the number of PAHs measured above the limit of quantification varied greatly between different biota, with the lowest average concentrations observed in tilapia, followed by tiger prawns, crabs, estuarine shrimp, and the highest concentrations were observed in periwinkles. Similar to biotic concentrations, BSAFs were found to vary greatly across species, sites, and PAHs, though BSAFs for all organisms except periwinkles were below a value of 1. In periwinkles, BSAFs exceeded a value of 1 for phenanthrene (BSAF = 1.7), pyrene (1.5) and benzo[k]fluoranthene (1.7). Risks to human health associated with consumption of these species were assessed using the BaP toxic-equivalent approach for cancer risks and the toxic unit approach which jointly considered carcinogenic but also non-cancer hazards. The BaP toxic-equivalent approach showed that the excess lifetime cancer risk resulting from daily consumption of 0.2 kg of seafood ranged between 1.3 × 10-6 for tiger prawn and tilapia to 4.1 × 10-6 for periwinkles, which is below the excess lifetime cancer risk of 10-4 used by Dutch and Nigerian authorities for sediment intervention values. This finding is supported by the results obtained from the toxic unit approach which indicates that the ratios of the estimated dose and the maximal permissible risk level for summed PAHs never exceeded 1.

Relevance of animal studies in the toxicological assessment of oil and wax hydrocarbons. Solving the puzzle for a new outlook in risk assessment.

Paraffin waxes and white mineral oils are distinct petroleum products separated from a common feedstock by crystallization, where only n-alkanes, iso- and cyclo-alkanes with a linear backbone of ∼ 20 carbon atoms long, selectively crystalize out from the oil to form the wax, which is solid at room temperature, whereas oils remain liquid. Up until the 90's, these differences were reflected in separated regulatory assessments. A paradigm shift occurred when Fischer 344 rats (F-344) developed liver epithelioid granuloma following exposure to low and medium viscosity oils or waxes. This lesion was used as common denominator between these products to be jointly assessed under the common term "mineral hydrocarbons - MHC", obviating compositional differences. This regulatory paradigm dominated for the next 30 years, exacerbated by the EFSA 2012 evaluation using the analytical term "MOSH" (mineral oil saturated hydrocarbons) which encompassed these products under single chromatography fraction. The reconstruction of historical developments, together with recent EFSA-sponsored studies of toxicity and accumulation and supporting literature, has allowed us to understand the etiology of the F-344 rat hepatic epithelioid granuloma, which is presented in an adverse outcome pathway (AOP). Considering chemical composition, it clearly demonstrates that the hepatic effects in F-344 rats caused by linear alkanes of waxes are irrelevant for humans. Waxes are thus not MOSH and should thus be evaluated on their own merit. The term MOSH should not include n-alkanes and be exclusively used to mineral oil fractions when considering their chemical makeup for a relevant human hazard assessment.

Assessment of the potential human health risks from exposure to complex substances in accordance with REACH requirements. "White spirit" as a case study.

The European chemical control regulation (REACH) requires that data on physical/chemical, toxicological and environmental hazards be compiled. Additionally, REACH requires formal assessments to ensure that substances can be safely used for their intended purposes. For health hazard assessments, reference values (Derived No Effect levels, DNELs) are calculated from toxicology data and compared to estimated exposure levels. If the ratio of the predicted exposure level to the DNEL, i.e. the Risk Characterization Ratio (RCR), is less than 1, the risk is considered controlled; otherwise, additional Risk Management Measures (RMM) must be applied. These requirements pose particular challenges for complex substances. Herein, "white spirit", a complex hydrocarbon solvent, is used as an example to illustrate how these procedures were applied. Hydrocarbon solvents were divided into categories of similar substances. Representative substances were identified for DNEL determinations. Adjustment factors were applied to the no effect levels to calculate the DNELs. Exposure assessments utilized a standardized set of generic exposure scenarios (GES) which incorporated exposure predictions for solvent handling activities. Computer-based tools were developed to automate RCR calculations and identify appropriate RMMs, allowing consistent communications to users via safety data sheets.