H1 receptor antagonists are commonly used for the treatment of allergic diseases. The aim of this study was to find out, if antihistaminic compounds like mepyramine have the ability to influence the activity of antibacterials. Therefore, the checkerboard method was chosen to detect these possible effects in vitro. Studies were performed with two different Escherichia coli (E. coli) strains as test microbes, treated with antibacterials in combination with mepyramine. The minimum inhibitory concentration (MIC) of E. coli ATCC® 25922™ and E. coli PIG 01 was reduced by combinations of the tested antibacterials with mepyramine. These results have to be confirmed in vivo, before the use of antihistamines should be considered as potential way to minimize the amount of used antibacterials for treatment of E. coli infections.

The effect of florfenicol against Escherichia coli (E. coli) was investigated in vivo to confirm results of an in vitro study of Bruer et al. (2019), which has shown positive effects of various antibacterial agents in combination with the antihistamine mepyramine (MEP). Therefore, pigs were treated in three different settings: An untreated control group, 10 mg/kg florfenicol (FFC) and 10 mg/kg FFC in combination with 20 mg/kg MEP. E. coli were isolated from faecal samples and analyzed in growth quantity and resistance to FFC. The FFC medication induced an increased number of resistant E. coli strains isolated from faecal samples. The number of colonies detected after cultivation of animal samples treated with 10 mg/kg FFC was higher than the number of colonies after treatment with 10 mg/kg FFC in combination with of FFC and MEP. Furthermore, the effect of both compounds was examined on bacterial susceptibility of Pasteurella multocida in vitro, where the combination of FFC with MEP resulted in a diminished minimum inhibitory concentration. We confirmed the development of bacterial resistance in the intestine as non-target tissue caused by the use of the antibacterial agent florfenicol. Moreover, the combination of FFC with an antihistamine like MEP offers a possibility to enhance the efficacy of an antibacterial treatment and modifies the effect on gut microbiota.

Zinc sulphide is a widely used inorganic powder, and its production has reached quantities greater than 1000 t/year. Therefore, in accordance with OECD guideline 436, an acute inhalation test was implemented to provide more accurate data. This study is crucial for ensuring the safety of workers exposed to zinc sulphide dust and complying with regulatory requirements for REACH. Due to particle-specific properties, the maximum attainable concentration of zinc sulphide for an inhalation study was not certain. Two dry dispersion systems were used to aerosolize the zinc sulphide powder, and the generated aerosol was supplied to a nose-only inhalation exposure system. The results showed a maximum attainable concentration of 0.82 mg/L at an MMAD of 1.5 µm over a 4 h exposure. In the inhalation study, all six rats showed no specific symptoms and good health status and survived a post-exposure observation period of up to 14 days. From the results observed, the status of Not classified was derived according to CLP. Based on the experimental results, an LC50 was not determined but is considered to be higher than 0.82 mg/L (the maximum achievable aerosol concentration). These findings highlight the importance of documenting efforts to achieve aerosol conditions when concentrations required by OECD test guidelines cannot be reached.

Fatty acid esters of 3-monochloropropane-1,2-diol (3-MCPD) are heat-induced contaminants formed from fats and sodium chloride. The mode of action for the 3-MCPD mediated induction of renal tubule neoplasms in rats is still unclear, which is in part due to lacking metabolism data. In the current study, urinary metabolites were identified by one- and two-dimensional ¹³ C nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry following oral administration of 3-MCPD or [ ¹³ C ₃ ]3-MCPD in rats. In addition to 3-MCPD itself, nine metabolites were identified. Four of those, N -acetyl-S-(2,3-dihydroxypropyl)cysteine (DHPMA), 3-MCPD sulfate, β-chlorolactic acid (β-ClLA) and oxalic acid have been reported before. Five novel metabolites in rat urine were thiodiglycolic acid (TDGA), thionyldiglycolic acid (TNDGA), 3-MCPD glucuronide (at least three isomers), 3-carboxy-2-hydroxypropyl mercapturic acid (CHPMA), and 3-(S-carboxymethyl)mercaptolactic acid (CMMLA). Only three metabolites were excreted at mean dose ratios > 1% (after treatment with 50 mg 3-MCPD/kg body weight in male and female rats), i.e. 3-MCPD (7.3%, 9.7%), DHPMA (3.5%, 1.7%) and TDGA (1.1%, 4.0%). The overall mean dose excretion in urine samples (males: 12.2%, females: 16.3%) supported hypotheses on formation of conjugates/adducts of reactive metabolites and the possibility that dechlorination leads to suitable building blocks for amino acid and fatty acid synthesis. The identification of TDGA indicated the interim formation 2-chloroacetaldehyde, previously identified to mediate specific nephrotoxic effects of the cytostatic ifosfamide in rats.

High concentrations of low-density particles may cause effects in acute inhalation toxicity studies which can be easily underestimated or misinterpreted following strictly the OECD TG 436, i.e., limited parameters as mortality and gross lesions will be evaluated only. Seven particle types (synthetic amorphous silica (SAS) HMDZ-SAS, silica gel, pyrogenic SAS, and precipitated SAS, calcium carbonate, aluminum oxide pyrogenic alumina, organic red pigment) were chosen at the highest technically feasible concentration of approximately 500 mg/m3 for acute inhalation studies with an expanded endpoint setup. Therefore additional parameters and a thorough histopathological evaluation of an extensive set of organs, including the respiratory tract emphasizing the nasal cavities were added. Six Crl:WI rats per study were exposed for four hours from which three animals were sacrificed after 24 hours and three animals after 14 days. HMDZ-SAS caused early death in all animals due to blockage of the nasal passages caused by its hydrophobicity. For all other Si-containing compounds, histology revealed minor inflammatory and reactive lesions in lungs after 24 hours that were still present after 14 days, except in silica gel-treated animals. After 14 days, for pyrogenic SAS, precipitated SAS, and pyrogenic alumina, granulomas formed in the BALT and lung-associated lymph nodes. In contrast, the calcium carbonate induced almost no findings, and the red pigment (also tested for the additional dose of 1000 mg/m3) stuck partially to the nasal mucosa without causing pathological damage and partly entered the lungs without showing any adverse effects. The results of the present study highlight the advantage of improving the rather simple study design of acute inhalation studies by implementing an extended study design.

Fatty acid esters of 2-monochlorpropane-1,2-diol (2-MCPD) are process contaminants formed during the heat treatment of foodstuffs containing fat and salt. The limited information on 2-MCPD metabolism hinders investigating the mechanisms of toxic effects observed in skeletal and heart muscle as well as kidneys of rats treated with 2-MCPD dissolved in water by gavage over 28 days. The aim of the present work was to expand the scheme of 2-MCPD metabolism in rats. After oral administration of [ ¹³ C ₃ ]2-MCPD (30 mg/kg bodyweight; bw) or 2-MCPD (3 or 30 mg/kg bw) by gavage, urine samples were collected between 0 and 8 h, 8–24 h and 24–48 h. Novel metabolites were identified by ¹³ C nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS), and the most abundant metabolites were quantified by isotope-dilution GC-MS and UPLC-MS/MS. The main compounds were 2-MCPD itself and the oxidation product 2-chlorohydracrylic acid (2-ClHA). Eight metabolites were detected for the first time. Products of conjugation reactions were 2-MCPD sulfate and 2-MCPD glucuronide. Six metabolites formed after degradation of glutathione conjugates were thiodiglycolic acid (TDGA), thionyldiglycolic acid (TNDGA), 3-(S-carboxymethyl)mercaptolactic acid (CMMLA), S-(carboxymethyl)-CysGly (CMCG), N-acetyl-S-(1-carboxy-2-hydroxyethyl)-Cys (CHEMA), and 2-[(2-carboxy-2-oxoethyl)sulfanyl]hydracrylic acid (2-COSHA). The mean excretion ratios of four main compounds quantified in male (m) and female (f) urine collected over 48 h following the low dose administration of 3 mg/kg bw were: 2-MCPD itself (m: 12.5%, f: 11.6%), 2-ClHA (m: 30.4%, f: 26.0%), TDGA (m: 8.5%, f: 8.1%) and 2-MCPD sulfate (m: 0.19%, f: 0.23%). In summary, the metabolites covered at least 51.6% (m) or 45.9% (f) of the dose, which allowed proposing a comprehensive scheme of metabolic pathways. Given that 2-MCPD and each of its metabolites may exert a toxic effect, two pairs of metabolites stand out due to their reactivity with glutathione: 2-chloroacetaldehyde/2-chloroacetic acid as well as 2-chlorolactaldehyde/2-ClHA.