Distillates (petroleum), solvent-dewaxed light paraffinic

Endpoint summary

Description of key information

Toxicokinetics of other lubricant base oils has been examined in rodents.  Absorption of other lubricant base oils across the small intestine is related to carbon chain length; hydrocarbons with smaller chain length are more readily absorbed than hydrocarbons with a longer chain length.  The majority of an oral dose of mineral hydrocarbon is not absorbed and is excreted unchanged in the faeces.  Distribution of mineral hydrocarbons following absorption has been observed in liver, fat, kidney, brain and spleen.  Excretion of absorbed mineral hydrocarbons occurs via the faeces and urine.  Based on the pharmacokinetic parameters and disposition profiles, the data indicate inherent strain differences in the total systemic exposure (~4 fold greater systemic dose in F344 vs SD rats), rate of metabolism, and hepatic and lymph node retention of C26H52, which may be associated with the different strain sensitivities to the formation of liver granulomas and MLN histiocytosis.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Read across justification

Although other lubricant base oils (OLBOs) have not been assessed in toxicokinetic studies, they are similar in composition to highly refined mineral oils (white oils), so similar toxicokinetic properties would also be expected.

Mineral hydrocarbons (including other lubricant base oils) are chemically inert, and, when ingested, most of the mineral oil (98%) remains unabsorbed in the faeces. Data from studies of “Highly Refined Mineral Oil” (white oil) suggests that small amounts of mineral oil (~2%) are absorbed as such by the animal or human intestinal mucosa and further distributed throughout the body. A very small fraction may undergo further biochemical transformation. Four key studies (Baldwin 1992, Halladay, 2002, TNO Quality of Life, 2010, and TNO Quality of Life, 2011) and 2 supporting studies (Albro, 1970 and Ebert, 1966) were chosen to assess the toxicokinetic activity of "sufficiently refined" (IP 346 < 3%) OLBOs and "insufficiently refined" (IP 346 ≥ 3%) OLBOs.

"Insufficiently Refined" Other Lubricant Base Oils (IP 346 ≥ 3%)

The test materials in this study, C₁₆ and C₁₈ hydrocarbons, are constituents of lubricant base oils, and accordingly, the data are expected to be similar to insufficiently refined (IP 346 ≥ 3%) lubricant base oils in toxicokinetic characteristics.

In a basic toxicokinetic study performed by Baldwin et al. (1992), oleum-treated white oil was mixed with the diet of male and female rats in concentrations of 0, 10, 100, 500, 1000, 5000, 10000, and 20000 ppm for a period of 13 weeks. After sacrifice, haematological, clinical chemistry, gross necropsy, tissue residue, and histopathological examinations were performed. There were no mortalities or adverse effects associated with feeding the rats oleum-treated white oil. Treatment related effects were generally dose-related and more marked in females than in males. After 90 days of treatment moderate multifocal granulomatous changes in mesenteric lymph nodes and liver were observed. Oleum-treated oil caused a greater pathological response then hydrotreated white oil. Oleum-treated white oils are suggested to undergo a process of omega oxidation.

"Sufficiently Refined" Other Lubricant Base Oils (IP 346 <3%)

In a basic toxicokinetic study performed by Baldwin et al. (1992), hydrotreated white oil was mixed with the diet of male and female rats in concentrations of 0, 10, 100, 500, 1000, 5000, 10000, and 20000 ppm for a period of 13 weeks. After sacrifice, haematological, clinical chemistry, gross necropsy, tissue residue, and histopathological examinations were performed. There were no mortalities or adverse effects associated with feeding the rats oleum-treated white oil. Treatment related effects were generally dose-related and more marked in females than in males. After 90 days of treatment moderate multifocal granulomatous changes in mesenteric lymph nodes and liver were observed. Oleum-treated oil caused a greater pathological response then hydrotreated white oil. The hydrotreated white oil (applicable to sufficiently refined hydrocarbons, IP 346 < 3%) is metabolized to the corresponding fatty acids of the same carbon chain length as the parent carbons, suggesting omega oxidation.

The disposition and pharmacokinetics of 14C-labeled eicosanylcyclohexane in female F-344 and Sprague-Dawley rats have been assessed (Halladay et al., 2002). Eicosanylcyclohexane was selected because it is a C26 hydrocarbon present in mineral oils and its pharmacokinetic behaviour was assumed to be representative of the constituents of complex white oils. For the disposition study, fasted female rats of both strains were given a single oral dose by gavage of 2 mL/kg bw of a 4:1 mixture of olive oil and food grade paraffinic white oil containing [1-14C]-eicosanylcyclohexane and a non-absorbable marker [1,2-3H]polyethylene glycol 4000. After dosing, the animals were held in metabolism cages over the following 96-hours. Urine, faeces and exhaled air were collected at 8, 16, 24, 48, 72 and 96 hours and were analyzed for total radioactivity. Ninety six hours post-dosing the animals were killed, and blood, liver, mesenteric lymph nodes and contents of the bladder and intestines were collected and analyzed for total radioactivity.

 

For the pharmacokinetic study [1-14C]-eicosanylcyclohexane in a mixture of olive oil and white oil (4:1) was administered as a single oral dose (1.8 g/kg) to female F-344 and Sprague-Dawley rats with indwelling jugular vein catheters. The animals were then held in metabolism cages for the collection of urine and faeces at 8, 16, 24, 48, 72 and 96 hours. At the same times, blood samples were taken via the catheters and analyzed for total radioactivity. Also at these times, at least three rats were killed and blood, liver, mesenteric lymph nodes and the contents of intestines and bladder were collected and analyzed for total radioactivity.

The bioavailability of total [14C] was greater in F-344 rats than in Sprague-Dawley rats as indicated by the area under the curve (AUC) of the plot of plasma concentration versus time. F-344 rats had a higher maximum blood concentration (Cmax) for total [14C], and a longer time to achieve Cmax compared to Sprague-Dawley rats. Faecal excretion was the major route of elimination for both strains. By 96 hours, 82% (F-344) and 87% (Sprague Dawley) of the dose was excreted in the faeces, but the rate of excretion was lower in the F-344 rats. Seventy percent of the label had been eliminated by 16 hours in the Sprague-Dawley rat, whereas, in the F-344 rat 11% of the dose was eliminated in 16 hours and 75% was eliminated in 48 hours. Urinary excretion was the second major route of excretion although the urinary profiles were different in the two strains. The Sprague-Dawley rats eliminated the radiolabel in the urine by 24 hours whereas excretion by the F-344 was linear over time during the 96 hour monitoring period and at this time only 7% of the administered dose was accounted for. The maximum amount of radioactivity in the liver was 2% at 8 hours for the Sprague-Dawley rat compared to 4% at 24 hours for the F-344 rats. Even after 96 hours 3% of the administered dose remained in the F-344 rat livers. The amount of radioactivity in the mesenteric lymph nodes was similar for both rat strains until 96 hours. At that time the percentage of the administered dose increased from 0.002% to 0.02% in the Sprague-Dawley rat.

Further information on strain differences in the single dose toxicokinetics of white oil (P15H) is available from TNO Quality of Life (2010) and Boogaard et al. (2012). In this study, female F-344 rats were dosed via oral gavage at 0, 20, 200, and 1500 mg Pl5H white oil/kg body weight while female Sprague Dawley rats received 0, 200 and 1500 mg P15H white oil/kg body weight. Blood samples (1, 2, 4, 8, 16, 24, 48, 96 hours) and livers (24, 48 and 96 hours) were collected at regular intervals over 4 days following treatment. The concentration of P15 white oil in blood and liver was measured by GC x GC – MS analysis and quantified based on the C19-C24 range of alkanes present. Blood concentrations were observed to increase to a maximum at 4 hr and then seen to decrease with time. In the F-344 strain, the blood concentrations were found to be clearly higher than in the Sprague-Dawley rat at dose levels of 200 and 1500 mg per kg body weight. Additionally, at sacrifice, F-344 rats in the 200 and 1500 mg/kg dose group exhibited higher concentrations of P15 white oil in liver and arterial blood. A measure of systemic exposure, the AUC0-∞,was higher by a factor of 4 in F-344 rats compared to Sprague-Dawley rats in both 200 (292 ± 18 vs. 62 ± 15 h*mg/L) and 1500 (700 ± 140 vs. 146 ± 49 h*mg/L) mg/kg body weight dose groups. The Cmax in F-344 rats was also higher than that observed in Sprague-Dawley rats. In the liver, maximum concentrations of the test material were seen 24 hours post exposure. Both Cmax and AUC at 200 mg/kg (4031 vs. 2267 h*mg/L) and 1500 mg/kg (8608 vs. 3124 h*mg/L) were higher in the F-344 rats than in Sprague-Dawley rats. However, dose-proportional kinetics was not observed in either strain. The results of this study confirm the strain-dependent differences in disposition of white oil reported by other studies and discussed above, and demonstrate that at doses of 200 and 1500 mg/kg body weight P15 white oil is more bioavailable in female F-344 rats than in female Sprague-Dawley rats.

In a study designed to investigate the absorption and kinetics of P15H white oil in humans, nine female volunteers (age 18 -35 years) were administered a single oral dose of a mixture of white oil- tetracosane via gelatine capsule at a mean received dose of 1.00 +/- 0.11 mg P15H/kg BW (TNO Quality of Life, 2011 and Boogaard et al. (2012). Blood was sampled at regular intervals over 7 days post-treatment and analysed using two-dimensional gas chromatography-mass spectrometry (GCxGC-MS). The subjects reported no clinical signs or adverse symptoms, however analytical results showed that the concentration of white oil in blood was below the average within laboratory detection limit (0.163 ug/mL) at all time points. While no kinetic information could be derived from the data, the results nonetheless put an upper bound on the concentration of white oil in blood following lows level of human ingestion.

A toxicokinetics study performed by Albro et al. (1970) evaluated absorption of hydrocarbon mixtures (IP 346 <3%). Simple mixtures of aliphatic hydrocarbons were administered to rats by gastric intubation at dose levels of up to 500 mg/kg b.w. The percentage retention of the aliphatic hydrocarbons was inversely proportional to the number of carbon atoms and ranged from 60% for C₁₄ to 5% for C₂₈ compounds. The major site of absorption was found to be the small intestine.

A toxicokinetics study performed by Ebert et al. (1966) evaluated distribution of tritiated mineral oil (IP 346 <3%) administered orally and via i.p. injections. Male and female rats were dosed with 0.66 mL of radiolabelled mineral oil for thirty-one consecutive days. Radioactivity was measured in extracted tissues after sacrifice. Results indicate that radioactivity is primarily found in liver, fat, kidney, brain, and spleen. Both oral and i.p. routes of administration exhibited the same characteristics of absorption.

A toxicokinetics study performed by Ebert et al. (1966) evaluated excretion of tritiated mineral oil (IP 346 <3%) administered orally and via i.p. injections. Male and female rats were dosed with 0.66 mL of radiolabelled mineral oil for thirty-one consecutive days. Urine and faeces were collected and stored daily for radioactivity analysis. Eighty percent of the tritiated mineral oil administered orally was not absorbed but rather excreted in the faeces two days after treatment. Only 11% of the total dose administered by i.p. injection was excreted in the faeces during the first 8 days of the study. About 8% of the radioactivity administered orally and via intrapeitoneal injection was excreted in the urine during the week following drug administration.