Hydrocarbons, C16-C22, n-alkanes, isoalkanes, <2% aromatics

Endpoint summary

Description of key information

Based on weight of evidence from subchronic toxicity studies on related substances covering the relevant carbon number range, it can be concluded that Hydrocarbons, C16-22, n-alkanes, isoalkanes, <2% aromatics, does not produce systemic toxicity effects relevant for hazard assessment at dose levels up to 750 or 1000 mg/kg bw/day. The most significant findings in the studies conducted were light hydrocarbon induced nephropathy in the kidney of male rats and forestomach lesions. Neither of these effects is relevant to humans (Baetcke, 1991). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

750 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

10 000 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

No repeated dose toxicity data are available for Hydrocarbons, C16-22, n-alkanes, isoalkanes, <2% aromatics itself. However, good quality repeated-dose toxicity studies for the oral route are available for related substances covering the relevant carbon number range. These are used as read-across to demonstrate the lack of toxicity of hydrocarbons in the relevant carbon number range.

GTL GASOIL (C8-C26)

A two-generation reproductive toxicity study (oral, gavage) has been carried out using GTL Gasoil following OECD Test Guideline 416 and conducted according to GLP (Faiola, 2011a). The test material was administered by gavage to four groups of male and female Crl:CD (SD) rats, each of 25 and 28 animals of each sex for the F₀and F₁generations, respectively. Test concentrations were 0 (control), 50, 200 and 750 mg/kg bw/day for the F₀and F₁generations. Dosing was performed for 70 consecutive days prior to mating. Males continued to be dosed during the 14-day mating period and post-mating holding (up to Day 107). Females were dosed during the mating period, gestation and lactation (up to Day 128). Additional endpoints (including detailed histopathology) were included in the test protocol such that the study can be used to assess general systemic toxicity in addition to reproductive effects.

Overall, there were 19 unscheduled deaths of parental animals (4 F0 males, 6 F0 females, 5 F1 males, and 4 F1 females). None of the deaths were directly attributed to the test item. Based on macroscopic (and in some cases microscopic) findings, 11 of the deaths were likely due to gavage error and/or aspiration of the dose formulation into the lungs. With the low viscosity nature of the test item and the use of corn oil as the vehicle, aspiration events were not unexpected. Two F0 females were injured by their mating partner and euthanized for humane reasons, and 1 F0 male was euthanized for humane reasons due to lesions on the neck, likely caused by scratching at the ear tag. One F0 female given 750 mg/kg/day was euthanized due to dystocia, and 1 F1 female given 750 mg/kg/day was found dead the day after dystocia was observed. The cause of death for 3 animals (1 F1 male given 50 mg/kg/day, 1 F1 male given 750 mg/kg/day, and 1 F1 female given 750 mg/kg/day) could not be definitively determined at necropsy.

There were no adverse test item-related effects on F0 and F1 parental body weights, body weight changes, feed consumption, and food efficiency. Test item-related histopathological lesions were identified in the lungs of both males and females of the F0 and F1 generations and the kidneys (males only) of the F1 generation. No test-item related histopathological changes were found in any of the organs that were evaluated beyond those of the standard OECD 416 protocol. There was an increased incidence and severity of chronic interstitial/alveolus inflammation in the F0 and F1 males and females given 750 mg/kg/day; this microscopic finding correlated with macroscopic observations in F0 and F1 males and F1 females, as well as increased absolute and relative lung weights in F0 and F1 males and females. As these lung lesions were considered to be secondary to aspiration of the dose formulation, and the chronic interstitial/alveolus inflammation finding was not unanticipated based on a previous 90-day, repeated-dose study with a similar test item, the lungs from the low and mid-dose animals were not evaluated. In the F1 males, test item-related slight increases in renal tubule degeneration/necrosis and renal tubule hyaline droplets, suggestive of hydrocarbon-induced alpha-2-microglobulin male rat nephropathy, were seen in the males given 750 mg/kg/day. Special staining of kidneys from males in the control and high-dose group confirmed this lesion to be hydrocarbon-induced alpha-2-microglobulin male rat nephropathy, an anticipated outcome of this study; therefore, the kidneys of the low- and mid-dose animals were not evaluated. In the F0 males, renal tubule mineralization was noted. Since this finding may be an artifactual change resulting from tissue fixation and/or processing, and since mineralized tubules were only observed in the F0 males given 750 mg/kg/day, with no similar mineralized tubules seen in the F0 control males, F0 females given 750 mg/kg/day, and F1 males and females given vehicle or 750 mg/kg/day, this finding was considered equivocal and non-adverse.

In conclusion, test item-related histopathological lesions were identified in the lungs (chronic interstitial/alveolus inflammation) of both males and females of the F0 and F1 generations with corresponding macroscopic findings and increased lung weights and the kidneys (renal tubule degeneration/necrosis and renal tubule hyaline droplets confirmed to be alpha-2-microglobulin) of F1 males only. The lung lesions were most likely secondary to aspiration of the test material and therefore not relevant for human risk assessment. The renal effects are a well known male rat specific effect which is induced by hydrocarbons and has no relevance for humans. Additional equivocal, non-adverse findings included renal tubule mineralization in the kidneys of F0 males given 750 mg/kg/day and slightly decreased spleen weights in F1 and F2 pups. Based on the absence of adverse, test item-related findings directly attributable to the test item in non-reproductive tissues, a dosage level of 750 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive and systemic toxicity.

 

GTL BASE OIL (C18-C50, branched, cyclic and linear)

A 90-day oral (gavage) toxicity study has been carried out using GTL Base Oil (C18-C50, CAS 858301-69-9), following OECD Test Guideline 408 and conducted according to GLP (Dunster et al., 2008). The test material was administered by gavage to three groups, each of ten male and ten female Sprague-Dawley Crl:CD (SD) IGS BR strain rats, for ninety consecutive days, at dose levels of 50, 200 and 1000 mg/kg/day in Arachis oil BP. Two recovery groups, each of ten males and ten females, were treated with the high dose or the vehicle alone for 90 consecutive days and then maintained without treatment for a further 28 days.

Animals of either sex treated with 1000 mg/kg/day and males treated with 200 mg/kg/day showed episodes of increased salivation throughout the treatment period. Such observations of this nature are often reported following oral administration of an unpalatable test material and, in isolation, are not indicative of systemic toxicity. No clinically observable signs of toxicity were detected in females treated with 200 mg/kg/day, animals of either sex treated with 50 mg/kg/day or in recovery animals following twenty-eight day treatment free period. No toxicologically significant effects were detected in the haematological and clinical chemistry parameters measured, nor were any toxicologically significant macroscopic abnormalities detected in terminal kill animals.

Microscopic histopathology, however, revealed some findings. A greater incidence of higher grades of severity of alveolar macrophage accumulations was observed for animals of either sex treated with 1000 mg/kg/day and at 200 mg/kg/day for males. The cytoplasm of macrophages seen in the lungs of animals of either sex treated with 1000 mg/kg/day and at 200 mg/kg/day for females was generally more vacuolated than that seen in alveolar macrophages in control animals. Vacuolated histiocytes were observed in relation to treatment for females treated with 1000 and 200 mg/kg/day but a similar effect was not seen for males treated with 200 mg/kg/day, or animals of either sex treated with 50 mg/kg/day.

Although the relevance to human health has not been established, the increased vacuolization of the macrophages seems adaptive in nature and did not have any health consequences in the animals. Gopinath (1987) refers to similar events when animals are exposed to various chemical forms such as phospholipids. Because contact to the material is via the gut and secondarily through aspiration of small quantities of test material in the lungs, such material is phagocytosed by the macrophage-like histiocytes. With some test materials, the cellular breakdown of such material may be slow and hence the accumulation of material may lead to a “foamy” appearance of the macrophage. Recovery may therefore exceed the normal twenty-eight day period as described in the test guideline but does not necessarily represent an irreversible change. The process can be regarded as neither proliferative or degenerative but merely part of a normal body process response to exposure to high levels of certain test materials which are inherently inert in their activity. As such the effects detected in the lungs and mesenteric lymph nodes in this study were not considered to be an adverse effect of treatment. The NOEL was considered to be 50 mg/kg/day. The effects detected at 1000 and 200 mg/kg/day in the lungs and mesenteric lymph nodes were not considered to be an adverse effect of treatment. The accumulation of petroleum hydrocarbons in mesenteric lymph nodes is a well known effect in the rat with little relevance to humans. In addition, it is related to the carbon chain length and not expected to occur to a significant extent with GTL Base Oil. The overall NOAEL considered relevant for human health hazard assessment of GTL Base Oil was considered to be 1000 mg/kg/day.

GTL BASE OIL 3 (C18 -C26)

A 28-day dietary study in rats has been conducted with GTL Base Oil 3 in accordance with OECD test guideline 407 and in compliance with GLP (McRae, 2014). The test item was administered by continuous dietary admixture to three groups, each of five male and five female Wistar Han™:RccHan™:WIST strain rats, for twenty-eight consecutive days, at dietary concentrations of 750, 3750 and 15000 ppm (equivalent to mean achieved dosages for males and females combined of 63, 308 and 1267 mg/kg bw/day). A control group of five males and five females were treated with basal laboratory diet. Clinical signs, functional observations, body weight, dietary intake and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all animals at the end of the study.

All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues from high dose and control animals was performed.

 

There were no unscheduled deaths during the study. There were no clinical signs, no changes in behavioural assessment, functional observations or sensory reactivity, and no effects on body weight, food consumption or food efficiency at any dose level. During the third week of treatment, males given the test item at all dose levels showed generally dose-related increases in water consumption levels in comparison with controls. There were no changes in water consumption for the treated females during the same period.

 

There were no treatment-related changes in the haematology or blood chemistry parameters examined, no macroscopic abnormalities at necropsy and no organ weight changes at any dose level. Microscopic examination of tissues revealed changes in male rats at the high dose level of 15000 ppm. During the third week of treatment, males given the test item at all dose levels showed generally dose-related increases in water consumption levels in comparison with controls. There were no changes in water consumption for the treated females during the same period.

 

On the basis of these findings the No Observed Effect Level was determined to be 15000 ppm for females and 3750 ppm in males

C9-C14 isoparaffins

The toxicity of C9-C14 isoakanes by inhalation route has been recently reviewed (Carrillo et al., 2013).

Results from a 13-week inhalation study in rats on a C10–C12 isoparaffinic solvent at nearly vapour saturated concentrations are compared to the results of repeated inhalation and oral toxicity studies of four other isoparaffinic hydrocarbon solvents. Statistically significant findings which were consistent across all studies included: nephropathy and small but significant changes in hematological parameters in male rats and liver enlargement in both male and female rats. The male rat kidney changes were due to an alpha-2u- globulin process and not relevant for human health or risk assessment. The liver enlargement without pathologic changes or elevations in liver enzyme markers was considered to be an adaptive response. The reason for the reductions in hematological parameters that were observed in males only is not clear, but it is suggested that these were either due to normal variation or a secondary consequence of the nephropathy. Thus, the overall No Observed Adverse Effect Concentration (NOAEC) was the highest concentration tested in the C10-C12 isoalkane study, >10,000 mg/m3. Because of the overall pattern of response, and the test being conducted at nearly saturated concentrations due to the low volatility this solvent, it is considered that the NOAEC determined for C10–C12 isoalkane solvents brackets the low end of the Hydrocarbons, C16-C22, n-alkanes, isoalkanes, <2% aromatics. Such high exposure concentrations would not be technically obtained in an inhalation study using Hydrocarbons, C16-C22, n-alkanes, isoalkanes, <2% aromatics, indicating that the NOAEC of >10,000 mg/m3 is a reasonable worse-case read across.

Conclusion

The available data indicate that repeated exposure to hydrocarbons in the carbon number range relevant for Hydrocarbons, C16-C22, n-alkanes, isoalkanes, <2% aromatics (C16 to C22) do not cause serious adverse effects relevant to human health via either the oral or inhalation routes. The most significant findings in the studies conducted were light hydrocarbon induced nephropathy in the kidney of male rats and forestomach lesions. Neither of these effects is relevant to humans (Baetcke, 1991).

Repeated dose inhalation studies are not available for constituents present in Hydrocarbons, C16-C22, n-alkanes, isoalkanes, <2% aromatics. This is due to the low volatility of hydrocarbons in the C16-C22 range. However, it is considered that the NOAEC determined for C10–C12 isoalkane solvents brackets the low end of Hydrocarbons, C16-C22, n-alkanes, isoalkanes, <2% Aromatics. Such high exposure concentrations would not be technically obtained in an inhalation study using Hydrocarbons, C16-C22, n-alkanes, isoalkanes, <2% aromatics, indicating that the NOAEC of , >10,000 mg/m³is a reasonable worse-case read across.

The key study is an extended 2-generation reproductive toxicity study (oral, gavage) with GTL Gasoil (C8-C26, branched and linear) reported a NOAEL of 750 mg/kg bw/day for systemic effects (Faiola, 2011a). Dosing in this study was performed for up to 107 consecutive days in males and up to 128 consecutive days in females (see Section 7.8.1 for further details).

In a 90-day oral (gavage) study with GTL Base Oil (C18-C50, branched, linear and cyclic), the NOAEL was 1000 mg/kg bw/day (Dunster et al., 2008).

In all cases the NOAEL was the highest dose tested.

Justification for classification or non-classification

Based on the absence of significant effects for human health in available sub-chronic toxicity studies there is no requirement to classify Hydrocarbons, C16-C22, n-alkanes, isoalkanes, <2% aromatics for specific target organ toxicity following repeated exposures, according to the criteria of Regulation (EC) No. 1272/2008.