C8-C26 branched and linear hydrocarbons – Distillates

Endpoint summary

Description of key information

A 2-generation reproduction study on 'Distillates (Fischer-Tropsch), C8-26 - branched and linear' was expanded to include traditional endpoints for evaluation of systemic toxicity (see IUCLID section 7.8.1). Therein a NOAEL of 750 mg/kg bw/day was concluded for systemic effects. 
Similarly, the conclusion of a 90-day oral (gavage) study with GTL Naphtha (C4-C10, branched and linear) was a NOAEL of 750 mg/kg bw/day for systemic effects relevant to human health. In both cases the NOAEL was the highest dose tested.
Additionally, a 90-day oral (gavage) study with GTL Base oil (C18-C50, branched, cyclic and linear) is available where the NOAEL was considered to be 1000 mg/kg bw/day, the highest dose tested.

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 - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

It it is considered unlikely that significant systemic effects would be observed following repeated dermal exposure since significant adverse effects did not occur by the oral route of exposure; thus, even with a default assumption of 100% absorption the dermal dose would not be greater.
Moreover, contact with skin is not considered to be the primary route of exposure.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Repeated dose toxicity data are available for GTL Diesel and a number of related substances. The data described here provide sufficient information to allow human health risk characterisation and an assessment of the secondary poisoning potential:

Repeated dose toxicity: oral

GTL GASOIL (see also IUCLID section 7.8)

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 F0males, 6 F0females, 5 F1males, and 4 F1females). 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 F0females were injured by their mating partner and euthanized for humane reasons, and 1 F0male was euthanized for humane reasons due to lesions on the neck, likely caused by scratching at the ear tag. One F0female given 750 mg/kg/day was euthanized due to dystocia, and 1 F1female given 750 mg/kg/day was found dead the day after dystocia was observed. The cause of death for 3 animals (1 F1male given 50 mg/kg/day, 1 F1male given 750 mg/kg/day, and 1 F1female given 750 mg/kg/day) could not be definitively determined at necropsy.

There were no adverse test item-related effects on F0and F1parental 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 F0and F1generations and the kidneys (males only) of the F1generation.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 F0and F1males and females given 750 mg/kg/day; this microscopic finding correlated with macroscopic observations in F0and F1males and F1females, as well as increased absolute and relative lung weights in F0and F1males 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 F1males, test item-related slight increases in renal tubule degeneration/necrosis and renal tubule hyaline droplets, suggestive of hydrocarbon-inducedalpha-2-microglobulinmale 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-inducedalpha-2-microglobulinmale rat nephropathy, an anticipated outcome of this study; therefore, the kidneys of the low- and mid-dose animals were not evaluated. In the F0males, 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 F0males given 750 mg/kg/day, with no similar mineralized tubules seen in the F0control males, F0females given 750 mg/kg/day, and F1males 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 F0and F1generations with corresponding macroscopic findings and increased lung weights and the kidneys (renal tubule degeneration/necrosis and renal tubule hyaline droplets confirmed to bealpha-2-microglobulin) of F1males 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 F0males given 750 mg/kg/day and slightly decreased spleen weights in F1and F2pups. 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 NAPHTHA (C4-C10, branched and linear)

A 90-day oral (gavage) toxicity study has been carried out using GTL Naphtha (C4-C10, CAS 858301-65-5), following OECD Test Guideline 408 and conducted according to GLP (Dunster et al, 2009). 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 750 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. There were no unscheduled deaths and no clinically observable signs of toxicity were detected in test or control animals throughout the study period. There were no toxicologically significant or treatment-related findings in functional performance tests, sensory reactivity assessments, bodyweight measurements, food and water consumption, opthalmoscopy or haematology.

Treatment-related liver and kidney effects were observed in males at all dose levels and in females at 750 mg/kg/day only. Statistically significant blood chemistry effects (increased plasma urea, calcium concentration, creatinine and cholesterol) were observed in males only at 200 and 750 mg/kg. These effects were not observed at the end of the recovery period, indicating reversibility. In the liver, centrilobular hepatocyte enlargement was observed in animals of both sexes at 750 mg/kg, but in the absence of associated inflammatory or degenerative changes was considered to be adaptive in nature. This view is supported by the regression of hepatocyte enlargement during a 28-day recovery period.

In the kidneys, tubular basophilia, tubular degeneration/necrosis and accumulations of globular eosinophilic material in the tubular epithelium were all seen as a consequence of treatment for males only treated with 750 mg/kg/day and 200 mg/kg/day. The majority of males at 50 mg/kg/day were affected only with accumulations of globular eosinophilic material in the tubular epithelium.

Although globular accumulations of eosinophilic material had regressed to background control levels amount recovery group animals, there was no evidence of regression of tubular basophilia or tubular degeneration/necrosis.

The kidney changes identified in males at all dose levels were consistent with well documented light hydrocarbon-induced male rat nephropathy, changes that are peculiar to the male rat in response to treatment with certain hydrocarbons. This effect was therefore considered irrelevant for the assessment of hazard to human health. In males, no NOEL could be established, based on liver effects. The report concluded that the NOAEL for males, excluding male rat hydrocarbon nephropathy, was 50 mg/kg/day, based upon adaptive changes to the liver and minor, reversible blood chemistry alterations. The NOAEL was 200 mg/kg/day in females, based only upon adaptive liver changes. For human health hazard assessment, liver changes that are adaptive in nature due to metabolism of large amounts of a xenobiotic are generally not considered to be adverse. For the purpose of hazard evaluation, the NOAEL is therefore regarded as 750 mg/kg/day.

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 (Faiola, 2011b). 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.

C10-C13 and C11-C14 alkanes

Two 90-day repeat dose oral (gavage) toxicity studies in rats were conducted with C10-13 and C11-C14 alkanes at doses up to 500 and 1000 mg/kg/day respectively (EMBSI 1991a and 1991b cited by ACC, 2004). There were some deaths which suggest aspiration of the test materials or dosing trauma. Primary findings in both sexes were gastrointestinal irritation and increased liver weights. The primary effect in males was consistent with alpha2-microglobulin induced nephropathy, which is specific to male rats and is not relevant to humans. The NOAEL for systemic toxicity was determined to be 500 and 1000 mg/kg/day, respectively, for C10-13 and C11-14 alkanes.

Repeated dose toxicity: inhalation

C9-C13 Dearomatized White Spirit

A 12-week inhalation study was performed using a mixture of C9 – C13 alkanes including 58% linear and branched and 42% cyclic constituents (Philips and Egan, 1984 cited by ACC, 2004). Male and female rats were exposed for 6 hours per day, 5 days per week to 300 or 890 ppm. The main purpose of the study was to determine susceptibility to kidney toxicity. There were slight decreases in body weights at the higher dose but no haematological or clinical signs. Increased liver/body weight ratios, especially in females, with no associated histopathology was considered indicative of an adaptive effect. Kidney weights were increased in males only, and histological findings were consistent with chronic progressive nephritis and/or alpha2-microglobulin induced nephropathy which is specific to male rats. The NOAEL was determined to be 300 ppm (ca. 2 mg/l), excluding kidney effects.

This study is of limited relevance to GTL Gasoil since the test material contained a significant proportion of cyclic constituents which are not present in the notified substance.

C10-C14 n-, iso- and cycloalkanes

The US National Toxicology Program conducted subchronic and carcinogenicity studies via inhalation in rats in mice on Stoddard Solvent IIC (NTP TR 519 cited by ACC, 2004, although report was not finalised at the time of writing). The test substance is a low aromatic (<1%) hydrocarbon solvent containing C10-C14 alkanes. Exposure was 6 hours per day, 5 days per week, for 13 weeks at concentrations of 0.138, 0.275, 0.550, 1.1 and 2.2 mg/l. In mice at the highest dose liver weights of males were increased, which may have been an adaptive effect, and decreased sperm motility was reported. In rats, relative increased kidney, liver and testis weights were reported at all dose levels. Male rats exhibited dose-related renal tubule hyaline droplet accumulation and other signs of nephropathy, which the study’s authors considered as evidence of an alpha2-microglobulin mechanism. There were no reported histological findings for the liver or testes, or on sperm counts, but sperm motility was reported to be decreased about 10% at 0.55 mg/l and above. There was no increased severity with increasing dose. No NOAEL is reported.

This study is of limited relevance to GTL Gasoil since the test material contained cyclic constituents which are not present in the notified substance.

C10-C11 isoparaffins

A 12-week inhalation study was conducted in rats with C10-C11 isoparaffins (Phillips and Egan, 1984 cited by ACC 2004). Exposure was to concentrations 1.97 and 5.61 mg/l. No details are available on the exposure duration. Decreased body weight gain was observed at both dose levels in males but not females. The most significant findings were increased male kidney weights and nephropathy, but the authors attributed this to species-specific chronic progressive nephritis. An apparent 5% decrease in erythrocytes in males at both doses was reported, although this effect was small and not dose-related.

Repeated dose toxicity: dermal

No data available for GTL Diesel. Data for related substance:

n-Tetradecane

A 20-day dermal toxicity in female Swiss mice gave an LOAEL of 9600 mg/kg/day. No further experimental details are available (IUCLID 2000, citing Sax and Lewis, 1989).

Table: Summary of available repeat dose toxicity data for relevant substances

Substance	Test method	Duration	Result	Comment	Reference
Oral exposure (gavage)
GTL Gasoil	OECD 416	>90 days	NOAEL ≥750 mg/kg/d	No adverse systemic toxicity effects up to the highest dose tested.	Faiola, 2011a (Reliability 1; see IUCLID section 7.8)
GTL Naphtha	OECD 408	90 days	NOAEL ≥750 mg/kg/d	No effects relevant to human health up to highest dose tested.	Dunsteret al., 2009 (Reliability 1)
GTL Base Oil	OECD 408	90 days	NOAEL≥1000 mg/kg/d	No effects relevant to human health up to highest dose tested.	Faiola, 2011b (Reliability 1)
C10-C13 alkanes	Unknown	90 days	NOAEL = 500 mg/kg/d	No effects relevant to human health up to highest dose tested.	EMBSI, 1991a, cited by ACC, 2004
C11-C14 alkanes	Unknown	90 days	NOAEL = 1000 mg/kg/d	No effects relevant to human health up to highest dose tested.	EMBSI, 1991b, cited by ACC, 2004
Inhalation exposure
n-Decane	Unknown	91 days	NOAEL = 3.2 mg/l	18 hours exposure per day. Increased body weight gain and white cell count.	IUCLID 2000, citing Nauet al., 1966
C9-C13 alkanes	Unknown	12 weeks	NOAEL = 2 mg/l	Primary aim of the study was to determine susceptibility to kidney effects in rats but other parameters were measured.	Philips and Egan, 1984 cited by ACC, 2004
Dermal exposure
n-Decane	Unknown	52 weeks	LOAEL = 25,000 mg/kg/day	No details available.	IUCLID 2000, citing Sax and Lewis, 1989
n-Tetradecane	Unknown	20 days	LOAEL = 9600 mg/kg	No details available.	IUCLID 2000, citing Sax and Lewis, 1989

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No study was available for 'Distillates (Fischer-Tropsch), C8-26 - branched and linear'.
However, a 2-generation reproduction study on 'Distillates (Fischer-Tropsch), C8-26 - branched and linear' was expanded to include traditional endpoints for evaluation of systemic toxicity (see IUCLID section 7.8.1). Therein a NOAEL of 750 mg/kg bw/day was concluded for systemic effects. Dosing in this study was performed for up to 107 consecutive days in males and up to 128 consecutive days in females.
Similarly, the conclusion of a 90-day oral (gavage) study with GTL Naphtha (C4-C10, branched and linear) was a NOAEL of 750 mg/kg bw/day for systemic effects relevant to human health (Harlan, 2009). In both cases the NOAEL was the highest dose tested.
Additionally, a 90-day oral (gavage) study with GTL Base oil (C18-C50, branched, cyclic and linear) is available where the NOAEL was considered to be 1000 mg/kg bw/day, the highest dose tested.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
It it is considered unlikely that significant systemic effects would be observed following repeated inhalative exposure since significant adverse effects did not occur by the oral route of exposure. Moreover, contact via inhalation is not considered to be the primary route of exposure.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
It it is considered unlikely that significant local effects would be observed following repeated inhalative exposure since significant adverse effects did not occur by the oral route of exposure. Moreover, contact via inhalation is not considered to be the primary route of exposure.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
It it is considered unlikely that significant local effects would be observed following repeated dermal exposure since significant adverse effects did not occur by the oral route of exposure; thus, even with a default assumption of 100% absorption the dermal dose would not be greater.
Moreover, contact with skin is not considered to be the primary route of exposure.

Justification for classification or non-classification

The available data indicate that repeated exposure to hydrocarbons in the range relevant for GTL Gasoil (C8 to C26) 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).

Few dermal data are available but it is considered unlikely that significant effects would be observed following repeated dermal exposure since significant adverse effects did not occur by the oral route of exposure; thus, even with a default assumption of 100% absorption the dermal dose would not be greater.

Repeated dose inhalation studies are available for a number of substances containing constituents present in GTL Gasoil. However, none of the available data are adequate to derive an inhalation NOAEL for GTL Gasoil.

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. .

Similarly, the conclusion of a 90-day oral (gavage) study with GTL Naphtha (C4-C10, branched and linear) was a NOAEL of 750 mg/kg bw/day for systemic effects relevant to human health (Dunster et al., 2009).

In a 90-day oral (gavage) study with GTL Base Oil (C15-C50, branched, linear and cyclic), the NOAEL was 1000 mg/kg bw/day (Faiola, 2011b).

In all cases the NOAEL was the highest dose tested.

Based on the absence of significant effects for human health in available sub-chronic toxicity studies GTL Gasoil and related substances, there is no requirement to classify for specific target organ toxicity following repeated exposures, according to the criteria of Regulation 1272/2008/EC.