Distillates (petroleum), intermediate catalytic cracked

Endpoint summary

Description of key information

No repeat dose toxicity studies have been identified for cracked gas oils, following inhalation or oral exposure.

The sub-chronic inhalation study of diesel fuel (OECD 413, a read-across study from VGO/HGO/Distillate Fuels) resulted in a conservative sub-chronic NOAEC of 0.88 mg/L determined for local effects on the lung (increased relative wet weight in the absence of histopathological change). A NOAEC of ≥1.71 mg/L was established for systemic effects, based on no significant findings at this level.

In a 28-day sub-acute study (OECD 410), dermal exposure to a light catalytically cracked distillate resulted in limited systemic changes and a NOAEL of 500 mg/kg body weight/day.  In a 90-day sub-chronic study (OECD 411), dermal exposure to light catalytically cracked distillate resulted in a systemic NOAEL of 25 mg/kg body weight/day for males, and 125 mg/kg body weight/day for females, based upon reductions in thymus weight.  In another 90-day sub-chronic study (OECD 411), dermal exposure to coker light gas oil resulted in a systemic LOAEL of 30 mg/kg body weight/day for males and females, based upon clinical signs and irritation noted at all doses.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 710 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

880 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Study duration:

subchronic

Species:

rat

Additional information

No repeat dose toxicity studies have been identified for cracked gas oils, following inhalation or oral exposure.

In a 28-day sub-acute study, dermal exposure to a light catalytically cracked distillate resulted in limited systemic changes and a NOAEL of 500 mg/kg body weight/day. In a 90-day sub-chronic study, dermal exposure to light catalytically cracked distillate resulted in a systemic NOAEL of 25 mg/kg body weight/day for males, and 125 mg/kg body weight/day for females, based upon reductions in thymus weight and associated histopathology. In an additional 90-day subchronic study, dermal exposure to coker light gas oil resulted in changes in some clinical parameters (glucose, ALAT, calcium), decreased lymphocyte counts and histological alterations in kidney tissue, as well as marked skin irritation at all doses. No NOAEL could be determined, so the LOAEL for systemic toxicity from this study was 30 mg/kg body weight/day.

The sub-chronic inhalation study of diesel fuel (a read-across study from VGO/HGO/Distillate Fuels) resulted in a conservative sub-chronic NOAEC of 0.88 mg/L determined for local effects on the lung (increased relative wet weight in the absence of histopathological change). A NOAEC of ≥1.71 mg/L was established for systemic effects, based on no significant findings at this level.

Inhalation Toxicity

Read across from VGO/HGO/Distillate Fuels is justified based on similar physical/chemical composition and properties to Cracked Gas Oils.

In a 90-day sub-chronic inhalation toxicity study on diesel fuel (read across from VGO/HGO/Distillate Fuels), groups of male and female Sprague-Dawley rats were exposed whole body to 250, 750 or 1500 mg/m³aerosol (MMAD 0.43-0.75 microns) 4 hour per day, two days per week for 13 weeks (total of 26 exposures) (analytical concentrations:0.35, 0.88, and 1.71 mg/L) (Lock et al., 1984). There were no deaths during the exposure phase or during the 2-month recovery period. Animals were described as inactive during treatment but no overt clinical signs were present. Body weight was decreased in both the sham control and the diesel-exposed groups relative to animal room controls at the start of exposure (that is, when the animals were first introduced into the chambers). Terminal body weights (after 25 exposures) were significantly decreased in the groups of females, relative to the sham controls. Body weights for exposed males were comparable to the sham control group by the third week of the recovery period, whereas statistically significant decreases remained in mid- and high-dose females until recovery weeks 7 and 5, respectively.

 

Results demonstrate statistically significant alterations in a number of parameters (body weight, food consumption, startle reflex, certain lung function parameters) in rats following sub-chronic inhalation exposure to diesel aerosol, however the magnitude of these changes was small suggesting that they are of doubtful biological relevance. Statistically significant increases in relative liver weight and relative wet lung weight were observed in animals exposed to 1.71 mg/L (analytical concentration) diesel aerosol for 13 weeks, however there was no histopathological involvement, again making the relevance of these findings unclear.  It is noted that the use of whole body exposure probably resulted in ingestion of the test sample during grooming, and may account for the systemic findings that were observed. All of the changes present following 13 weeks exposure were reversed after a 2-month recovery period. A conservative sub-chronic NOAEC of 0.88 mg/mL is determined for local effects on the lung (increased relative wet weight in the absence of histopathological change). A NOAEC of ≥ 1.71 mg/L is established for systemic effects, based on no significant findings at this level.

Dermal Toxicity

A key 28 -day sub-acute dermal study was conducted on rats using a light catalytically cracked distillate (Klimisch score = 1, API 1985).The test material covered an area of approximately 10% total body surface, under occlusion in 4 male and 4 female rabbits. A dose-related decrease in body weight gain was noted in mid-dose and high-dose groups. The test substance produced a significant 9% decrease in final body weight in males treated with 500 or 1000 mg/kg body weight/day for 28 days. The female test animals were unaffected. Draize scores of 2.2, 4.3 and 5.4 recorded at study termination for the low-dose, mid-dose and high-dose groups, respectively were recorded, which the study authors reported to be moderate to severe dermal irritation. Microscopic examination of skin from the test site revealed minimal to moderately severe inflammatory changes after application of 1000 to 2000 mg/kg body weight/day, with concurrent increased granulopoiesis in bone marrow from these animals (lower dose groups not examined). Serum alkaline phosphatase activity was also decreased by approximately 50-60% in animals treated with one sample at 2000 mg/kg body weight/day. Based on these limited changes, a systemic NOAEL of 500 mg/kg body weight/day is derived.

 

 In a supporting 28-day dermal toxicity study, rats were exposed to FCCU light cycle oil at dose levels of 0.001 (10% dilution with acetone), 0.01, and 1.0 ml/kg (Klimisch score = 1, ARCO 1992h). No mortality or adverse effects on body or organ weights were noted. There were no significant findings in haematology or clinical chemistry of treated animals compared to sham/vehicle controls. At necropsy, mild to moderate dermal irritation and/or eschar were observed at the test site in a dose-dependent manner, and these were the only treatment-related findings. Under the study conditions, the NOEL was 0.001 ml/kg for males and less than 0.001 ml/kg for females based on dermal irritation. The systemic NOEL was determined to be 1.0 ml/kg for males and females.

In a supporting 28-day dermal toxicity study, rats were exposed to FCC light cycle oil under semi-occlusive conditions at dose levels of 0.05, 0.5, or 1.0 ml/kg/day (Klimisch score = 1, ARCO 1991b). Very slight erythema was observed in male and female animals on day 2 at all dose levels tested. No dermal irritation was noted in the sham control group. A statistically significant increase in creatinine levels of the 0.05 mg/kg group females was not considered treatment-related. A statistically significant increase in relative liver weights in the male 0.5 and 1.0 ml/kg groups was not considered treatment-related or biologically relevant. Treatment-related pathology included acanthotic and hyperkarototic epidermal lesions and inflammatory dermal lesions in the male and female rats dosed with 1.0 ml/kg/day test material. Dose-related changes in dermal irritation were observed in male and females rats at 0.05, 0.5, and 1.0 ml/kg/day.Since dermal irritation was observed at the lowest dose level tested (0.05 ml/kg/day), a NOAEL could not be established.

 

In a supporting 28-day dermal toxicity study, rats were exposed to light thermocracked distillate at dose levels of 0.001 (10% dilution in acetone), 0.01, and 1.0 ml/kg/day (ARCO 1992i, Klimisch score = 1).No mortality or treatment-related differences in body or organ weight were observed. Very slight to severe dermal irritation was observed in the 0.01 and 1.0 ml/kg/day dose groups. Open lesions were observed in the 1.0 ml/kg/day group on day 5. A secondary response to dermal irritation (higher percentage of neutrophils and lower percentage of lymphocytes) was observed in the 1.0 ml/kg/day group. Histopathological findings revealed moderate irritation at the high dose testing site. Based on the study results, the NOEL is 0.001 ml/kg (in 10% acetone) based on dermal irritation, and the systemic NOEL is 1.0 ml/kg.

 

In a supporting 28-day dermal toxicity study, rats were exposed to light thermocracked distillate at dose levels of 0.0001 (0.01 ml/kg 1% dilution in acetone), 0.005 (0.01 ml/kg 50% dilution in acetone), or 0.01 ml/kg (ARCO 1992j, Klimisch score = 1). No mortality or treatment-related differences in body or organ weight were observed. No test-article related clinical signs were observed. Very slight to severe dermal irritation was observed in the 0.005 and 0.01 ml/kg/day dose groups. Oedema and fissuring were also noted. Based on the study results, the NOEL is 0.0001 ml/kg (0.01 ml/kg 1% dilution in acetone) due to dermal irritation, and the systemic NOEL is 0.01 ml/kg.

 

In a key 90 -day sub-chronic dermal exposure rats were exposed to light catalytically cracked distillate at dose levels of 0, 8, 25, 125, 500 or 1250 mg/kg body weight/day (Klimisch score = 2, Mobil 1985c). All rats dosed with 1250 mg/kg body weight/day were sacrificed during the second week of the study because of the severity in response to the test material. Males dosed with 500 mg/kg body weight/day had reduced growth rates and weighed approximately 25% less than the controls at the end of the study. The females in the 500 mg/kg/day group were similarly affected and weighed approximately 4% less than the controls at the end of the study. Severe skin reactions were observed for rats dosed at 1250 and 500 mg/kg/day.  Rats dosed with 125 mg/kg/day experienced moderate skin reactions and slight skin reaction was experienced for those rats in the 25 and 8 mg/kg/day groups. No dose-related effects in any of the other haematological , clinical chemical or urinalyses in any dose group were observed. 

 

The target organ for LCO in both males and females treated at 500 mg/kg/day was the thymus. The thymus of males and female animals was smaller than normal, as determined by visual inspection and by weight. Relative thymus weights were 41% and 20% less than the controls for males and females, respectively, for the 500 mg/kg/day dose group, while in the 125 mg/kg/day group relative thymus weights were reduced in males only (17% relative to controls). Microscopic examination of the thymus revealed depletion of lymphocytes and a slight increase in the amount of connective tissue present (more prevalent in the males than in the females).  Study authors attributed the reduced thymus size to have resulted from the depletion of lymphocytes within the thymus. The liver weights were increased in both males (35%) and females (27%) treated with 500 mg/kg body weight/day and liver cells from males contained more fat than did the controls.

 

A systemic NOAEL of 25 mg/kg body weight/day was obtained for males, and 125 mg/kg body weight/day for females, based upon reductions in thymus weight. The NOAEL for local skin effects was 125 mg/kg body weight/day, however this information is of limited value for the purposes of risk characterisation since the test area was not reported and the dose per unit area is therefore unknown.

 

In a subchronic dermal toxicity study, Beaumont coker light gas oil was applied to the shaved skin of Sprague-Dawley rats (10/sex/treatment) at dose levels of 0, 30, 125, 500, or 2,000 mg/kg/day 5 days a week for 13 weeks (Mobil, 1991). Animals wore Elizabethan collars to minimize ingestion. Skin was wiped each Saturday morning and collars were removed.

 

Animals treated with 2000 or 500 mg/kg groups were sacrificed early (during weeks 2 and 9, respectively) due to severe skin irritation and moribund condition. Erythema and signs of chronic skin deterioration were observed in all treatment groups and, in general, the degree of skin irritation was severe. With the exception of animals in the 500 and 2000 mg/kg/day groups, mean body weights for the remaining treated animals increased normally, compared to controls, throughout the study, although a slight statistically significant decrease (5-10%) was present in the 125 mg/kg body weight/day groups (both sexes) at week 13. There were no treatment-related changes in urine analysis or sperm evaluations.

 

Serum chemistry analyses revealed the presence of a number of statistically significant changes at week 13, with glucose decreased 17-20% in both sexes at 125 mg/kg body weight/day, and by 12% in males only at 30 mg/kg body weight/day. ALAT was significantly increased (31-33%) in both groups of surviving males (females unaffected), while serum calcium was significantly decreased (5-6% reduction) in surviving females (males unaffected). Alkaline phosphatase was increased (30-35%) in both sexes treated with 125 mg/kg body weight/day while females only exhibited an increase (22%) in urea nitrogen at this dose. Serum sorbital dehydrogenase activity was statistically significantly increased (40%) in females from the 30 mg/kg/day group and significantly decreased (30%) in females at 125 mg/kg/day, suggesting effects unrelated to treatment. The clinical chemistry changes of probable biological relevance are the reductions in blood glucose, ALAT and calcium and the increases in alkaline phosphatase. The other differences appear of doubtful significance.

 

Several haematology parameters were significantly altered following dermal exposure to coker light gas oil. White blood cell counts were increased significantly at week 5 in the 500 mg/kg body weight/day groups (32-77% increase for males and females, respectively), and at week 13 in the 125 mg/kg groups (increased 22-29% for males and females, respectively). Lymphocyte counts at week 5 were decreased by 17-22% in both sexes following treated with 125 mg/kg body weight/day, and by 29-35% in the 500 mg/kg/day group. Following 13 weeks treatment, lymphocyte counts were decreased by 9% and 18% in males treated with 30 or 125 mg/kg body weight/day, respectively and by 20% females from the 125 mg/kg group. The number of segmented neutrophils was increased approximately three-fold (significant) in both sexes following 5 or 13 weeks exposure to 125 mg/kg body weight/day.

 

Following necropsy at week 13, absolute thymus weights were found to be statistically significantly lower in males from the 125 and 30 mg/kg body weight/day groups (decreased 34% and 25%, respectively) and in females from the 125 mg/kg/day group (decreased 23%) however values for other organs were unaffected. Several differences in relative organ weights were apparent in animals from the 125 mg/kg body weight/day groups, however only changes in females (kidneys +8%, heart +6%, liver +22%, spleen +19%) appeared related to treatment, with effects in males most likely secondary to a 10% reduction in terminal body weight.

 

Histopathological examination found treatment-related changes in several organs. Skin at the treatment site was severely affected in all treatment groups, with extensive damage (including congestion, crust formation, degeneration, dyskeratosis, oedema, hyperkeratosis, hyperplasia, inflammation, and ulcer formation). In animals sacrificed early, adrenal hypertrophy was present in both sexes at 500 mg/kg body weight/day only, with a severe reduction in erythropoietic cells and megakaryocytes in bone marrow in the 2000 mg/kg groups. At scheduled termination, megakaryocitic changes (characterised by larger, vacuolated and/or nuclei darkened or clumped cell effects) were also observed in bone marrow from animals treated with 125 mg/kg body weight/day and greater. A range of changes were present at week 13 in the kidneys from males and females at 30 and 125 mg/kg body weight/day, including, cysts, degeneration, fibrosis, and inflammation, while haematopoiesis, leukocytosis, necrosis, and nodules were present in livers from the 125 mg/kg body weight/day groups (both sexes). Other sporadic histological changes were considered by the authors to be secondary to reduced body weight gain, treatment-related skin injury, slight septicaemia and stress.

 

No NOAEL could be determined for coker light gas oil, with changes in some clinical parameters (glucose, ALAT, calcium), decreased lymphocyte counts and histological alterations in kidney tissue reported following sub-chronic dermal treatment at 30 mg/kg body weight/day. Marked irritation of the treatment site was also present in all dose groups. The LOAEL for systemic toxicity from this study is therefore 30 mg/kg body weight/day. The LOAEL for local effects is also 30 mg/kg body weight/day, based on macroscopic and microscopic changes at the treatment site, however this information is of limited value for the purposes of risk characterisation since the dose per unit area is not known.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

one of 8 repeat dose dermal toxicity studies

Repeated dose toxicity: dermal - systemic effects (target organ) cardiovascular / hematological: thymus

Justification for classification or non-classification

In a 90 day repeat dose dermal study, the NOEL was 25 mg/kg/day, with a LOEL of 125 mg/kg/day. In another study the LOAEL is identified as 30 mg/kg/day. Based on these data cracked gas oils are classified for repeat dose toxicity as STOT (repeated exposure) Cat 2, H373 according to EU CLP Regulation (EC No.1272/2008) criteria. The NOAEC of > 1710 mg/m3 derived from the 90-day inhalation read-across study also does not indicate classification under EU CLP Regulation (EC No. 1272/2008) criteria.