Registration Dossier

Administrative data

Description of key information

No repeat dose toxicity studies have been identified for other gas oils, following oral exposure. However, OECD 422 studies by the oral dietary route are now planned on a number of substances within the category to fill this data gap and to act as range-finding for the EOGRTS (OECD 443) which is the subject of a testing proposal.

In two 28 day inhalation studies with hydrodesulphurised middle distillates the LOAEL values were 23  and 24 mg/m3 (OECD 412).  These studies and  values were considered unreliable.  

A 90-day inhalation study of diesel fuel (aerosol) (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 greater than or equal to 1.71 mg/L was established for systemic effects, based on no significant findings

at this level (OECD 413).

The systemic NOAEL for 28-day dermal exposure to other gas oils was 1000 mg/kg/day, based on moribund state and early mortality in the

higher dose groups (OECD 410).

In a read-across study (from CGOs), 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 (OECD 411).  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
Quality of whole database:
Two supporting studies following 28 day exposure were considered limited due to only one dose level and inconsistent findings.

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
Quality of whole database:
Two 90-day dermal studies identified which gave similar results. NOAEL in range 25-30 mg/kg/day

Additional information

There were no repeat-dose, oral studies on Other Gas Oils identified.

Inhalation Exposure

The effects of 28-day inhalation exposure to two samples of hydrodesulfurised middle distillate has been investigated in studies, in SD rats (20 per sex) following whole body inhalation exposure to nominal concentrations of 25 mg/m3, 6 hours/day, five days/week, for a total of 4 weeks (Klimisch score = 2, API 1986a). All rats survived the 4 week treatment period with no exposure related effects on appearance or behaviour in any of the groups. There was a statistically significant increase in leukocyte count in both males and females (approximately 30%) treated with the second sample only. Statistically significant organ weight increases were observed in male rats treated with the first sample in the kidney (9%), liver (14%), liver/body weight ratio (5%), testes (8%) whereas the brain/body weight ratio was decreased (-9%). In the females, liver weight was increased by 9% and lung/trachea weight by 7%.  Rats exposed to the second sample of hydrodesulfurised middle distillate also exhibited several minor, but statistically significant increases in kidney weight (9%), liver weight (14%), liver/body weight ratio (5%) and testis weight (8%). 

The results demonstrate increased leukocyte counts and inflammation of the respiratory mucosa in rats following sub-acute inhalation exposure to two samples of hydrodesulfurised middle distillate. The toxicological significance of these findings is difficult to assess, however, since only a single exposure concentration was employed and there was no consistency in biological response between the two samples. Although only limited information is available on the effects of repeated inhalation exposure to gas oils, comparable effects were not reported in other studies of longer duration involving exposure to higher concentrations of diesel fuel (e. g. Lock et al., 1984, below). Overall, the LOAEL of 25 mg/m3 in this study is considered unreliable for use in risk characterisation.

Read across from VGO/HGO/Distillate Fuels to Other Gas Oils is justified based on similar physical/chemical properties and chemical composition. In a key 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 nominal (MMAD 0.43-0.75 microns) 4 hour per day, two days per week for 13 weeks (total of 26 exposures) (Klimisch score = 2, 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 (actual 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/L is determined for local effects on the lung (increased relative wet weight in the absence of histopathological change). A NOAEC of greater than or equal to 1.71 mg/L is established for systemic effects, based on no significant findings at this level.

 

Dermal Exposure

In two separate key 28-day dermal toxicity studies, hydrodesulfurised middle distillate was applied for 24 hours (occluded) at dose levels of 200, 1000, or 2000 mg/kg body weight/day to the clipped backs of groups of 5 male and 5 female New Zealand White rabbits three times/week for a total of 12 treatments (Klimisch scores = 2, API 1983b, c).  Treatment related clinical signs included flaking, cracking, scabbing and necrosis of skin at the treated site. Skin irritation (Draize scale) increased in a dose dependent manner. There were no treatment related trends in any of the haematology or clinical chemistry parameters, and no statistically significant differences in absolute or relative mean organ weights. Based on these findings, the skin was the primary site of toxicity for hydrodesulfurised middle distillate. The NOAEL for systemic toxicity of the two samples tested was 1000 mg/kg/day, based on moribund state and early mortality in the higher dose groups.

 

Read across from Cracked Gas Oils to Other Gas Oils is justified based on similar physical/chemical composition and properties to Other Gas Oils. In a key read-across 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 1985). 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.

Read across from Cracked Gas Oils to Other Gas Oils is justified based on similar physical/chemical composition and properties to Other Gas Oils. In a key read-across 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.

Results seen in repeated-dose dermal studies support the classification of other gas oils as harmful after repeated exposure. 

Additional data support that OGOs are harmful to health by prolonged exposure to skin (CONCAWE, 1993, Dally et al., 1996, Nessel et al., 1998). This information is presented in the dossier.

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

Read across study selected because it is a well conducted study of 90 day duration and examined a number of parameters following exposure to high concentrations.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

Based on effects on lung weight observed in the absence of histological change

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

Justification for classification or non-classification

Based on a NOAEL of 25 mg/kg/day in one 90-day dermal toxicity study, and a LOAEL of 30 mg/kg/day from another 90 -day dermal toxicity study, carcinogenic Other Gas Oils (see OIN 14) are classified for repeat dose toxicity as H373 according to the EU CLP Regulation (EC No. 1272/2008). 

The NOAEC of > 1710 mg/m3 derived from the 90-day inhalation read-across study does not indicate classification according to the EU CLP criteria.