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Description of key information

There are no key repeated dose studies (subacute, subchronic, or chronic) for 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.

A key 'read across' 90-day dermal study in rats was identified in which vacuum tower overheads was applied to the shaved skin of rats, 5 days a weeks for 90-days. The NOAEL was 30 mg/kg/day, based on findings in liver, thymus and blood.

A 28 day repeated dose toxicity studies in rabbits was identified for dermal exposure, plus a supporting 28 day dermal study in rats.  There was one key read-across 90-day repeated dose toxicity study (OECD 413) for inhalation.

For the read-across 90-day inhalation study, a NOAEC of 0.88 mg/L for local effects on the lung (increased relative wet weight in the absence of histopathological change) was established in rats expose to aerosol.  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.

For the 28-day dermal study, a LOAEL of 200 mg/kg/day was established based on local irritation. No NOEL was determined for local irritation.  The NOAEL for systemic effects in rabbits following repeated dermal exposure was greater than or equal to 2000 mg/kg/day.

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:
no adverse effect observed
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

There are no repeated dose studies (subacute, subchronic, or chronic) for oral exposure.  A key 'read-across' chronic dermal study in rats was identified together with supporting short-term repeat dose dermal studies in rats and rabbits. A 'read-across' 90- day inhalation study with diesel fuel was also identified.

 

Inhalation Toxicity

A study on diesel fuel (Lock, 1984; Klimisch score =2) was included as a source of information for read-across to straight run gas oils.Compositional and physico-chemical data show that VGOs/HGOs/Distillate Fuels are very similar to Straight-Run Gas Oils. It is considered appropriate, therefore, to read across from the VGOs/HGOs/Distillate Fuels data to Straight-Run 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)(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 (analytical concentration) diesel aerosol for 13 weeks, however there was no histopathological involvement, again making the relevance of these findings uncertain.  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

In a key 'read-across' sub-chronic dermal study, vacuum tower overheads was applied to the skin of rats, 5 days/weeks for 90 -days. Dose levels were 30, 125 or 500 mg/kg/day. Treatment related effects were seen in liver (increased liver weight), thymus (decreased thymus weight) and blood (decreased red blood cells, haematocrit and haemaglobin). The NOAEL was 30 mg/kg/day.

In a supporting 28-day dermal toxicity study Klimisch scores=2), straight run middle distillate (API 83 -11) was applied to rabbit (5 per sex per dose) skin at doses of 200, 1000 or 2000 mg/kg/day, three times/week for a total of 12 applications (API, 1985b). The sample was applied under occlusion for 24 hours to clipped backs. Each animal was observed twice daily during the treatment period for clinical signs of toxicity. An assessment of dermal reaction to the test material was made daily and body weights were recorded weekly. At the end of the 28-day treatment period all surviving animals were sacrificed and a gross necropsy was performed. Blood samples were collected and analysed for a range of clinical chemistry and haematological parameters. Major organs were weighed, and a range of tissues from control and high-dose animals were subjected to microscopic examination.

One low dose male rabbit died on day 12 (death considered incidental). The only reported clinical signs were soiling of the anal area and soft faeces in one low-dose male (days 22 and 23) and thin appearance for one high-dose female (days 12, 13, and 18-20). Animals from the high- dose group failed to gain weight during the study, whereas, mean body weight gains for the low- and mid-dose animals of both sexes were comparable to the controls. 

Dose-dependent skin irritation developed gradually over the course of the study, with mean irritation scores (Draize scale) of 0.55, 2.2 and 2.95 for the combined low-, mid- and high-dose groups at study termination. Treatment related skin changes were present in all treated rabbits and included erythema and oedema as well as cracked, flaky, and/or leathery appearance of skin at the test site. Haematological parameters were relatively unaffected by treatment and limited to a statistically significant increase in haemoglobin concentration in the 1000 mg/kg body weight/day males only. In the absence of comparable effects in females or in high-dose males, these findings are not regarded as treatment-related. Similarly, an isolated (10%) increase in blood urea nitrogen in the high-dose male group was considered a chance event (all other clinical chemical parameters were comparable to control values). Absolute and relative right kidney weights, and the relative left kidney weight, were decreased (approx 20%) in high-dose males, but in the absence of supporting changes in clinical chemistry or microscopic pathology, these findings are judged not to be treatment related. Other minor organ weight differences were not dose-related and, in the absence of any other related changes, were not attributable to the test substance.

 

Treatment related macroscopic findings in moribund- and terminally sacrificed animals were confined to the treatment site and consisted of dry, scaly, fissured, crusted, and/or thickened skin. Microscopically, slight to moderate proliferative changes were present in treated skin from all high-dose rabbits, with minimal inflammatory changes also present. These were accompanied in four high-dose males and five high-dose females by increased granulopoiesis of the bone marrow (lower dose groups not examined). This is in contrast to the controls in which there were no findings. There were no changes in any other tissues. No treatment-related effects were noted in examination of the weights of ovaries and testes, nor in the histopathology of ovaries and testes at 2000 mg/kg.

Based on these findings, the skin was the primary site of effects for straight run middle distillate with dose-dependent increases in irritation and inflammation apparent both macroscopically and microscopically. Local irritation was minimal in animals treated with 200 mg/kg body weight/day. Increased granulopoiesis of bone marrow was present in high-dose animals, and was considered by the study authors to be linked to skin damage at the treatment site; however, since lower dose groups were not examined no NOAEL can be established for this finding. Therefore, a LOAEL of 200 mg/kg/day is established based on local irritation. However, there were no systemic findings that were considered treatment related. Accordingly, the systemic NOAEL is greater than or equal to 2000 mg/kg/day.

 

In a supporting 28 -day dermal toxicity study, gas oil intermediate was applied to the shaved skin of four groups of ten males and ten female Sprague-Dawley rats, at dose levels of 0.01, 0.10, and 0.50 ml/kg and a sham control(API, 1985b; Klimisch score=2). Animals were dosed once a day, 5 times a week for 4 weeks. No animals died or were sacrificed moribund during the observation period. No significant body weight changes were noted between dose groups and sham group. No treatment-related effects were noted in examination of the weights of ovaries and testes, nor in the histopathology of ovaries and testes at 0.50 ml/kg.

Very slight to slight dermal irritation was noted during the study (dried skin, erythema and/or eschar). Dermal irritation in five animals was the only test article-related finding noted at necropsy. No treatment-related differences were noted between dose groups and sham group. Similarly no significant differences were noted between dose groups and sham group for haematology or clinical chemistry values. Findings indicate that the application of the test article induced mild epidermal irritation and minimal dermal inflammation at the high dose site. The dermal irritation NOAEL, based on very slight to slight irritation, was 0.01 ml/kg and the systemic NOAEL was 0.50 ml/kg, based on the test protocol.

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

Based on well conducted read-across inhalation study with diesel fuel

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

Read across dermal sub-chronic from VHGO category.

Repeated dose toxicity: dermal - systemic effects (target organ) cardiovascular / hematological: bone marrow; digestive: liver; other: skin

Justification for classification or non-classification

Results from dermal exposure indicate irritation at the application site in addition to systemic effects observed in rats at 125 mg/kg bw/day in a read-across sub-chronic study. Straight run gas oils meet the criteria for classification for Specific Target Organ Toxicity (repeated exposure) Category 2 (H373) under the EU CLP Regulation (EC No. 1272/2008).

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