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Administrative data

Description of key information

In a read-across 90-day oral study (equivalent to OECD 408) from distillate aromatic extract, a NOAEL could not be identified and is less than 125 mg/kg/day to male rats.  

In a read-across subacute inhalation study (non-guideline) from other lubricant base oils (IP 346 < 3%), the NOAEC for pulmonary effects was 500 mg/m3, and the NOAEC for systemic effects resulting from inhalation exposure was ≥1500 mg/m3 in rats.

One key 28-day dermal study (OECD 410) was identified, along with one read-across 90-day dermal study (OECD 411) from distillate aromatic extract. For the 28-day dermal study, the systemic NOAEL in this study is 1000 mg/kg/day for rabbits dosed with 0, 200, 1000, or 2000 mg/kg/day. The dermal NOAEL is <200 mg/kg/day based on the irritation at the treatment site.  For the 90-day dermal read-across study conducted with rats at dose levels of 30, 125, 500, or 1250 mg/kg/day, the LOAEL is 30 mg/kg/day, based on body weight, clinical chemistry, organ weights, gross pathology, and histopathology. A NOAEL is not identified.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 500 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
500 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

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

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
12.5 mg/cm²
Study duration:
subacute
Species:
rabbit

Additional information

One read-across 90 -day oral study was identified from distillate aromatic extract. One read-across subacute inhalation study was identified from other lubricant base oils (IP 346 < 3%). One key 28-day dermal study was identified. One read-across 90-day dermal study was identified from distillate aromatic extract. Distillate aromatic extracts are considered “worst case”, in that the extract will contain higher concentrations of biologically active components (polycyclic aromatic compounds) than the unrefined / acid treated oils, due to the concentration effect of the solvent extraction process.

Repeated Dose - Oral

In a subchronic oral toxicity study, heavy paraffinic distillate aromatic extract was administered to 10 male Sprague-Dawley rats/dose at dose levels 0, 125, or 500 mg/kg bw/day 5 days a week for 13 weeks (Mobil, 1990a; Klimsich score=1). Four of ten rats in the 500 mg/kg/day group were sacrificed prior to scheduled termination. All animals in the 125 mg/kg/day survived to date of sacrifice. No details on clinical signs were provided. Body weight was significantly reduced in the 500-mg/kg/day group. A significant decrease (p<0.05) in red blood cell (RBC) parameters (including RBC count, haemoglobin, and haematocrit) and platelet in males dosed orally at 500 mg/kg/day. Males orally dosed at 125 mg/kg/day showed a significant decrease in RBC parameters; platelet counts were slightly decreased in these rats but did not achieve statistical significance. There were no significant differences in the RBC morphology or WBC differential data. The only statistically significant difference between the serum data from control and orally dosed rats was observed for SDH (0 mg/kg/day = 5±2 IU/l, 150 mg/kg/day = 8±2 IU/l, 500 mg/kg/day = 9±7 IU/l). Treatment-related dose-dependent changes in relative organ weights included increased liver weight in both groups, decreased prostate weight in both groups, decreased seminal vesicle weight in the high-dose group, and decreased thymus weight in both groups. Focal areas of red discoloration and or generalized reddening were also observed in the brain, spinal cord, stomach and testes of many of the rats dosed orally at 500 mg/kg/day. Treatment-related histopathology was generally dose-dependent and occurred in the following tissues: adrenals, bone marrow, liver, stomach and thymus. Atrophy occurred in the male sex organs (testes, seminal vesicle, and prostate). Sperm evaluations showed a significant increase in the frequency of sperm with abnormal heads in the rats dosed orally at 500 mg/kg/day (1.9% in controls and 3.2% in treated rats). 

NOAEL for heavy paraffinic distillate aromatic extract could not be identified and is less than 125 mg/kg/day when administered orally. This compound is a distillate aromatic extract and provides a worst case scenario for unrefined/acid treated oils due to the concentration effect of the solvent extraction process.

Repeat Dose – Inhalation

Two solvent-extracted paraffinic mineral base oils (sufficiently refined, IP 346 < 3%) were evaluated in supporting 2-week inhalation toxicity studies (Klimisch score = 2; Exxon, 1991a, Exxon, 1991b, and Whitman, 1989).  The oils spanned a range of 60 – 150 SUS @ 40°C, approximately 12-30 mm2/s). Rats were exposed 6 hours/day to aerosol concentrations of approximately 0, 50, 500, and 1500 mg/m3. There were no mortalities. Exposure-related changes were noted in animals from the most highly exposed groups. These changes, including focal infiltrations of inflammatory cells, focal hyperplasia and squamous metaplasia of the nasal mucosa, and accumulations of inflammatory exudates in the lumen of the nasal cavity, were interpreted as the result of a mild irritating process in the nasal mucosa. No other microscopic changes were observed in any other tissues that indicated systemic toxicity from exposure to the lubricant base oils. The NOAEC for pulmonary effects was 500 mg/m3, and the NOAEC for systemic effects resulting from inhalation exposure was 1500 mg/m 3.

Repeated Dose - Dermal

A 28-day dermal repeated-dose study (API, 1986b; Klimisch score=1) was conducted in NZW rabbits with an unrefined light paraffinic distillate (CAS No. 64741-50-0). In this study, the undiluted test material was applied at doses of 200, 1000 and 2000 mg/kg, once a day, three times a week for 4 weeks to the shorn dorsal skin of groups of five male and five female rabbits. The applied material was covered with an occlusive dressing for 6 hours and was then removed. At that time, the skin was wiped with dry gauze to remove any residual material. A group of five rabbits of each sex served as sham controls. The test skin site of each animal was examined and scored for irritation prior to each application of test material. Mortality and morbidity checks were performed twice daily, and body weights were recorded weekly. At termination, blood samples were taken for a range of haematological and clinical chemical measurements. Urine samples were also collected and frozen for possible future examination. A complete gross necropsy was performed on all animals. Major organs were weighed, and tissues were processed for subsequent histopathological examination.

Treatment-related findings included erythema and oedema at the application site in the 1000 and 2000 mg/kg groups with increasing frequency and severity with increasing dose, i. e., the 2000 mg/kg group displayed moderate irritation and proliferative changes in the skin. Only minimal irritation was observed in the 200 mg/kg dose group. Bodyweight losses were observed in 1 male and 3 females at 2000 mg/kg, and the group mean bodyweights were significantly less than the controls. There was no other evidence of systemic toxicity. No treatment-related trends were evident based on the haematology, clinical chemistry or organ weight data. The deaths of a low dose female, a high dose male and a sham-treated control male were not considered to be treatment-related. The systemic NOAEL in this study was 1000 mg/kg/day, based on reductions in body weight. The dermal NOAEL was <200 mg/kg/day based on the irritation at the treatment site.

In a 90-day read-across dermal toxicity study (Mobil, 1989; Klimsich score=1), distillate aromatic extract (DAE) was applied to the shaved skin of 10 Tac: N(SD) fBR rats/sex/dose at dose levels of 0, 30, 125, 500 or 1250 mg/kg bw/day, 5 days a week for 13 weeks (total of 65 applications). Rats were fitted with Elizabethan collars to prevent ingestion of the test article.  

 

There were clinical signs of toxicity in the 500- and 1250-mg/kg/day groups. The signs included pallor and skin cool to the touch (indicating reduced body temperature). All the animals in the 1250-mg/kg/day group were dead or sacrificed prior to study termination. In the 500-mg/kg/day group, all the males and three of the females were dead or sacrificed moribund. Minimal skin irritation occurred in the treated groups, but data were not provided in the study report (stated to be in Appendix 6.1, which was not provided). Male rats in the two highest dose groups and all female treatment groups had a significantly reduced body weight by study termination. There were several significant changes in haematology parameters including decreased red blood cell count, haematocrit, haemoglobin, and platelets at doses greater than or equal to 125 mg/kg/day. Haematology effects were noted at both the 5 and 13 week time points and were generally dose-dependent. There were also numerous effects noted in clinical chemistry, some beginning as early at 5 weeks including changes in uric acid, urea nitrogen, cholesterol, triglycerides, and sorbitol dehydrogenase. There were no treatment-related effects on urinalysis. Organ weight changes related to treatment included dose-dependent increases in liver weights and decreases in thymus weights. Gross pathological changes were noted in the skin of all treatment groups (red foci, areas of discoloration, streaks, scabs, and sores or raised areas). In the highest two groups, focal areas of red discoloration occurred in the brain, spinal cord, stomach, and testes. The thymus was noticeably small as is indicated by decreased organ weights. The male sex organs (epididymides, prostate, seminal vesicles and testes) were stated to be small in the two high dose groups. These groups did not have organs weighed due to mortality. Treatment-related histopathology was generally dose-dependent and occurred in the following tissues: adrenals, bone marrow, kidneys, liver, lymph nodes, treated skin, stomach and thymus. Atrophy occurred in the male sex organs (testes, seminal vesicle, and prostate). There was a significant increase in abnormal sperm heads in the 500 mg/kg/day group. The LOAEL is 30 mg/kg/day, based on body weight, clinical chemistry, organ weights, gross pathology, and histopathology. No NOAEL is identified.

Justification for Read Across

DAE is produced as a by-product in the refining of lubricating oil base stocks and waxes. Straight run vacuum distillates are extracted with solvents such as furfural, phenol, or N-methyl-2-pyrrolidone to selectively remove the undesirable polycyclic aromatic compounds, (especially 3-7 fused ring structures). DAE can be considered “worst case” by comparison to unrefined / acid treated oils, in that the extract contains higher concentrations of biologically active components than the unrefined / acid treated oils. Since PAC are not likely to cause any adverse local effects in lungs after sub-acute exposure, the sufficiently refined lubricant base oils can be used as read-across for this endpoint.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

well conducted study

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: bone marrow; cardiovascular / hematological: thymus; digestive: liver; digestive: stomach; glandular: adrenal gland; urogenital: seminal vesicle; urogenital: testes

Repeated dose toxicity: dermal - systemic effects (target organ) cardiovascular / hematological: bone marrow; cardiovascular / hematological: lymph nodes; cardiovascular / hematological: thymus; digestive: liver; glandular: adrenal gland; urogenital: kidneys

Justification for classification or non-classification

Although systemic toxicity was observed in a read-across 90 -day oral exposure study, classification and labelling of unrefined/acid treated oils via oral exposure is not necessary because the primary exposure for humans is by the dermal route. Systemic toxicity was not observed in a 2 -week inhalation study that was conducted with other lubricant base oils (IP 346 < 3%). Systemic toxicity was observed in a read-across sub chronic dermal study using distillate aromatic extract at all dose levels. Using this as a worse case, unrefined/acid treated oils are classified under the EU CLP Regulation (EC No. 1272/2008) as STOT Rep. Exp. 1 (H372) for repeated dose toxicity for dermal exposure.