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Description of key information

Based on 28-day studies, the rabbit dermal repeat-dose NOAEL is 1000 mg/kg, the rat inhalation repeat-dose NOAEC (local effects) is > 220 mg/m3, and systemic effects are seen at doses > 980 mg/m3.

The 90-day dermal studies gave a sub-chronic NOAEL of greater than 2000 mg/kg for sufficiently refined other lubricant base oils, and a NOAEL of less than 30 mg/kg for insufficiently refined other lubricant base oils.  

A subchronic oral toxicity NOAEL of <125 mg/kg/day was determined for insufficiently refined other lubricant base oils using read-across to a 90-day subchronic toxicity study an untreated distillate aromatic extreact.

Sufficiently refined other lubricant baseoils are not classified according to CLP for repeat-dose toxicity. Insufficiently refined other lubricant base oils are classified as carcinogenic.

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
980 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
100 mg/kg bw/day
Study duration:
chronic
Species:
mouse

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No repeat-dose oral toxicity studies on either sufficiently refined other lubricant base oils (IP 346 < 3%) or insufficiently refined other lubricant base oils (IP 346 > 3%) have been performed. No repeat-dose inhalation studies on insufficiently refined other lubricant base oils (e.g., IP346 > 3%) have been performed. For insufficiently refined other lubricant base oils (IP 346 > 3%) for subchronic oral and dermal toxicity, data was read-across from untreated distillate aromatic extract (UDAE). This read across was based on the fact that UDAEs are a by-product from the extraction of aromatic components from the vacuum distillates used to produce OLBOs. In that sense, they can represent a fraction derived from unrefined/poorly refined OLBO that potentially has a higher content of polycyclic aromatic compounds (PACs) compared to the OLBO. Since systemic effects are most likely to be related to the level and profile of PACs, UDAE might represent a worst-case example of effects from the poorly refined OLBO.

 

Oral Repeated Dose Toxicity Studies

Subchronic Oral Repeat Dose Toxicity

In a key read-across subchronic oral toxicity study, heavy paraffinic distillate aromatic extract (UDAE) 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 mice 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). 

 

A NOAEL for heavy paraffinic distillate aromatic extract (UDAE) could not be identified and is less than 125 mg/kg/day when administered orally. This compound is a UDAE and provides a worst case scenario for insufficiently refined other lubricant base oils due to the concentration effect of the solvent extraction process.

Dermal Repeated Dose Toxicity Studies

 

Short-term Dermal Repeat Dose Toxicity

A number of 28-day repeat dose dermal toxicity studies have been conducted on other lubricant base oils with IP 346 < 3% and IP 346 > 3%. 

Sufficiently Refined Other Lubricant Base Oils (IP 346 < 3%)

In a key study conducted according to OECD Guideline 410 (Klimisch score = 1), dermal effects of hydrotreated heavy naphthenic oil (CAS 64742-52-5) were evaluated (sufficiently refined, IP 346 < 3%, API, 1987b). There was no mortality observed at any concentration tested. Statistically significant treatment-related decreases in mean body weight were observed in males and females at the 2000 mg/kg concentration. As well as irritation noted at various doses, topical administration of hydrotreated heavy naphthenic oil at 2000 mg/kg to both male and female rabbits was seen to induce changes in the liver characterized by multifocal to diffuse enlargement of hepatocytes (hepatocytomegaly) accompanied by multifocal areas of inflammation (subacute hepatitis). The systemic toxicity NOAEL is 1000 mg/kg, based on the lack of adverse systemic effects observed at this dose level. 

The American Petroleum Institute (API, 1982a; 1982b; 1982c; 1982d; 1982d; 1982e; 1982f; 1982g) conducted an additional series of supporting short-term (28-day) dermal studies in rabbits using 10 different lubricant base oils (sufficiently refined, IP 346 < 3%, Klimisch score = 2). The studies were carried out using similar protocols as that of the key study, and although they were not OECD guideline studies, they were nevertheless robust studies and underwent a quality assurance audit. In these studies, undiluted test material was applied to the occluded skin of male and female New Zealand White rabbits 6 hours, 3 times weekly for up to 4 weeks.  The most consistent finding with all materials tested was the occurrence of skin irritation which ranged from minimal to moderate. Other effects, confined to one hydrotreated base oil, were an increase in liver weight along with increases in Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvic Transaminase (SGPT) at a dose level of 2000 mg/kg. Although SGOT and SGPT were also elevated at 1000 mg/kg in one study, no other effects were observed at that dose level. In summary, based on a review of the available data, the NOAELs for these 28-day repeat dose dermal studies are 1000 mg/kg.

Supporting dermal toxicity data are also available from a study conducted by Trimmer et al. 1989. This study was conducted for 28-days using five paraffinic base oils administered at a dose of 1000 mg/kg bw/day. These lubricant base oils were applied to the shorn skins of New Zealand rabbits in an occluded manner, 5 times weekly for 28 days, and, some irritation was observed, most likely exacerbated by the occlusive patch conditions, but no other effects were observed. The NOAEL was therefore determined to be 1000 mg/kg.

Insufficiently Refined Other Lubricant Base Oils (IP 346 ≥3%)

A key 28-day repeat dose dermal toxicity study (API, 1986j, Klimisch score = 1) was conducted on hydrotreated light naphthenic oil (insufficiently refined, IP 346 > 3%). The study was conducted according to or similar to OECD Guideline 410 without exceptions. No mortality was observed at any dose level tested.  Minimal irritation was observed in animals dosed at 200 mg/kg, slight irritation was seen at 1000 mg/kg, and moderate irritation was seen in animals dosed at 2000 mg/kg. Mean body weights and body weight gain were lower (statistically significant) than control in the high-dose (2000 mg/kg) males and in the mid-dose (1000 mg/kg) and high-dose (2000 mg/kg) females. Mean terminal body weights of mid-dose (1000 mg/kg) females and high-dose (2000 mg/kg) males and females were observed to be lower (statistically significant) than the corresponding control animals. Absolute left and right testis weights and relative right testis weights for the high-dose (2000 mg/kg) dose males were also found to be lower (statistically significant) than the corresponding controls. Systemic effects may be a secondary effect due to effects at primary site of application.The systemic toxicity NOAEL for this 28-day dermal toxicity study in the rabbit is 1000 mg/kg, based on the lack of adverse systemic effects observed at this dose level.

  

Based on the above data, the systemic dermal NOAEL for other lubricant base oils is 1000 mg/kg bw/day. 

 

Subchronic Dermal Repeat Dose Toxicity

Sufficiently Refined Other Lubricant Base Oils (IP 346 < 3%)

In a 90-day dermal toxicity key study (Klimisch score = 1, Mobil Environmental and Health Science Laboratory, 1983a), effects of Stock 141 (a sufficiently refined other lubricant base oil, IP 346 < 3%) on rat skin were assessed according to OECD Guideline 411. Treatment-related pathologies occurred in all groups, were never severe, and included liver enlargement and microscopic skin changes.  The absolute liver weight was 19% larger in males treated with Stock 141 than in control males. The relative liver weight was 17% larger. The skin of the controls (sham-treated) showed epidermal thickening (hyperplasia), slight in males and trace in females. The skin of most test-treated animals showed epidermal hyperplasia (trace to mild, in excess of that in the controls) and/or trace chronic inflammation of the superficial dermis. Both findings were very minimal in animals treated with Lubricant base oil Stock 141. The study authors conclude that these findings are not biologically significant. The NOAEL is greater than 2000 mg/kg/day based on lack of local or systemic toxic effects. 

 

An additional 90-day supporting study (Mobil Environmental and Health Science Laboratory (1983b); Klimisch score = 1) on a sufficiently refined lubricant base oil had a LOEL=1720 mg/kg. Only one dose was used, and the LOEL was based on morphological degenerative effects on the liver (occasional small aggregates of cells with foamy-appearing cytoplasm). The liver effects were thought to be of minimal pathological significance.

Insufficiently Refined Other Lubricant Base Oils (IP 346 ≥ 3%)

In a 90 day dermal toxicity key study (Klimisch score = 1, Mobil, 1990b), a light paraffinic distillate solvent extract (UDAE; CAS # 64742-05-8, used as read across to insufficiently refined other lubricant base oil, IP 346 > 3%) was applied to the clipped backs of male and female Sprague-Dawley rats (10 animals/gender/group) for five days per week for thirteen weeks at dose levels of 30, 125, 500, and 1250 mg/kg/day.Clinical signs, including pallor and decreased body temperature, indicative of system toxicity were observed in the 500 and 1250 mg/kg/day animals. At the 1250 mg/kg/day dose 10 of the female rats died during the study, one due to a laboratory accident, and 10 of the male rats died during the study. At the 500 mg/kg/day dose all of the males and three of the females died during the study. There were no mortalities in those animals applied with the remaining doses. Minimal skin irritation was observed. The administration of UDAE had an adverse effect on survivability, body weights, organ weights (particularly the liver and thymus), and variety of haematology and serum chemistry parameters in exposed animals. Histopathological changes which were treatment-related were most prominent in the adrenals, bone marrow, kidneys, liver, lymph nodes, skin, stomach, and thymus. Based on the results of this study, the NOAEL for the test material was less than 30 mg/kg/day.  

 

Chronic Dermal Repeat Dose Toxicity

Sufficiently Refined Other Lubricant Base Oils (IP 346 < 3%)

In a key chronic dermal carcinogenicity study (Klimisch score = 1), male C3H/HeNCrlBR mice (50/group) were dermally exposed to propane deasphalted mildly hydrofined and dewaxed residuum from low cold test crude (IP 346 < 3%, sufficiently refined) and the appropriate controls at a frequency of twice per week for 24 months or until observation of carcinoma at which time the animal was sacrificed (ExxonMobil Biomedical Sciences, Inc., 1991c). The dermal application of the test materials produced considerable irritation in the positive control group (group 951) and in the vehicle control group (group 722). This irritation was noted macroscopically as desquamation, exfoliation, atonia, eschar, erythema and/or oedema. Microscopic examination revealed acanthosis and subepidermal inflammatory infiltrate. Treatment groups 011, 012, 014, 016 and the negative control group 721 were generally free of dermal irritation during most of the study and at histopathological examination. Forty-five of the fifty Group 951 animals (positive control) had confirmed squamous cell carcinomas at histopathology. All other groups were free of any skin neoplasms. With the exception of the positive control group, there were no statistical differences in time to tumour and tumour production between groups. Survivorship analysis indicated that the positive control displayed the lowest survivorship; however, this finding is related to the fact that animals were euthanized following the appearance of a carcinoma. The test materials did not cause local or systemic effects when applied neat.  The NOAEL was determined to be 150 mg/kg bw/day. 

 

Insufficiently Refined Other Lubricant Base Oils (IP 346 ≥3%)

In a chronic study conducted according to OECD Guideline 453 (Klimisch score = 1), mice were dermally exposed to a variety of other lubricant base oils (insufficiently refined, IP 346 > 3%, Chasey & McKee, 1993).  All test materials were applied undiluted twice weekly at 37.5 µL (100 mg/kg bw/day). The two largest subsets of the database are the solvent extracted oils (i.e., 21 oils) and the solvent extracted and hydrotreated oils (i.e., 37 oils). The data for these subsets were highlighted due to the importance of solvent extraction in many lubricant base oil manufacturing schemes. The results demonstrate the influence of refining severity in controlling carcinogenicity. Most extracted distillates (19 out of 21), and extracted and hydrotreated distillates (33 out of 37), produced fewer than two tumour-bearing animals per test group. Two out of 21 solvent extracted distillates and 4 out of 37 hydrotreated distillates (all insufficiently refined, IP 346 > 3%) resulted in tumor bearing animals (greater than or equal to 4%).  Based on the incidence of tumors, the LOAEL was determined to be 100 mg/kg bw/day and insufficiently refined other lubricant base oils are classified as carcinogenic.  

Inhalation Repeated Dose Toxicity Studies

 

Short-term Inhalation Repeat Dose Toxicity

Sufficiently Refined Other Lubricant Base Oils (IP 346 < 3%)

Key 28-day repeat dose inhalation toxicity studies (Klimisch score = 2) have been conducted on two different other lubricant base oils with IP 346 < 3% (sufficiently refined) (Dalbey, et al., 1991). In the first study, Sprague-Dawley rats were exposed to an aerosol of a severely hydrotreated and hydrocracked heavy paraffinic oil (CAS No. 64742-54-7). Viscosity of the oil was 161 SUS at 40°C (approximately 34 mm2/s). Mean aerosol concentrations were 0, 47, 220, and 980 mg/m3; mass median aerodynamic diameter (MMAD) was ~1.2mm and GSD was ~1.8. Endpoints included a haematological profile (cell counts, differential, haemoglobin, haematocrit, cell volumes), 22 clinical chemistry measurements (e.g., plasma enzymes, proteins, electrolytes,etc.), weights of 7 organs (lung, liver, kidney,etc.), and histopathology of major organs. A second, similar study was conducted with a solvent-extracted, catalytically dewaxed heavy paraffinic oil (CAS No. 64742-70-7).  Except for the lung and associated lymph nodes, no significant changes were observed following the last exposure for each of the mineral base oils. The main changes in the lungs were concentration-related accumulations of foamy macrophages (FM) in alveoli, particularly those near alveolar ducts. A mild infiltrate of neutrophils and lymphocytes was sometimes observed with the FM, and the alveolar wall was slightly thickened near accumulations of FM at the higher aerosol concentrations. A mild accumulation of alveolar macrophages in the absence of other significant toxicity does not constitute an adverse effect. Thus, the NOEC for lung changes associated with oil deposition in the lungs was 220 mg/m3. As no systemic toxicity was observed, the overall NOAEC for systemic effects was > 980 mg/m3.

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 Biomedical Sciences, Inc., 1991a; 1991b & 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 NOAECs for pulmonary effects were 500 mg/m3, and the NOAECs for systemic effects resulting from inhalation exposure were >1500 mg/m3. 

 

Chronic Inhalation Repeat Dose Toxicity

Sufficiently Refined Other Lubricant Base Oils (IP 346 < 3%)

In an older, supporting chronic study (Klimisch score = 2), five species (dog, rabbit, rat, hamster, and  mouse) were exposed for 12 to 26 months, for 6 hours per day, to a sufficiently refined petroleum base mineral oil mist (materials similar in composition to OLBOs; IP 346 < 3%) at concentrations of 5 and 100 mg/m3(Wagner et al., 1964). The mineral oil contained 85% naphthenes and 5%  paraffins and the Saybolt viscosity was given at 85-95, making this oil  comparable in viscosity to light motor oil. Mice were exposed daily for 6 hr at 5 mg/m3 for 12 months or at 100 mg/m3 for 16 months. For dogs, 6, 12, or 26 months of daily 6-hr exposures were conducted for the 5 and 100 mg/m3 concentrations. Rabbits were exposed at 5 mg/m3 daily for 6 or 12 months or at 100 mg/m3 daily for 6, 12, or 18 months. Rats and hamsters were exposed similarly to rabbits, the exception being that the rat and hamster 100 mg/m3 groups were sacrificed at 16 and 15 months, respectively. The study showed no systemic effects, resulting in a systemic NOAEC of >100 mg/m3. Macrophage accumulation was found in lungs of animals exposed at the high dose, so the NOAEC for lung effects is 5 mg/m3.

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

Only oral repeat dose toxicity study available

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

One of three repeat dose inhalation toxicity studies available

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

One of Two dermal chronic toxicity studies.

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

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

Sufficiently refined other lubricant base oils (IP 346 < 3%) are not classified according to the EU CLP Regulation (EC No. 1272/2008) for repeat-dose toxicity.

 

Insufficiently refined (IP 346 > 3%) other lubricant base oils are classified as STOT RE 1 (H372: Causes damage to adrenals, bone marrow, liver, lymph nodes, kidney, stomach and thymus through prolonged or repeated exposure) according to the EU CLP Regulation (EC No. 1272/2008) for repeat-dose toxicity.