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Description of key information

For subchronic oral exposure, a NOEL of 20 ppm (approx. 2 mg/kg bw/day) has been established for 4 of 6 white oils, a NOEL was not established for N15H (but the LOEL was 20 ppm, approx. 2 mg/kg bw/day), a NOEL of ≥ 20,000 ppm was established for P100H (approx. 1900 mg/kg bw/day), based on histiocytosis, and after exposure to P15H, a NOEL was not established experimentally in the F-344 rat (but the LOEL was 2000 ppm) whereas for the Sprague-Dawley rat the NOEL was ≥ 20,000 ppm (approx. 1900 mg/kg bw/day) (similar to OECD 408).  As these effects are now shown to be strain-specific, the adversity of the MLN histiocytosis is questionable; accordingly, the results are presented as NOELs rather than NOAELs.

For chronic oral exposure, the NOAEL was ≥ 1200 mg/kg bw/day for both P70H and P100H (OECD 453). There was no carcinogenic potential or chronic toxicity of highly refined base oil administered via the diet for twenty-four months.  These results were confirmed for a mixture of medium-viscosity highly refined base oils in the most sensitive F-344 rat strain.  

The NOEL for subacute inhalation exposure was considered to be 50 mg/m3 and LOEL was 210 mg/m3 due to the increase in lung weight. However, this effect is due to oil accumulation in the tissues and not necessarily a toxic endpoint (OECD 412).

For subchronic dermal exposure, the NOAEL was ≥ 2000 mg/kg bw/day after exposure to a white mineral oil (OECD 411).  A read across dermal subacute study from lubricating base oils established a conservative NOAEL of 1000 mg/kg/day, based on liver toxicity as measured by enzyme levels and histopathology (OECD 410).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 200 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

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

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Based on a lack of adverse affects, even with the highest doses administered, an oral chronic NOEL of ≥ 1200 mg/kg bw/day, and a dermal subchronic NOAEL of ≥ 2000 mg/kg bw/day, highly refined base oils are not classified as harmful to health after prolonged exposure.

Throughout this summary, samples are identified as being derived from either paraffinic (P) or naphthenic (N) crude oil and having been treated with acid (A) or hydrogen (H). The viscosity of each sample at 40°C is also indicated in the respective sample description. For example, N10 (A) was a white oil derived from a Naphthenic crude oil, and it had a viscosity of 10 cSt at 40°C and had been refined using an Acid treatment. P100 (H), however, was derived from Paraffinic crude oil and had a viscosity of 100 cSt at 40 °C and been refined using hydrotreatment.  

 

Oral Exposure

A key 2 -year dietary combined chronic toxicity/carcinogenicity study (Klimisch score = 1; Trimmer et al., 2004) has been conducted on highly refined base oil P70H and P100H at doses of 0, 60, 120, 240, or 1200 mg/kg/day via the diet. The study was GLP compliant and was conducted to OECD guidelines. Results were similar for both compounds. Survival was unaffected at any dose level and no treatment related clinical effects were observed. Food conversion efficiency, ophthalmology, serum chemistry, haematology, urinalysis, mortality, and neoplastic lesions were unaffected by treatment. In the 1200 mg/kg/day group, food consumption was increased, which was associated with an increase in body weight. The high-dose group had increased mesenteric lymph nodes and increased severity of infiltrating histiocytes, which occurred to a greater extend in the P70H treated animals. This was considered not to be toxicologically significant. Mineral hydrocarbons were detected in the liver, but was reversible. Although maximal mineral hydrocarbon levels in the liver were the same regardless of the white oil, the maximal level occurred more rapidly in the rats treated with P70H. The NOAEL was >= 1200 mg/kg bw/day. There was no carcinogenic potential or chronic toxicity of highly refined base oil administered via the diet for twenty-four months.     

 

A blend white mineral oil (mineral oil, medium viscosity, class I), of equal quantities of eight commercially available paraffinic white mineral oils obtained from eight member companies of the Japan Liquid Paraffin Industry, was fed in the diet to Fischer 344 rats in a chronic oral study (Klimisch score = 2; Shoda et al. 1997). The oils also complied with the requirements of the Japanese food additive standards and the Japanese pharmacopoeia. Five of the component white mineral oils had been derived from petroleum by acid treatment, and the other three had been derived by hydrotreatment.  The physical properties of the blended mineral oil were intermediate between those of P70H and N70H.  The study was conducted in accordance with OECD chronic toxicity/carcinogenicity testing guidelines (OECD Guideline 453, 1981). Groups of 50 male and 50 female Fischer 344 rats were fed diets containing 2.5% or 5% of the composite medium-viscosity white mineral oil (962.2 or 1941.9 mg/kg/day for males, 1135.4 or 2291.5 mg/kg/day for females), continually for 104 weeks. Body weights and food consumption were measured throughout the study. At the end of the study, the animals were killed and blood samples were collected for hematological and clinical chemical measurements. A full necropsy was performed on all animals; the major organs were weighed, and a range of tissues, including liver, mesenteric lymph node, heart and spleen, were taken for histological examination.

 

The food consumption and body weights of animals of each sex given 5% mineral oil were slightly increased. The frequency of clinical signs, mortality and hematological parameters were unaffected by treatment. In the group given 5%, the absolute weights of the liver and kidney were increased in males and the absolute and relative weights of the submaxillary gland were reduced in females. The increased absolute organ weights were attributed to the slightly increased body weights of males at this concentration. The absolute and relative weights of the heart and spleen were unaffected by treatment. A variety of tumors developed in all groups, including the control group, but all the neoplastic lesions were histologically similar to those known to occur spontaneously in Fischer 344 rats, and no statistically significant increase in the incidence of any tumor type was found for either sex in the treated groups. An increased grade of small granulomatous foci of macrophages was observed in the mesenteric lymph nodes of both sexes at 2.5 and 5% in comparison with the respective control groups (Klimisch score = 2; Shoda et al. 1997). The authors did not consider this finding to be a toxic effect but rather an indication of over exposure to white oil. The NOAEL in this study was considered to be greater than or equal to 1,941.9 mg/kg/day for males and greater than or equal to 2291.5 mg/kg/day for females.  These were the highest doses tested in each sex.

 

Firriolo et al. (Klimisch score = 1; 1995) reported on a 90-day study that was conducted to compare the effects of dietary administration of food-grade white oil in F-344 and Sprague-Dawley rats. Groups of 15 female rats of each strain were fed diets containing 0, 0.2 or 2.0% (2000 and 20,000 ppm) P15H white oil. Ten animals were sacrificed after 90 days for toxicological evaluation, and the remaining 5 rats were sacrificed after 91 days for a tissue analysis for mineral hydrocarbon content. In addition 20 extra female F-344 rats were fed diet containing 0 or 20,000 ppm (2%) white oil. Ten of these animals were sacrificed after 30 days treatment and the remaining ten animals after 61 days treatment. These extra animals were included to follow the time course of the development of any lesions that developed. All animals were observed daily and body weights and food consumption were recorded weekly. At each scheduled sacrifice blood samples were taken for a wide range of haematological and serum chemistry determinations. There were no clinical signs in either rat strain at any dose level during the study and, apart from a transient decrease in body weight for one day at one dose level in one strain of rat, there were no effects on either food intake or growth rate.

 

In the F-344 rats the only haematological change was an increase in white cell count. At day 30, this was observed in the 20,000 ppm group. By 90 days this was seen in both dose groups in a dose-related manner. There were also marginal differences in some serum chemistry values of F-344 rats compared to controls, but these changes were not considered clinically significant. The absolute and relative liver weights of the F-344 rats in the 20,000 ppm group were increased by 1.2- and 1.3-fold, respectively and in the 2000 ppm group both absolute and relative liver weights were increased 1.1-fold. The mesenteric lymph nodes were only increased in the 20,000 ppm group. The increases were more than 3-fold for both absolute and relative weights. Accumulation of hydrocarbons in the livers of the treated F-344 rats consisted of an increased incidence of microgranuloma. These were not present at day 30 but were present in more than 80% of the animals in the 20,000 ppm dose group after 61 days. By 90 days microgranuloma were also observed in the 2000 ppm dose group (incidence not stated in the publication). Central necrosis and/or the presence of Langhan’s type cells were seen in occasional microgranuloma. The incidence and severity were both dose- and temporally-related as the appearance of granuloma occurred at 61 days in the high dose group and was present in both dose groups at 92 days. Histiocytosis occurred in the mesenteric lymph nodes of the F-344 rats in the 20,000 ppm dose group after 30 days. Microgranulomas were observed at 61 and 92 days in the 20,000 ppm and also in the 2000 ppm groups at 92 days. The incidence and severity of the microgranulomas were increased in a dose related manner.

 

In contrast, in the Sprague-Dawley rats, there were no significant differences in haematology or serum chemistry values and organ weights were unaffected by treatment rats fed white oil. Histopathological examination of the livers of the Sprague-Dawley rats revealed that, in contrast to the F-344 rats, there were no microgranulomas in either dose group, but there was a slightly increased incidence of minimal multifocal chronic inflammation in the 20,000 ppm dose group. No histological changes were observed in the mesenteric lymph nodes of the Sprague-Dawley rats at either dose level.

 

A NOEL was not established experimentally in the F-344 rat whereas for the Sprague-Dawley rat the NOAEL was greater than or equal to 20,000 ppm

 

Consistent with the idea that F-344 rats are more sensitive to white mineral oil, six white oils were examined in F-344 rats (Klimisch score = 1; Smith et al. 1996). Groups of 20 male and 20 female F-344 rats were fed diets containing one of the 6 different white oils at dietary concentrations of 0.002, 0.02, 0.2 and 2.0% [20, 200, 2000 and 20,000 ppm] for 90 days. Further, groups of 60 male and 60 females were fed untreated control diet. Additionally groups of 20 rats of each sex were fed diets containing 2.0% coconut oil. High-dose dietary exposure produced an accumulation of hydrocarbons in liver and mesenteric lymph nodes with response greater in females than in male F-344 rats. Additionally, lower viscosity oils produced a greater effect than higher viscosity oils. Effects include increased organ weights, evidence for the presence of nonpolar hydrocarbons, and other observations suggestive of an inflammatory response.

 

The NOELs and LOELs for the six oils were based on the occurrence of histiocytosis in the mesenteric lymph nodes, with the lower viscosity oils displaying a greater magnitude of histiocytosis than the higher viscosity oils. A LOEL of 20 ppm (approx 2 mg/kg bw/day) was established for N15H due to the presence of MLN histiocytosis at all doses, a NOEL of 20 ppm (approx 2 mg/kg bw/day) was established for, N10A, P15H, N70A, and N70H, due to MLN histiocytosis at 20 ppm and greater, and a NOEL of greater than or equal to 20,000 ppm (approx 1900 mg/kg bw/day) was established for P100H due to the absence of treatment-related effects at all doses. As these effects are strain-specific, the adversity of the MLN histiocytosis is questionable; and most probably irrelevant to humans (Carlton et al. 2001). Accordingly, the results are presented as NOELs rather than NOAELs.

 

Further, in another supporting subchronic study, Baldwin et al. (Klimisch score = 2; 1992) reported on two 90-day dietary studies in rats in which two food-grade white oils were studied. One of the oils had been processed by oleum (acid) treatment, whereas the other had been processed by hydrotreatment. In the first study, groups of 10 male and 10 female F-344 rats were fed diets containing either of the oils at dietary concentrations of 5000, 10,000 or 20,000 ppm. In the second study (Baldwin et al.,1992), groups of 10 female-only rats were fed diets containing 10, 100, 500, 5000, 10,000 or 20,000 ppm of either the oleum processed or the hydrotreated oil for 90 days and 20 females served as controls.  

 

Within the study, five extra female animals were also fed 500 or 10,000 ppm of either oil for 25 days. The results from this dosing are considered to be supporting short-term oral exposure data (Klimisch score = 2, Baldwin et al., 1992).  

 

No clinical signs of toxicity were observed in either subchronic study and body weights were unaffected by treatment. The only haematological changes (not quantified in the publication) attributed to treatment were slight leukocytosis and granulocytosis in rats of both sexes fed either white oil at 20,000 ppm while slight hypochromic microcytic anemia was observed in the females fed diets containing 20,000 ppm oleum-treated oil. Changes in clinical chemical parameters were indicative of slight hepatic effects and were more severe and affected more parameters in female rats than in males. Furthermore more effects were noted in animals fed diets containing oleum treated oil than were noted in rats fed hydrotreated oil.  

 

Animals sacrificed after 25 days in the short-term study did not exhibit treatment-related histological changes in the mesenteric lymph nodes. A NOEL was not reported but can be assumed to be >= 10,000 ppm based on the lack of effects. The NOELs for subchronic oral administration of white oils, based on the occurrence of histiocytosis in the mesenteric lymph nodes, were 10 and 100 ppm (equivalent to 0.65 and 6.4 mg/kg/day) for the oleum-treated and hydrotreated white oils, respectively.

 

Additional studies in species/strain other than F-344 do not identify histiocytosis in the mesenteric lymph nodes, supporting that these effects are specific to F-344 rats.

 

Bird et al. (1990) reported on a 90 day feeding study of four white mineral oils (one low-viscosity oleum-treated oil, one low viscosity hydrotreated oil and two higher viscosity hydrotreated oils) in rats and dogs. The oils were fed to Long Evans rats (20/sex/dose) at dietary concentrations of 0, 300, and 1500 ppm. Forty rats of each sex served as controls. Four beagle dogs of each sex were also fed white oil at the same dietary concentrations. Evaluations of mortality, physical observations, food consumption, organ weights and ratios, haematology, clinical chemistry, urinalysis, gross pathology and histopathology did not reveal any evidence of significant toxicological effects in either the Long Evans rats or the beagle dogs. It should be noted that this report was an abstract of a paper presented to a scientific meeting and no details were available to support the results. The studies were also cited in API (1992) in which some more details were provided. Although the original reports were not available for review, the information provided suggest that the F344 rat is unusually sensitive to white oils compared to some other rat strains and species.

 

In a study reported by McKee et al. (1987), white oil was used as vehicle and also as control substance in a combined 90 –day repeat dose and reproductive toxicity study of experimental coal-derived fuels. Only the information on controls will be summarised here since the experimental samples were not white oils, and therefore, not relevant to this summary.

 

The control group comprised 90 females and 36 males and the white oil was administered orally by gavage at a dose of 5 ml/kg, five times weekly for 13 weeks. At the end of 13 weeks dosing 18 females were removed from the study for an evaluation of repeat dose toxicity. The males were then used for mating and after mating were evaluated for repeat dose toxicity. Fourteen days after cessation of administration of white oil, blood samples were collected, and the animals were sacrificed and necropsied. A wide range of haematological and clinical chemical measurements were made, major organs were weighed and a wide range of tissues were examined histologically. Although effects were noted in those groups of animals exposed to the test materials, the report made no comment that the control values (i. e. those for white oil exposed animals) were outside of the normal range for control animals. Furthermore no adverse histological observations were made for those animals exposed to the white oil. This report is of limited use in risk characterization because the white oil was used as a control and the responses to it were not compared to an untreated control. Nevertheless it provides supportive information of the lack of effects in a gavage study of 13 weeks duration.

 

In conclusion, the relatively large range of white oil viscosities evaluated in subchronic feeding studies generally produced nothing more than an increase in organ weights (liver, lymph nodes, spleen) in most animal models at the highest oral concentrations evaluated over the 90 day periods. In the F-344 rat, white mineral oil produced strain-specific accumulation of hydrocarbons evident in the mesenteric lymph nodes. Essentially the white oil is a lipid-like component and is absorbed, distributed and deposited in certain organs over time. Some minimal histologic changes were associated with the deposited oils; the deposition level is inversely related to the molecular weight/viscosity of the oil. The lower molecular weight/viscosity white oils did produce some attendant evidence of physiological organ damage (increased liver enzymes, glucose levels, haematological changes) at the highest levels, but not at the lower tested levels. Thus, although a number of effects were noted in the various studies, the toxicological significance of the majority of the findings is, at best, questionable. It is for this reason that the results are summarised as no observed effect (NOEL), as opposed to no observed adverse effect (NOAEL), levels.

Inhalation Exposure

Dalbey et al.(Klimisch score = 1; 1991) reported on a four-week inhalation study in rats in which two refined base oils and a white oil were examined, which will serve as key short-term inhalation data. One of the oils (WTO) was white oil that had been prepared by severely hydrotreating a dewaxed feedstock followed by acid washing with fuming sulphuric acid. Groups of 10 male and 10 female rats, 11-12 weeks of age, were exposed to aerosol concentrations of the three test materials at nominal concentrations of 0, 50, 220 and 1000 mg/m³.  

 

Apart from occasional loose stool there were no treatment related clinical observations and body weights were unaffected by exposure. No treatment related effects were found in any of the haematological or clinical chemical parameters that were measured.  The percent sperm with aberrant morphology, including breakage, was unaffected by exposure to any of the three base oils. There were no treatment-related observations at necropsy and, with the exception of the lungs, there were no significant changes in organ weights. Wet and dry lung weights increased in a dose-related manner with a significant increase observed in the high-dose group. The ratios of wet to dry lung weights were significantly increased for both sexes at the highest dose concentration. Morphologically, treatment-related changes were only observed in the lungs and tracheobronchial lymph nodes. Foamy macrophages with numerous vacuoles of varying size were present in the alveolar spaces of the lungs of many of the exposed animals.  

 

The NOEL was considered to be 50 mg/m3 and LOEL was 210 mg/m3 due to the increase in lung weight. The adversity of the majority of the findings (i. e., histiocytosis and lung weight) is questionable. Therefore, a NOEL has been established as opposed to a NOAEL for the majority of the studies.

Dermal Exposure

Subacute dermal studies have been reported on a series of lubricant base oils and information from these studies may be used as surrogates since they are less-refined than white oils and will therefore represent a worst case. Compositional and physico-chemical data also show that white mineral oils are very similar to lubricating base oils, and it is therefore considered appropriate to read across from the lubricating base oils data to white mineral oils.  

 

A key subchronic study is available on 80SUS white mineral oil (Klimisch score = 1; Mobil 1988). Rats were administered test material at doses of 0, 125, 500, or 2000 mg/kg for 13 weeks (5 days/week) as part of a protocol initially designed as a reproductive study. The study was redesigned to include assessment of subchronic dermal toxicity. Administration of the test material to the skin produced skin irritation at all dose levels, which included erythema, flaking of the skin, and scabs at the site of test material application. Male and female rats dosed at 500 and 2000 mg/kg bw/day showed a decrease in body weight when compared to the controls, and was a statistically significant decrease for males exposed to 500 and 2000 mg/kg bw/day and females exposed to 2000 mg/kg bw/day. Urinalysis and haematological effects were of doubtful toxicological significance. There were no other compound-related effects on mortality, clinical signs, food consumption, organ weights or clinical chemistry. The NOAEL for local effects is < 125 mg/kg based on skin irritation, while the NOAEL for systemic effects is greater than or equal to 2000 mg/kg, in the absence of significant toxicological findings of concern at the highest dose tested.

In a supporting 28-Day repeat dose dermal toxicity study (API, 1985; Klimisch score = 2), five New Zealand White rabbits/sex/dose were topically administered Hydrotreated heavy naphthenic oil six hours/day, three times a week for a period of 28 -days at concentrations of 0, 200, 1000, or 2000 mg/kg body weight. All animals were observed twice daily for mortality and signs of clinical toxicity and dermal irritation was scored daily (according to the Draize system). Body weights were measured and recorded for each rabbit at the end of the quarantine period, at weekly intervals during the study, and prior to termination. The systemic toxicity NOAEL is 1000 mg/kg, based on the lack of adverse systemic effects observed at this dose level.

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

One of nine  repeat dose oral toxicity studies.

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

Only one repeat dose inhalation toxicity study available.

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

One of two repeat dose dermal toxicity studies

Justification for classification or non-classification

Based on the lack of adverse affects, even with the highest doses administered, an oral chronic NOEL of ≥ 1200 mg/kg bw/day, and a dermal subchronic NOAEL of ≥ 2000 mg/kg bw/day, highly refined base oils are not classified under EU CLP Regulation (EC No. 1272/2008).