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Toxicological information

Carcinogenicity

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Description of key information

Highly refined base oils are not carcinogenic via oral, dermal, or inhalation exposures (OECD 453).  

Key value for chemical safety assessment

Carcinogenicity: via oral route

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

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
100 mg/m³
Study duration:
chronic
Species:
other: Rat, Dog, Hamster, Rabbit, & Mouse

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
mouse

Additional information

Two 2-year dietary combined chronic toxicity/carcinogenicity studies have been conducted on two white oils (P70H and P100H). The studies were GLP compliant and were conducted to OECD guidelines (Klimisch score =1; ExxonMobil 2001a,b study on P70H = key, study on P100H = supporting; also published in Trimmer et al., 2004). Groups of 50 male and 50 female F-344 rats were fed diets containing either white oil at concentrations suitable to achieve doses of 0, 60, 120, 240 or 1200 mg/kg/day. 

 

For the P70 H compound, survival was unaffected at any dose level and no treatment-related clinical effects were observed. Food consumption, food conversion efficiency, body weight, ophthalmology, serum chemistry, haematology, and urinalysis were unaffected by treatment. Males in the 1200 mg/kg/day group had increased mesenteric lymph node weights (absolute, relative to body weight and relative to brain weight). This effect was observed at 12 and at 24 months but did not occur in the recovery group animals. In females absolute mesenteric lymph node weights were increased in all dose groups (13, 15, 20 & 20% for the 60, 120, 240 & 1200 mg/kg/day groups, respectively). Increases in mesenteric lymph node/body weight and mesenteric lymph node/brain weight ratios were also slightly increased in all female dose groups at 24 months. There was also a significant increase in absolute mesenteric lymph node weights for 240 (55%) and 1200 mg/kg/day females (36%) in the recovery study.

 

Histiocytosis was observed in the mesenteric lymph nodes at all dose levels and also in the controls at 24 months, but the severity was slightly greater in the treated animals than the controls. It appeared that the increase in severity above controls was dose-related in the males, but not in the females. For the males, on a scale of 1 to 4 for increasing severity, the responses were 1.2, 1.6, 1.8, 2.3 and 2.1 for the 0. 60, 120, 240 and 1200 mg/kg/day groups, respectively. In the females the control value was 1.6 and all other dose groups ranged from 2.4 to 2.6 but not in a dose-related fashion. No neoplastic or other significant histological changes were observed in animals fed diets containing P70H.

 

For the P100 H compound, survival was unaffected at any dose level and no treatment-related clinical effects were observed. Food consumption, food conversion efficiency, body weight and ophthalmology, serum chemistry, haematology and urinalysis were unaffected by treatment. In the 1200 mg/kg/day group (females only), the absolute mesenteric lymph node weights were increased by 33% at 24 months. There was also an increase in lymph node/body weight ratio (17%) and lymph node/brain weight ratio (50%). At 24 months, minimal to mild histiocytosis was observed in both sexes and at all dose levels (including controls) at the same incidence and was not dose related.  The authors concluded that the NOEL for both white oils tested was greater than or equal to 1200 mg/kg/day and that in neither study was there any evidence that the oils were carcinogenic.

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 (Klimisch score = 1; 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 (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.

 

In a dermal carcinogenicity study, the white oil (typically 75 µL) was applied to the skin of C3H mice two or three times weekly for up to 104 weeks. Medicinal white oils have been used routinely as a negative control and as a vehicle for test substances in dermal carcinogenicity studies (Klimisch score = 1, Chasey and McKee, 1993).  The incidence of skin tumours in all bioassays with the highly refined base oil was zero extremely low. On rare occasion, a single animal in the highly refined oil group developed a papilloma. This incidence is considered to be within the historical negative control incidence and thus not considered to be an indication of carcinogenic potential. No group ever contained more than one tumour-bearing animal, and only benign tumours were produced.

In a supporting pre-guideline and pre-GLP inhalation study, five species of animal (males only) were exposed to a white oil mist (Klimisch score = 2, Wagner et al., 1964).  Groups of 9 dogs (mongrel), 23 rabbits (Dutch), 80 rats (Sprague-Dawley), 106 hamsters (Golden-Syrian) and 69 mice (CF1) were exposed to mineral oil mist at concentrations of 5 and 100 mg/m³.  Additional groups of similar sizes were unexposed and served as controls.  An extra group of 250 mice (CAFi/ Jax), known to be susceptible to pulmonary tumors was exposed to the oil mist at 100 mg/m³ and a further 250 mice of the same strain served as controls.  For those animals exposed to oil mist at a concentration of 5 mg/m³, exposures were made six hours daily for up to 12 months.  Serial sacrifices were made at 3 and six months and at study termination.  For animals exposed to 100 mg/m³, exposures were for up to  26 months and serial sacrifices were made at 3, 6, 12, 18 and 26 months.  No dogs were included in the 3 or 18 month sacrifice period.  Body weights were recorded bi-weekly and determinations of hematological and limited serum chemistry parameters (basic and magnesium activated  phosphatase activities only as indicators of damage to cells of the  respiratory tract) were made at the times of the serial sacrifices.   Respiratory function was determined in rabbits in both dose groups and this was assessed routinely after exposures throughout the study.

  

Body weight gains, hematology and respiratory function values were observed to be comparable to controls. Biochemical studies showed a significant increase in basic and magnesium-activated phosphatase activity in the serum and lung tissue of serially sacrificed dogs and rats exposed to oil mist at a concentration of 100 mg/m³.  Significant pulmonary alveolar and hilar lymph node oil deposition and/or lipid granuloma formation was observed after approximately 12 months exposure in dogs and rats in the 100 mg/m³ group. The character of the oil deposition was shown by infrared spectroscopy to be similar to the oil to which the animals had been exposed. On the basis of gross and histological examination of lung tissue from the CAF1/Jax mice, there was no convincing evidence of an acceleration of pulmonary tumor formation as a consequence of exposure to the oil mist at a concentration of 100 mg/m³ for 16 months.

 

Additional data support that HRBOs are not carcinogens (Shoda et al., 1997; CONCAWE, 1994; Doak et al., 1983). This information is presented in the dossier.

Justification for selection of carcinogenicity via oral route endpoint:

One of three studies available.

Justification for selection of carcinogenicity via inhalation route endpoint:

One inhalation study available

Justification for selection of carcinogenicity via dermal route endpoint:

Only dermal carcinogenicity study available

Justification for classification or non-classification

Based on the data presented above, highly refined base oils are not classified as carcinogenic according to EU CLP Regulation (EC No. 1272/2008).