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Data available on similar materials are sufficient to adequately characterize the repeated oral toxicity and the repeated dermal toxicity of sufficiently refined petrolatum. The data are consistent in that they demonstrate minimal effects in rats and rabbits with the exception of minimal to moderate skin irritation following repeated dermal exposures and histopathological changes with questionable relevance to humans following repeated oral exposures. Potential exposures by inhalation are expected to be low due to the low vapour pressures of petrolatum. Accordingly, it does not seem likely that there is any potential for petrolatum to produce repeated dose toxicity by an inhalation route.

Key value for chemical safety assessment

Additional information

Oral repeat dose toxicity

 

No oral repeated dose studies have been reported for severely refined petrolatum, but data have been reported for paraffin and hydrocarbon waxes which are similar to sufficiently refined petrolatum constituents.

 

Two key read-across studies were identified to evaluate the subchronic oral toxicity potential of sufficiently refined petrolatum.

 

In a 90-day oral feeding study (BIBRA, 1992), three different waxes (low melting point wax, high melting point wax, and high sulphur wax) were administered to Fischer 344 rats (20/sex/dose for waxes, 60/sex for control) at dose levels of 0.002, 0.02, 0.2, or 2.0% in diet (equivalent to approximate average daily consumption values of 1.5, 15, 150, 1500 mg mineral hydrocarbon/kg body weight/day) for 90 days. The various test articles examined in the study varied widely in their biological effects. In general the magnitude of effects was greatest with the low melting point wax. The high melting point wax and high sulphur wax were without effect.

 

Almost without exception, the effects seen during the study were much more severe in females than in males. In animals treated with low melting point wax, effects in the mesenteric lymph node comprised of focal histiocytosis and increased organ weights. Effects on the liver comprised of an increase in organ weight and the formation of granuloma. Increases in serum liver enzymes aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase were also observed and indicative of hepatic damage. The significance of an inflammatory lesion of the mitral valve of the heart in females dosed with 0.2% low melting point wax is not known. Spleen weight was significantly increased, but no concomitant histopathological changes were observed, and the toxicological significance is not known. Haematological effects appeared to be related to histopathological findings in the lymph node and liver. The increase in the serum glucose levels were not considered to be clinically significant.

 

Therefore, for the low melting point wax, the NOAEL is equal to 0.002% in diet (equivalent to 1.5 mg/kg/day) for males and females based on histiocytosis in the mesenteric lymph nodes, granuloma in the liver, and inflammation of cardiac mitral valve.

 

For the high melting point wax and the high sulphur wax, the NOAEL is greater than or equal to 2% in diet (equivalent to 1500 mg/kg/day) for males and females.

 

In another 90 -day oral feeding study (BIBRA, 1993b), three waxes designated as low melting point wax (LMPW), microcrystalline/paraffin wax mixture (MP), and paraffin 64, intermediate melting point wax (IMPW) were administered via the diet. The tests included a main study, a reversal study and a tissue level study. The reversal group was treated for 90 days followed by 85 days with untreated diet. Group size was 20 rats/sex/untreated control or dose for the main study, 10 rats/sex/the untreated control or high dose (2.0%) for the reversal study, and 5 rats/sex at the high dose only for the tissue level study. Fewer dietary concentration levels were used: IMPW and MP were administered at 0.02, 0.2, and 2.0% and LMPW at 2.0% only. All animals were monitored for weight gain, food uptake and clinical condition throughout the study. An ophthalmic examination was conducted prior to treatment and prior to necropsy on the animals in the main study and those in the reversibility study.

 

There were no effects on food intake, growth rate, or clinical conditions of animals fed paraffin waxes (LMPW, IMPW, or MP). There were some increases in organ weights which included increased spleen and liver weights (0.2 and 2.0% groups). Although some reductions were noted during the reversal period, the weights were still higher in the 2.0% group. Mesenteric lymph node weights were also increased in the high dose group animals, and, like the spleen and liver weights, did not return completely to control weights during the reversal period. There were also changes in haematological parameters with a greater response observed in females. Serum enzymes including alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), and gamma glutamyl transferase (GGT) were elevated in females from the 0.2 and 2% groups treated with paraffin wax (LMPW) and a mix of paraffin and microcrystalline waxes (MP) and from the 2% group treated with intermediate melting point paraffin wax (IMPW) and in males from the 2% LMPW, MP, and IMPW groups.  Serum bilirubin was also elevated in females from the 2% dose group. Histopathological changes in most organs were considered to be consistent with the age of the animals and not treatment-related, but changes in the liver, MLNs, and the cardiac mitral valve were considered to have been treatment-related. The effects were dose-related, more severe in females than males, and greater with LMPW than IMPW and MP.

 

A NOAEL could not be determined because adverse effects were noted at the lowest dose (0.02% in diet).

 

A key chronic toxicity (Oser et al. 1965) evaluated the long-term oral toxicity potential of sufficiently refined petrolatum. In this study, three pharmaceutical and food-grade petrolatum blends were tested in FDRL rats. To conduct the study, 50 FDRL rats of each sex, individually housed, were given ad libitum access to diets containing 5% of each of the three petrolatum blends for 2 years. A group of 100 rats of each sex served as controls and was fed normal diet that had been supplemented with 1% vitamin mix and 0.2% Aurofac 10. The animals were observed daily for appearance, behaviour and survival. Weekly measurements were made of body weight for the first 12 weeks of the study, and weights were measured biweekly thereafter. Weekly measurements were also made of food intake for the first 12 weeks. Measurements of haematological parameters were made at 12, 26, 52, 72 and 100 weeks. Surviving rats were sacrificed at scheduled termination. These, as well as, rats dying spontaneously were necropsied, and weights of the liver, kidneys, spleen, heart, adrenals, thyroids and pituitary were recorded. Organs removed for microscopic examination included liver, spleen, stomach, large and small intestine, pancreas, kidney, urinary bladder, adrenal, thyroid gland, testis or ovary, salivary gland, lymph node, heart, lung, muscle, skin, spinal cord, brain, thymus, bone marrow, and all abnormal growths.  

 

Growth rates were unaffected, and there were no differences in survival. There were small, statistically significant differences in food consumption, but these were judged to have not been toxicologically important. Haematological and clinical parameters were unaffected by treatment. There were no differences at necropsy between petrolatum-exposed and control animals. Furthermore, there were no histological changes that could be attributed to dietary exposure to petrolatum. Finally, none of the petrolatum blends caused an increased tumour incidence in any tissue or organ examined. Accordingly, petrolatum was judged to be non-carcinogenic following oral administration and a chronic NOAEL of 5% (i. e., 5000 mg/kg/day) was determined.

 

Supporting read-across oral chronic toxicity data (Shubik. et al. 1962) from paraffin and hydrocarbon waxes (materials similar to refined petrolatum) indicate that paraffin waxes are not toxic when administered in diet for a period of 24 months. The NOAEL for this study was determined to be >5700 mg/kg/day.

 

Dermal repeat dose toxicity

 

No dermal repeated dose studies have been reported for sufficiently refined petrolatum, but data have been reported for other lubricant base oils (IP 346 < 3%), materials similar to the oil entrained in sufficiently refined petrolatum.

 

In a key read-across 28-Day repeat dose dermal toxicity study (API, 1987c), five New Zealand White rabbits/sex/dose were topically administered API 83-15 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.

 

There was no mortality observed at any concentration tested, and clinical signs such as decreased food consumption, soft stool and staining around the anal region were observed in a few animals in both sexes. Statistically significant treatment-related decreases in mean body weight were observed in males and females at the 2000 mg/kg concentration. High-dose (2000 mg/kg) and mid-dose (1000 mg/kg) males and females were slightly irritated by the administration of API 83-15. Low-dose (200 mg/kg) males and females exhibited minimal irritation from administration of the test article. All observed haematology parameters appeared normal in controls and in animals treated with API 83 -15. SGOT levels were elevated in males exposed at 1000 and 2000 mg/kg and in females administered 2000 mg/kg API 83-15. SGPT levels were also elevated in male rabbits exposed to the test material at concentrations of 1000 and 2000 mg/kg. Total protein levels in females at 2000 mg/kg were significantly lower than the control animals. Mean relative liver weight in females exposed at the high-dose were significantly higher than the concomitant control. Statistically significant increases in the mean absolute and relative right and left adrenal weights in females dosed at 2000 mg/kg was considered treatment-related, although indirectly related to toxic stress. Treatment-related gross pathologic findings were confined to the liver and consisted of yellow discolorations in the livers of low-dose rabbits; prominent lobular pattern in one mid-dose male; yellow granular surface or white nodular area in two high-dose males and a prominent lobular pattern in four high-dose females. Topical administration of API 83 -15 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.

 

In a key read-across 90-day dermal toxicity study (Mobil Environmental and Health Science Laboratory, 1983), Stock 141 (a solvent refined paraffinic base oil) was applied to the intact, shaved skin of Sprague-Dawley rats (10/sex/dose) at a dose level of 0 or 2000 mg/kg/day, 5 days/week for 13 weeks. 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 Stock 141. The study authors conclude that these findings are not biologically significant. The NOAEL was determined to be greater than 2000 mg/kg/day, based on lack of local or systemic toxic effects.

 

In a key read-across chronic dermal toxicity/carcinogenicity study (Exxon Biomedical Sciences, Inc. 1991), male C3H/HeNCrlBR mice (50/group) were dermally exposed to MRD-87-016 (a solvent-extracted/hydrotreated paraffinic distillate; IP 346 < 3wt%) and the appropriate controls at a frequency of twice per week (150 mg/kg/day) for 24 months or until observation of carcinoma at which time the animal was sacrificed. The dermal application of the test materials produced considerable irritation in groups 951 (positive control) and 722 (vehicle control). 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. Gross post-mortem examination showed a high incidence of liver masses in all groups except 951. These liver masses as well as other lesions noted histopathologically were of the usual type and incidence in this strain and age and were considered to be unrelated to treatment. Therefore, the test materials did not cause local or systemic effects when applied neat. The NOAEL was determined to be 150 mg/kg/day, based on the lack of systemic or local toxicity effects observed in the study.

 

Repeat dose inhalation toxicity

 

In accordance with column 2 of REACH Annex VIII, testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. Inhalation exposure to sufficiently refined petrolatum is not expected to occur under normal conditions due to the very low vapour pressures of these substances and therefore testing for this endpoint is not considered necessary.

Justification for classification or non-classification

Sufficiently refined petrolatums do not meet the EU criteria for repeat dose toxicity by the oral, dermal, or inhalation route and are therefore not classified for the same.