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Administrative data

Description of key information

Data available on similar materials are sufficient to adequately characterize the repeated oral toxicity and the repeated dermal toxicity of insufficiently refined petrolatum and 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

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 study available

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

Insufficiently Refined Petrolatum (Carcinogenic or Unknown Feed-stock)

Oral repeat dose toxicity

No oral repeated dose studies have been reported for insufficiently refined petrolatum (carcinogenic or unknown feed-stock) but data have been reported for untreated distillate aromatic extracts. This data provides a worst-case scenario due to the concentration effect of the solvent extraction process.

In a key read-across 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 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). 

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 an untreated distillate aromatic extract and provides a worst case scenario for petrolatum (carcinogenic or unknown feed-stock) due to the concentration effect of the solvent extraction process.

Dermal repeat dose toxicity

No dermal repeated dose studies have been reported for insufficiently refined petrolatum, but data have been reported for unrefined/acid treated lubricant base oils, materials similar to the oil entrained in insufficiently refined petrolatum.

In a key read-across 28-day dermal repeated-dose study (API, 1986b), New Zealand white rabbits were treated with API 84-01, 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 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. The dermal NOAEL was <200 mg/kg/day based on the irritation at the treatment site.

In a key read-across 90-day dermal toxicity study (Mobil, 1990a), 318 Isthmus Furfural Extract 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 deter 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 was identified.  

In a key chronic dermal toxicity study (Chasey and McKee, 1993) male C3H mice, approximately 6 to 10 weeks of age were treated dermally with solvent extracted distillates and solvent extracted and hydrotreated distillates. The test materials were applied by automatic pipette in either 37.5 μl aliquots twice a week or 25 µl (100 mg/kg/day) aliquots three times a week.  All test materials were applied undiluted. In early studies, the treatment continued until the animals died spontaneously or were sacrificed in a moribund state.  In later studies, surviving mice were sacrificed after either 24 months of treatment or at the time at which grossly diagnosed squamous cell carcinomas developed. Animals were examined twice weekly for the appearance of dermal tumours.  Each tumour in the treatment area was examined carefully and classified grossly.  All grossly diagnosed tumours were examined microscopically after study termination. 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., 27 oils).  The data for these subsets were highlighted due to the importance of solvent extraction in many lubricant base oil manufacturing schemes.  All commercial products refined in this way produced negative bioassays.  The solvent extracted oils that produced tumours were refined by experimental conditions that are not representative of those used in commercial refineries. Based on the incidence of tumours observed in this study, the test materials were considered to be carcinogenic and the chronic dermal toxicity LOAEL was determined to be 100 mg/kg/day.

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 insufficiently 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.

Sufficiently Refined Petrolatum (Non-carcinogenic Feed-stock)

Oral repeat dose toxicity

Only one oral repeated dose toxicity study has been reported for severely refined petrolatum. Data have also been reported for paraffin and hydrocarbon waxes which are similar to sufficiently refined petrolatum constituents.

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

In a key read-across 90 -day oral feeding study (BIBRA, 1993f), 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.

In a key read-across long-term repeat-dose toxicity study (Shubik et al., 1962), 5 types of paraffin wax were tested in male and female Sprague-Dawley rats (50 to 53/sex/dose) over a 2-year period at a dose of 10% in diet given ad libitum. No pathologic finding attributable to the treatment was observed in rats fed 10% wax in their diet for a period of two years and then observed until their death. The incidence of tumours observed is consistent with that in untreated controls. No other toxic effects were found at histologic examination and the survival rates and average weights show no abnormality. This study indicates that the five waxes tested by feeding at the level of 10% in the diet in rats are devoid of carcinogenic or other toxic action by this route of administration. Therefore the NOAEL is greater than 10% (>5700 mg/kg/day) in diet.

Available supporting data from oral subchronic toxicity studies conducted in rats (API, 1999; Hoglen et al., 1998; BIBRA, 1993g; 1993h) indicate that paraffin and hydrocarbon waxes do not meet the EU criteria for classification following repeat exposure via the oral route.

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, 1987a), 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, 1983a), 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. 1991a), 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 selection of repeated dose toxicity via oral route - systemic effects endpoint:

One of 8 available oral repeat dose toxicity studies.

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

One of 6 available dermal repeat dose 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 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.

Insufficiently refined petrolatums are classified as STOT RE 1, H372 according to EU CLP Regulation (EC No. 1272/2008) for repeat-dose toxicity.