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Description of key information

No oral repeat dose toxicity data are available for slack waxes (non-carcinogenic feed-stock). Data are available on similar materials (Paraffin waxes) to adequately characterize the repeated dose toxicity of slack waxes (Non-carcinogenic feed-stock). The data are consistent in that they demonstrate that paraffin and hydrocarbon waxes were found to be of low acute toxicity by the oral route.  A subchronic oral toxicity NOAEL of <125 mg/kg/day was determined for slack waxes (carcinogenic or unknown feed-stock) using read-across to a 90-day subchronic toxicity study that tested untreated distillate aromatic extracts. For dermal repeat dose toxicity, data are available on similar materials to adequately characterize the repeated dose toxicity of  slack waxes (carcinogenic or unknown feed-stock and non-carcinogenic feed-stock). The data are consistent in that they demonstrate minimal effects in rabbits with the exception of minimal to moderate skin irritation following repeated dermal exposures. For inhalation repeat dose toxicity, no data are available on slack waxes.  However, inhalation exposure to slack waxes is not expected to occur under normal conditions due to the very low vapour pressures of these substances.

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

Slack waxes are waxes with entrained oils. Since paraffin and hydrocarbon waxes are non-hazardous the category hazard profile is determined by the entrained oils. Since the entrained oils are a minor portion of the slack waxes, this is considered to be a worst-case approach.

Slack Waxes (Carcinogenic or Unknown Feed-stock)

Oral Repeat Dose Toxicity:

Data for oral repeat dose toxicity are not available for slack waxes (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 slack waxes (carcinogenic or unknown feed-stock) due to the concentration effect of the solvent extraction process.

Inhalation Repeat Dose Toxicity:

Data for inhalation repeat dose toxicity are not available for slack waxes (carcinogenic or unknown feed-stock).

Dermal Repeat Dose Toxicity:

Short-term Dermal Toxicity

Read across justification

No dermal repeated dose studies have been reported for slack waxes (carcinogenic or unknown feed-stock), but data have been reported for unrefined/acid treated lubricant base oils, materials similar to the oil entrained in slack waxes (carcinogenic or unknown feed-stock).

One key read-across study (API, 1986b) has been identified for short-term (28 days) repeat dose toxicity of slack waxes (carcinogenic or unknown feed-stock).

In a 28-day dermal repeated-dose study (API, 1986b) API 84-01, an unrefined light paraffinic distillate (CAS No. 64741-50-0) was applied undiluted 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 New Zealand white rabbits. The applied material was covered with an occlusive dressing for 6 hours and was then removed. The skin was wiped with dry gauze to remove any residual material and a group of five rabbits/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 female rabbits 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.

Subchronic Dermal Toxicity

Read across justification

No dermal subchronic toxicity studies have been reported for slack waxes (carcinogenic or unknown feed-stock) but data has been reported for untreated distillate aromatic extracts (UDAE) which can be used for read-across. A UDAE is produced as a by product in the refining of lubricating oil base stocks and waxes. Straight run vacuum distillates (lubricant base stocks) are extracted with solvents such as furfural, phenol, or N-methyl-2-pyrrolidone to selectively remove the undesirable polycyclic aromatic compounds, (especially 3-7 fused ring structures). A UDAE can be considered “worst case” by comparison to unrefined / acid treated oils, in that the extract contains higher concentrations of biologically active components than the unrefined / acid treated oils.

One key read-across study (Mobil Environmental and Health Science Laboratory, 1990a) has been identified to evaluate the subchronic dermal toxicity of slack waxes (carcinogenic or unknown feed-stock).

In this key read-across 90 day subchronic dermal toxicity study, light paraffinic distillate solvent extract 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. A group of 10 males and 10 females served as controls. Each animal was observed once daily during the pre-treatment and dosing phases for normal or abnormal clinical signs. On weekdays, animals were checked for moribundity and mortality twice daily, at least six hours apart. On weekends and holidays, they were checked once, as soon as practical each day. The parameters used to assess toxic response included clinical observations, skin irritation, body weights, haematology, serum chemistry, urinalysis, organ weights, histopathology, and sperm morphology.

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 Light paraffinic distillate solvent extract 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 is less than 30 mg/kg/day.

Chronic Dermal Toxicity

Read across justification

No dermal chronic repeat dose studies have been reported for slack waxes (carcinogenic or unknown feed-stock), but data have been reported for insufficiently refined lubricant base oils, materials similar to the oil entrained in slack waxes (carcinogenic or unknown feed-stock).

One key read-across study (Chasey and McKee, 1993) was identified to evaluate the chronic dermal toxicity of slack waxes (carcinogenic or unknown feed-stock). In this study, male C3H mice, approximately 6 to 10 weeks of age were obtained from Jackson Laboratories (C3H / HeJ) or, (C3H / HeNCrlBR).  These mice were randomly distributed into test groups of 40 or 50 animals.  In early studies, mice were housed five per cage in suspended wire-mesh cages.  In later studies, they were housed singly in the same type of cages.  The hair in the interscapular area was clipped once weekly to facilitate test material application.  The test materials were applied by automatic pipette in either 37.5 μl aliquots twice a week or 25 µl 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., 37 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.

The LOAEL was determined to be 100 mg/kg/day based on the incidence of tumours observed.

Slack Waxes (Non-carcinogenic Feed-stock)

Oral Repeat Dose Toxicity:

No oral repeat dose toxicity studies have been reported for slack waxes (Non-carcinogenic feed-stock), but many studies have been reported for paraffin waxes, materials similar to slack waxes (Non-carcinogenic feed-stock). Paraffin and hydrocarbon waxes were found to be of low acute toxicity by the oral route. Among the repeated dose toxicity data are results of a number of 90-day repeat oral studies of paraffin and hydrocarbon waxes. Few findings were noted in these studies, and those that were regarded as toxicologically important to rats were not judged to be relevant to humans. For purposes of human health risk assessment, the no observed adverse effect level (NOAEL) was the highest concentration tested (2% in the diet), equivalent to approximately 1500 mg/kg/day.

In a key study (BIBRA, 1993b), 3 waxes designated as low melting point wax, a 1:1 mix of low and high melting point wax, and intermediate melting point wax were administered via the diet (at 2% only, at 0.02, 0.2, and 2.0%, and at 0.02, 0.2, and 2.0%, respectively). There were no effects on food intake, growth rate, or clinical conditions of animals fed paraffin waxes (low melting point wax, intermediate melting point wax or mixed melting point wax).  Changes in the liver, mesenteric lymph nodes, 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 low melting point wax than either of the other two.

In a key long-term repeat-dose toxicity study (Shubik et al., 1962), 5 types of paraffin wax were tested in male and female Sprague-Dawley rats 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 deaths. The incidence of tumours observed is consistent with that in untreated controls. No other toxic effects were found at histological 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.

In a 90-day dietary feeding study (API, 1999) to compare the effects of paraffin wax in Fischer-344 and Sprague-Dawley rats. Female rats were fed diet containing low melting point wax at concentrations of 0, 0.2% or 2.0%.  There were no treatment-related effects on survival, clinical signs, body weight gain, or food consumption with low melting point wax in either rat strain. Treatment-related changes either occurred only in Fischer-344 rats or were considerably more severe in Fischer-344 rats than in Sprague-Dawley rats.  A NOEL was not established experimentally in either strain; however, the results demonstrated the differential response to dietary mineral hydrocarbon between rat strains.

Differential effects of dietary exposure to 2% low melting point wax on female Fischer-344 and Sprague-Dawley rats was also examined in a 60-day study.  While mean body weights were not affected in either strain throughout the course of the study, a number of changes within the livers of Fischer-344 rats were observed, but not in livers from Sprague-Dawley rats.  Total white blood cell and neutrophil counts were significantly elevated in blood of Fischer-344 rats.  The observed differences in KC function between the two species may account for the strain differences in the response to low melting point wax. No significant changes in these functions were observed in KC isolated from Sprague-Dawley rats exposed to low melting point wax or from control rats. A NOEL was not established from this study.

In 28- and 90-day feeding studies, groups of female Fischer-344 rats were administered 0 or 2% low melting point wax.  There were no overall differences in body weight during the course of either the 28- or 90-day studies. At the end of the 28-day feeding study, a statistically significant increase in absolute and relative weights of the mesenteric lymph nodes was seen in the group of rats given low melting point wax. At the end of the 90-day study, statistically significant increases were seen in absolute and relative weights of the livers and spleens in the low melting point group over the control group. Both the proximal and distal mesenteric lymph nodes showed statistically significant increases in absolute and relative weights in the low melting point group.  A NOEL was not established from this study. 

A series of 180-day feeding studies in rats were performed on chewing-gum bases containing hydrocarbon wax in proportions ranging from 2 to 57% of the gum.  Calculated feeding levels for the waxes were reported to vary from 0.16% to 4.75% of the diet.  Test animals were fed diets consisting of 75% basal diet, 8.3% gum base, and 16.67% wood flour.  No treatment-related effects were observed from these studies.

Inhalation Repeat Dose Toxicity:

Data for inhalation repeat dose toxicity are not available for slack waxes (non-carcinogenic feed-stock).

Dermal Repeat Dose Toxicity:

Short-term Dermal Toxicity

Read across justification

No dermal repeated dose studies have been reported for slack waxes (non-carcinogenic feed-stock), but data have been reported for refined lubricant base oils, materials similar to the oil entrained in slack waxes (non-carcinogenic feed-stock).

One key read-across study (API, 1987a) has been identified for short-term (28 days) repeat dose toxicity of slack waxes (non-carcinogenic feed-stocks).

In a 28 -day repeat dose dermal toxicity study (API, 1987a), 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. 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 hydrotreated heavy naphthenic oil. Low-dose (200 mg/kg) males and females exhibited minimal irritation from administration of the test article. All observed hematology parameters appeared normal in controls and in animals treated with hydrotreated heavy naphthenic oil. SGOT levels were elevated in males exposed at 1000 and 2000 mg/kg and in females administered 2000 mg/kg hydrotreated heavy naphthenic oil. 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 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 was 1000 mg/kg, based on the lack of adverse systemic effects observed at this dose level.

Subchronic Dermal Toxicity

Read across justification

No dermal repeated dose studies have been reported for slack waxes (non-carcinogenic feed-stock), but data have been reported for refined lubricant base oils, materials similar to the oil entrained in slack waxes (non-carcinogenic feed-stock).

One key read-across study (Mobil Environmental and Health Science Laboratory, 1983) was identified to evaluate the subchronic dermal toxicity of slack waxes (non-carcinogenic feed-stock).

In this 90-day dermal toxicity study, mineral oil basestock 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 mineral oil basestock 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 mineral oil basestock. The study authors conclude that these findings are not biologically significant.

The NOAEL was 2000 mg/kg/day, based on lack of local or systemic toxic effects.

Chronic Dermal Toxicity

Read across justification

No dermal repeated dose studies have been reported for slack waxes (non-carcinogenic feed-stock), but data have been reported for refined lubricant base oils, materials similar to the oil entrained in slack waxes (non-carcinogenic feed-stock).

One key read-across study (ExxonMobil Biomedical Sciences, Inc., 1991a) was identified to evaluate the chronic dermal toxicity of slack waxes (non-carcinogenic feed-stock).

In this dermal carcinogenicity study, male C3H/HeNCrlBR mice (50/group) were dermally exposed to a lubricant base oil (designated MRD-87-016) 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. The dermal application of the test material 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 edema. Microscopic examination revealed acanthosis and subepidermal inflammatory infiltrate. Treatment group 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 postmortem 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 material 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 treatment-related histopathology or gross pathology changes observed in the study.

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

One of 7 oral repeat dose toxicity studies available.

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

One of 2 available long term dermal 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

Data for oral and inhalation repeat dose toxicity are not available for slack waxes (carcinogenic or unknown feed-stock and non-carcinogenic feed-stock). Slack waxes (non-carcinogenic feed-stock) are not classified under the EU CLP Regulation (EC No. 1272/2008) criteria for dermal repeat dose toxicity. Slack Waxes (carcinogenic or unknown feed-stock) are classified as STOT Rep. Exp. 1 (H372) for dermal repeat dose toxicity.

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