Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
other: literature assessment of topical exposure
Adequacy of study:
key study
Study period:
17 August 1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The Klimish rating is considered appropriate in accordance with ANNEX XI -GENERAL RULES FOR ADAPTATION OF THE STANDARD TESTING REGIME SET OUT IN ANNEXES VII TO X, Para 1.2 which states that: 1.2. Weight of evidence There may be sufficient weight of evidence from several independent sources of information leading to the assumption/conclusion that a substance has or has not a particular dangerous property, while the information from each single source alone is regarded insufficient to support this notion. There may be sufficient weight of evidence from the use of newly developed test methods, not yet included in the test methods referred to in Article 13(3) or from an international test method recognised by the Commission or the Agency as being equivalent, leading to the conclusion that a substance has or has not a particular dangerous property. Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available: – further testing on vertebrate animals for that property shall be omitted, – further testing not involving vertebrate animals may be omitted. In all cases adequate and reliable documentation shall be provided. The literature paper presented presents evidence from a number of studies conducted using mineral hydrocarbon oil and exposure conducted topically. In each study, evidence is presented for the lack of absorption topically, as well as no evidence of irritation or toxicity noted. This, in conjunction with the in vitro studies indicates that there is low potential for absorption. In accordance with REACH Annex VIII, section 8.5.3, this study should be conducted in the event that the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin. This is not the case for a substance of this type.

Data source

Reference
Reference Type:
publication
Title:
A toxicological review of topical exposure to white mineral oils
Author:
Nash, J.F; Gettings, S.D; Diembeck, W; Chudowski, M, Kraus, A.L
Year:
1995
Bibliographic source:
Fd Chem. Toxic. Vol. 34, No. 2, pp. 213-225, 1996

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Various exposure durations and applications are cited within the literature paper. These are summarised below, and the literature paper is attached for reference purposes.
GLP compliance:
not specified
Test type:
other: weight of evidence on topical applications.
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid: viscous
Details on test material:
The mineral oil used in these studies was described as “highly refined white oil” (e.g. Mineral Oil, USP). No other data is presented.

Test animals

Species:
other: mice, rats and rabbits
Strain:
not specified
Sex:
male/female

Administration / exposure

Type of coverage:
other: various
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Several lifetime, topical exposure studies of petroleum distillates and oils, using white mineral oil as a negative control have been conducted (Biles et al., 1988; McKee et al., 1986, 1989 and 1990; McKee and Lewis, 1987). A summary of the design and results of these studies is presented in the table below. In general, male C3H mice were exposed topically on the shaved dorsal surface, two to three times each week for at least 24 months, to a variety of petroleum distillates, oils or Mineral Oil, USP. Importantly, in each study, a complete autopsy was performed and histological evaluation included the liver, kidney, spleen and mesenteric lymph nodes. The average dose of mineral oil delivered topically to the mice was 296 mg/kg/day, depending on the density of the material. There was no evidence of any treatment-related histopathological changes in any of the organs examined after lifetime topical exposure to white Mineral Oil, USP. In addition, there was no evidence of turnout formation either at the site of application or in any of the internal organs examined in mice treated with white mineral oil. Topical exposure to white mineral oils in this species caused no measurable detrimental effects based on these data.Topical 90-day studies using refined mineral oil as a negative control have been conducted by the National Toxicology Program (NTP) (1992) (see below). Male and female F344/N rats and C3H mice were exposed topically to mineral oil, approximately 41 mg/kg/day and 143 mg/kg/day, respectively, for 91 days. Complete autopsy and histopathological examination were performed on each animal. In addition, selected organ weights were obtained. Finally, the results obtained in topical administration studies using rabbits are presented in the table below (Johnson & Johnson Consumer Products, 1992, unpublished data). New Zealand White rabbits were exposed topically to products containing either 16 or 99% mineral oil. In both studies, the rabbits were administered 2 g/kg/day of finished product over 10% of the body surface area for 20 days. Test material was not administered for 14 days before sacrifice. A complete autopsy and histopathological examination was performed on each animal.
Duration of exposure:
Variable. See tabulated data below.
Doses:
Variable. See tabulated data below.
No. of animals per sex per dose:
Variable. See tabulated data below.
Control animals:
not specified
Details on study design:
Variable. See tabulated data below and details listed above under "Details on Dermal Exposure".
Statistics:
None reported.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
other: lifetime exposure
Effect level:
> 296 other: mg/kg/day
Based on:
test mat.
Remarks on result:
other: 4 separate studies on C3H/HeJ mice at this dose level are reported. No effects or toxicity is noted in any study
Sex:
male
Dose descriptor:
other: lifetime exposure
Effect level:
> 238 other: mg/kg/day
Based on:
test mat.
Remarks on result:
other: Study on C3H/HeJ mice at this dose level are reported. No effects or toxicity are noted.
Sex:
male/female
Dose descriptor:
other: 91 day exposure
Effect level:
> 41 other: mg/kg/day
Based on:
test mat.
Remarks on result:
other: Study on F344 Rat at this dose level are reported. Histopathological observations in the skin or internal organs of either species exposed to mineral oil were within normal limits.
Sex:
male/female
Dose descriptor:
other: 91-day exposure
Effect level:
> 143 other: mg/kg/day
Based on:
test mat.
Remarks on result:
other: Study on C3H mice at this dose level are reported. Histopathological observations in the skin or internal organs of either species exposed to mineral oil were within normal limits.
Sex:
male/female
Dose descriptor:
other: 21 day exposure
Effect level:
> 2 000 other: mg/kg/day
Based on:
test mat.
Remarks on result:
other: Study on New Zealand White Rabbit at this dose level are reported; 99% and 16% solutions. There was no evidence of dermal, haematological or histopathological changes associated with administration of products containing mineral oil.
Mortality:
No data reported; assumed that no changes were noted due to the lack of effects observed.
Clinical signs:
No data reported; assumed that no changes were noted due to the lack of effects observed.
Body weight:
No data reported; assumed that no changes were noted due to the lack of effects observed.
Gross pathology:
An increase in liver and kidney weights was observed in the male and female F344/N rats treated topically with mineral oil; liver weights were increased in both sexes of C3H mice. Histopathological observations in the skin or internal organs of either species exposed to mineral oil were within normal limits. The NTP concluded that only cutaneous irritation in the mouse represented treatment-related toxicity following topical exposure to Mineral Oil, USP. This effect is surprising in that previous studies involving topical exposure to mineral oil have not resulted in irritation and this finding is inconsistent with the emollient properties (i.e. prevention of water loss) of mineral oil (Blank, 1988).
Other findings:
Conclusions on dermal absorption are based on the results of experiments with hydrocarbon surrogates. Rossmiller and Hoekstra (1966), reported that 48 hr after the application of [14C] hexadecane in mineral oil to the backs of guinea pigs only a very small amount, less than 0.1% of the applied dose, was found in the dermis. Following a single topical application (2.0 g/kg) of chlorinated paraffins to rats, Yang et al. (1987) reported that less than 1% of C18 paraffin and less than 0.1% of C28 paraffin was recovered in faeces, urine, expired air or tissues over 96 hr. In vitro human skin penetration studies with [14C] n-pentadecane and [14C] n-undecane in chlorinated paraffins have reported 0% and less than 0.01% of the applied dose, respectively, in the receptor fluid after 54 hr (Scott, 1989). The results of microscopic studies suggest that the depth of penetration of hydrocarbons such as octadecane is limited to the stratum corneum in mouse (Ghadially et al., 1992) and human skin (Zesch and Bauer, 1985). Collectively, these data support the view that mineral oil does not effectively penetrate the skin beyond the stratum corneum, resulting in minimal (<1%) absorption of white mineral oils after topical exposure.More recently, the results of studies by Brown et al. (1995), Diembeck and Duesing (1993) and Diembeck and Grimmert (1993) investigating percutaneous absorption of [14C] hexadecane and [3H] docosane from petrolatum or mineral oil after topical application to excised pig skin have confirmed and extended earlier studies. The distribution of the test material between the skin surface, horny layer, epidermis, dermis and receptor fluid was determined. Percutaneous absorption and dermal penetration of [14C] hexadecane and [3H] docosane from petrolatum and Mineral Oil, USP was measured 24 hr after topical application to excised pig skin. Neither radiolabelled compound was measured in the receptor fluid and, in the dermis, 0.8% or less of the total radioactivity was measured 24 hr after application to the skin. These data are further evidence that topically applied mineral hydrocarbons penetrate the skin barrier very slowly and that less than 1% reaches the dermis.On the basis of these findings and reports of negligible epidermal penetration of topically applied white mineral oils, there is no evidence of any hazard identified for topical exposure to white mineral oils at any dose in multiple species, and only minor deposition may occur in the stratum corneum.. This conclusion is supported by the long and uneventful human use of white mineral oils in drug and non-drug topically applied products.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
All available evidence suggests that subchronic or chronic topical exposure to highly refined white mineral oils does not produce gross or histopathological changes in the internal organs or at the site of application in either C3H mice, F344/N rats or New Zealand White rabbits. Similarly, there is no evidence that chronic topical exposure to white mineral oils produces any adverse effects or shortens the lifespan of animals. On the basis of this review of the available literature, it seems unlikely that sufficient amounts of mineral hydrocarbons will be absorbed after topical administration to result in systemic concentrations high enough to cause deposition in the mesenteric lymph nodes and/or liver and thus lead to histiocytosis and granuloma formation. In this regard, following subchronic and chronic topical application there have been no reported effects on any internal organ system attributable to white mineral oils. Considering the long history of use of white mineral oils in topical applied products, the lack of any substantive toxicological findings in rodents and humans suggests the absence of any health risk.
Executive summary:

A full justification for the read across applied for this substance is contained within Section 1.4, reference " Explanation of NovaSpec Base Oil - FINAL". This document contains a full explanation of the manufacturing route for the substance and discussion on why this substance should be considered as a UVCB white oil. Physical properties of the crude reaction product and the different product grades (or distillate fractions) derive from the general chemical structure characteristics (linear-branched alkanes with characteristic branching length and position). Specific unique chemical structures are not isolated in any process step and due to the tens of thousands of isomers and the high degree and variable nature branching and chain length, the base oil bulk properties are the result of the average structure characteristics. The unique viscosity grades each contain all the same typical chemical structures and predominantly overlapping Molecular Weight distributions. The unique viscosity and volatility characteristics of each viscosity grade derive from the boiling point distribution, a result of the short-path distillation (wiped film evaporation). This is identical to the production of petroleum derived white oils.

In order to avoid the requirement to further test a substance that is a derived white oil on animals, a weight of evidence approach is utilised to provide evidence of lack of dermal toxicity. This is via the utilisation of various literature papers.

Conclusions on dermal absorption are based on the results of experiments with hydrocarbon surrogates. Rossmiller and Hoekstra (1966), reported that 48 hr after the application of [14C] hexadecane in mineral oil to the backs of guinea pigs only a very small amount, less than 0.1% of the applied dose, was found in the dermis. Following a single topical application (2.0 g/kg) of chlorinated paraffins to rats, Yang et al. (1987) reported that less than 1% of C18 paraffin and less than 0.1% of C28 paraffin was recovered in faeces, urine, expired air or tissues over 96 hr. In vitro human skin penetration studies with [14C] n-pentadecane and [14C] n-undecane in chlorinated paraffins have reported 0% and less than 0.01% of the applied dose, respectively, in the receptor fluid after 54 hr (Scott, 1989). The results of microscopic studies suggest that the depth of penetration of hydrocarbons such as octadecane is limited to the stratum corneum in mouse (Ghadially et al., 1992) and human skin (Zesch and Bauer, 1985). Collectively, these data support the view that mineral oil does not effectively penetrate the skin beyond the stratum corneum, resulting in minimal (<1%) absorption of white mineral oils after topical exposure.

More recently, the results of studies by Brown et al. (1995), Diembeck and Duesing (1993) and Diembeck and Grimmert (1993) investigating percutaneous absorption of [14C] hexadecane and [3H] docosane from petrolatum or mineral oil after topical application to excised pig skin have confirmed and extended earlier studies. The distribution of the test material between the skin surface, horny layer, epidermis, dermis and receptor fluid was determined. Percutaneous absorption and dermal penetration of [14C] hexadecane and [3H] docosane from petrolatum and Mineral Oil, USP was measured 24 hr after topical application to excised pig skin. Neither radiolabelled compound was measured in the receptor fluid and, in the dermis, 0.8% or less of the total radioactivity was measured 24 hr after application to the skin. These data are further evidence that topically applied mineral hydrocarbons penetrate the skin barrier very slowly and that less than 1% reaches the dermis.

On the basis of these findings and reports of negligible epidermal penetration of topically applied white mineral oils, there is no evidence of any hazard identified for topical exposure to white mineral oils at any dose in multiple species, and only minor deposition may occur in the stratum corneum.. This conclusion is supported by the long and uneventful human use of white mineral oils in drug and non-drug topically applied products.

All available evidence suggests that subchronic or chronic topical exposure to highly refined white mineral oils does not produce gross or histopathological changes in the internal organs or at the site of application in either C3H mice, F344/N rats or New Zealand White rabbits. Similarly, there is no evidence that chronic topical exposure to white mineral oils produces any adverse effects or shortens the lifespan of animals. On the basis of this review of the available literature, it seems unlikely that sufficient amounts of mineral hydrocarbons will be absorbed after topical administration to result in systemic concentrations high enough to cause deposition in the mesenteric lymph nodes and/or liver and thus lead to histiocytosis and granuloma formation. In this regard, following subchronic and chronic topical application there have been no reported effects on any internal organ system attributable to white mineral oils. Considering the long history of use of white mineral oils in topical applied products, the lack of any substantive toxicological findings in rodents and humans suggests the absence of any health risk.

A NOAEL was not reported, as no effects were noted but is proposed to be greater than or equal to 2000 mg/kg/day (the highest dose tested) based on the lack of treatment-related effects.

This study received a Klimisch score of two and is classified as reliable with restriction because it is an acceptable and well-documented literature study report following basic scientific principles.

No classification is applicable.