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Federal Register / Vol. 86, No. 193 / Friday, October 8, 2021 / Rules and Regulations the Kp and 2 the use of fractional absorption. Kp is a constant i.e., the rate at which a chemical penetrates across the stratum corneum the outermost layer of the skin, e.g., centimeters per hour cm/h or meters per second m/s.
The fractional absorption is the percentage of the total amount of lead applied that is absorbed through the skin and depends on the study design e.g., duration of exposure, how much of the test material is in contact with a given surface area, the concentration of the substance in the matrix, etc.. Thus, the extension of an experimental fractional absorption number is only scientifically valid when the experimental conditions are similar, if not identical, to the intended condition of use. As discussed previously, the experimental conditions in the Moore study are significantly different from the intended conditions of use for the lead acetate-containing hair dye. For example, as mentioned in our response to Objection 9, Moores study was conducted with formulations containing 6 millimole per liter mmol/L or 9
mmol/L lead acetate equivalent to 0.12
or 0.18 percent lead respectively, which are three to five times lower than the maximum use level 0.6 percent lead in hair dyes. Second, the test formulations were reportedly applied to a skin surface area of 8 to 10 cm2 on the forehead, an area of the skin without hair follicles, while lead acetatecontaining hair dye is intended to be applied to the full scalp that has many hair follicles and a skin surface area of approximately 580 cm2. Third, the 12hour application period in the Moore study may be too short to assess the full extent of percutaneous absorption of lead under the intended conditions of use, which in some cases could remain on the scalp for 24 hours or longer and may accumulate due to repeated applications. Therefore, application to the small surface area, use of a formulation with a lower lead concentration, and a shorter exposure period used in the Moore study all resulted in an underestimation of the fractional absorption number of lead acetate.
Therefore, we believe it is appropriate to use the Kp which allows the incorporation of parameters, such as the surface area, concentration, and duration of exposure in the modeling to determine dermal absorption. We note that Kp is often the preferred, more reliable, and commonly utilized parameter to quantify percutaneous absorption of chemicals from solutions Refs. 15 and 16., We also note that the ConsExpo dermal absorption model can be applied
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to an organic or inorganic compound because the underlying basis for the model is the well-known Ficks law, which describes the transport of mass, through diffusion, from a region of higher concentration to a region of lower concentration. The Ficks lawbased equation for the ConsExpo dermal absorption model is described in the user manual as follows Ref. 17:
Aabs = Askin 1expP S t/V
Where:
Aabs = Amount of substance absorbed kg Askin = Amount of substance on the skin kg P = Permeability of the skin m/s Equivalent to Kp in the context V = Volume of the substance on the skin m3
S = Exposed skin area m2
t = Exposure time s
As shown in the equation above, the only physicochemical property related to the chemical itself is the Kp; chemical composition is not a part of the equation. Thus, this Ficks law-based approach, which is not dependent on chemical composition, does not need to be specifically validated according to whether the substance is organic or inorganic because the permeability Kp is a set number. As discussed above in our response to Objection 9, we used the ConsExpo dermal absorption model to fill in the existing experimental data gaps i.e., related to the small surface area, lower lead concentration, and shorter duration of exposure in order to address the differences between the experimental conditions and the approved intended conditions of use.
Because the objection failed to provide new data that would change our conclusion, and the information discussed in the objection is insufficient to justify a hearing 12.24b3, we are denying the request for a hearing on this objection.
Objection 13. Combe objects to FDAs use of a permeability coefficient for lead acetate that EPA repudiated and replaced with a much lower estimate.
See Submission, page 45. Combe states that FDA used a permeability coefficient for lead acetate from, an internal report that EPA has since repudiated. Ibid.
Combe further states: FDAs reliance on this figure is particularly unsupportable given that EPA in 2004
actually published a permeability coefficient for lead acetate that is an order of magnitude lower than the internal interim 1992 estimate. Ibid.
Response to Objection 13 We acknowledge that we used the permeability coefficient in EPAs 1992
interim report Ref. 18 the larger Kp value of 4 106 cm/hr, rather than in EPAs 2004 final guidance Ref. 19 the smaller Kp value of 0.0005 103 cm/
hr, which is 5 107 cm/hr, entitled
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Risk Assessment Guidance for Superfund Volume I: Human Health Evaluation Manual. The Kp values in EPAs 1992 and 2004 documents were both based on the same data set the Moore study and they are both valid.
Specifically, the fractional absorption reported by the Moore study was in a range between 0 to 0.3 percent Refs. 18, 19, 21, and 22. While the Kp value in EPAs 1992 document was based on the upper limit of the reported range namely a fractional absorption of 0.3
percent, the Kp value in EPAs 2004
document 7 was based on the mean of the reported data range minus the highest value for injured skin dry and scratch in the Moore study namely a fractional absorption of 0.058 percent, instead of 0.3 percent. Using a higher Kp valuethe upper limit of the reported rangeis more conservative because it results in higher predictions of dermal absorption. FDAs use of this more conservative Kp value is consistent with ensuring there is a reasonable certainty of no harm from the use of this color additive.
Had FDA used the smaller Kp value from EPAs 2004 guidance, the predicted fractional absorption number would have been 3.8 percent acknowledged by Combe in Objection 13; see Submission, page 47. The 3.8
percent fractional absorption is more than 10 times higher than what had been reported in the Moore study as the highest absorption value. This discrepancy in fractional absorption supports our conclusion that the Moore study underestimated the amount of lead absorbed and therefore was flawed.
In addition, as stated in the Wyatt memorandum Ref. 2, p. 19, FDA did not rely on the predicted levels of transdermal absorption from modeling to quantify the extent of lead acetate absorption. Rather, FDA used the predictions from modeling to show that the Moore study, which was relied on for the listing of lead acetate as an approved color additive in 1980, may have significantly underestimated exposure to transdermally absorbed lead from the use of lead acetate hair dyes Ref. 2.
The objection failed to provide new data that would change our conclusion that there is no longer reasonable certainty that no harm would result from the listed use of lead acetate in hair dye, and the information discussed in their objection is insufficient to 7 We disagree with Combes characterization of EPA repudiating the prior Kp value in the EPA
1992 document. We also note that in its 2004
document, FDA did not independently derive the Kp value of 0.0005 103 cm/hr for lead acetate and instead cited Hostynek et al. 1998.

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