# **Responses to EPA's Development of an Acceptable Exposure Limit (AEL) for nPB**

Proposed Rule for n-Propyl Bromide (40 CFR Part 82, Federal Register of
June 3, 2003, pp. 33284-33316)

Docket identification number:OAR-2002-0064

Comments Prepared by SLR International

Work on n-propylbromide (nPB) conducted by SLR International Corp (SLR)
was mentioned repeatedly in the Proposed Rule. We have read the Proposed
Rule in detail, and offer the following comments. Some of the comments
focus specifically on statements made by SLR that we feel were wrongly
interpreted by EPA. However, the majority of our comments focus on three
primary areas of the Proposed Rule:

1.  Relevance of EPA approach for developing an AEL

2.  Application of Uncertainty Factors

3.  Identification of toxicological endpoints

The first two areas are discussed together below, followed by comments
on identification of endpoints. We end by providing a comparison of AELs
identified in the proposed rule, but using more appropriate uncertainty
factors.

## Relevance of Approach and Use of Uncertainty Factors. 

We begin by commenting on the statements made in the proposed rule
regarding the validity and relevance of the acceptable exposure level
(AEL) of 25 parts per million (ppm), and then focusing on comments made
regarding the Occupational Exposure Level (OEL) developed by SLR
International Corp (SLR).

The proposed rule states (p. 33289 of the Fed Reg) "EPA expected users
to defer to any permissible exposure limit ultimately established by
OSHA." This discussion continues with "because OSHA operates under a
different statue, employs different methodology, and will presumably
have additional data at some point in the future, OSHA's derivation of a
PEL may result in a different number than the AEL we set using EPA's own
methodology and the data available today."

There are several problems with these statements. First and foremost is
the correct statement that "section 6 of the Occupational Safety and
Health Act requires OSHA to make specific legal findings to support a
standard." Therefore, it is our opinion that EPA has no jurisdiction to
develop *any* AEL designed to be applicable to a workplace environment.
The further fact that EPA methodology is different than OSHA
methodology, and only OSHA can develop legally binding exposure levels,
makes any value developed by EPA misleading because levels established
using EPA methods are *not applicable* to workplace settings.

This issue is also central to our problems with EPA's interpretation of
the work conducted by SLR. As stated by EPA (p. 33298 of the Fed Reg.),
"based on EPA's RfC guidelines, an uncertainty factor of 3 is necessary
to account for interspecies differences in pharmacodynamcs between rats
and humans. Had SLR applied what EPA considers appropriate uncertainty
factors, their recommended AEK would have been 17 ppm." SLR never
intended to develop an RfC for nPB, but focused on developing an
occupational level that would be applicable as a PEL. As discussed
above, EPA and OSHA have different goals and methods when developing
"safe" concentrations. This point is clearly made in EPA's document on
"Methods for Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry" (EPA, 1994).

EPA (1994) states in Section 1.5 "occupational exposure limit (OEL) is a
generic term...pertaining to human exposure to airborne contaminants.
Due to their derivation methods, attendant assumptions, and intended
application, they represent risk management values, and this distinction
with the RfC as a dose-response estimate must be emphasized." They
further state "OELs are generally time-weighted average concentrations
of airborne substances to which a healthy worker can be exposed during
defined work periods and under specific work conditions throughout a
working lifetime, without material impairment of health. An important
underlying assumption of most OELs is a workplace setting in which
industrial hygienists are able to control the environments."

Since the purpose of SLR's document was to derive an OEL, we feel it is
highly inappropriate, and in fact inadmissible, for EPA to incorporate
uncertainty factors or other assumptions used to derive RfCs in their
review, discussion, and interpretation of SLR's work, or to develop
their own recommended OEL for nPB.

In fact, EPA (1994) continues by saying "the evaluation of toxicity data
by agencies deriving OELs may differ from that of EPA with respect to
weight-of-evidence classification, application of UFs, and other
issues...the use of OELs is established to protect the average healthy
worker (ages 18 to 65 years) against the adverse effects of inhaled
pollutants to which they are exposed only a fraction of a day (i.e.,
during a typical 8-h work shift). Inhalation reference concentrations,
however, are relevant to those of any age and health status and are
aimed at protecting the most sensitive members of the population,
assuming long-term continuous exposures. Therefore, the EPA does not
endorse the use of OELs in deriving RfCs."

It is axiomatic that this statement also works in reverse, i.e., "RfCs
are not endorsed in deriving OELs". Therefore, we do not agree with EPAs
statement that SLR should have applied UFs consistent with EPA's RfC
approach, and also do not agree with their use of UFs in deriving their
own OEL. The text above indicates that EPA recognizes that, unlike RfCs,
OELs incorporate all of the following:

-   Exposure by healthy adults

-   Fractional daily exposure

-   Intermittent exposure (i.e., not every day).

[]{.mark}

Based on EPA's own statements reproduced above, it is clear that the use
of a UF to account for sensitive members of a population (e.g.,
intraspecies UF of 3 recommended in the Fed. Reg.) is necessary when
developing a RfC. However, since OELs are only intended to protect
healthy adult workers, the use of a UF to account for the most sensitive
individuals in a population is counter to the goals of an OEL. What is
relevant and appropriate in developing an RfC is not relevant for OELs.
Since SLR intended their value to be a provisional PEL, we strongly
disagree that the discussed uncertainty factors are "appropriate".
Therefore, a UF of 1 should be used for this parameter.

## EPA's Identification of Toxicological Endpoints

EPA developed an AEL in accordance with EPA risk assessment guidance on
derivation of a reference concentration and application of benchmark
dose modeling. Using EPA-defined criteria for selection of endpoints,
they selected the following for BMD modeling:

-   Decreased sperm motility in F~0~ and F~1~ generation male rats (WIL
    Research 2001)

-   Liver cell vacuolization in male and female rats (ClinTrials 1997).

As such, EPA accepted the liver changes, which were mild, possibly
reversible, and dose-dependent only in the male, as toxicologically
significant, relevant to humans, reproducible across multiple studies,
and meeting quality criteria for dose-response. It should be noted that
although SLR questioned the applicability of liver data, BMD modeling
was also conducted for this endpoint.

EPA also questioned whether the data were test-related based on WIL
Research comments that the results for sperm motility, while decreased
compared to study controls, were within the historical range for the
laboratory. Nonetheless, EPA modeled these data, although the change was
"slight", based on statistical significance of the decrease in motility
and consistency of the change with results seen at 500 and 750 ppm
(i.e., evidence of a dose relationship; Fed. Reg. page 33296).

EPA questioned whether data from the F~1~ generation were applicable to
derivation of a workplace exposure limit (Page 33293), "particularly in
relation to the potential mechanisms by which nPB exerts its effects on
the reproductive system" because "the available data do not rule out the
possibility that the effects on the F~1~ generation occurred as a result
of effects on parental germ cells (sperm or ova) or effects mediated by
changes to the endocrine system." EPA went on to state that it is
appropriate and protective, as well as consistent with EPA guidelines to
use the endpoint observed at the lowest effect level to derive the AEL",
in view of the "lack of mechanistic data on developmental and potential
trans-generational effects of nPB."

We find it interesting that EPA and SLR identified the same sensitive
endpoint across the many available toxicity studies on this chemical
upon which to base development of an AEL or OEL. Also, results of
benchmark dose modeling by EPA and SLR yielded essentially the same
BMDL. The only difference in EPA and SLR recommended values lies in the
application of uncertainty factors, as discussed above.

The benchmark dose-low (BMDL) calculated by EPA 169 ppm. If EPA used the
same UFs as SLR, their recommended AEL would be 177 ppm (adjusting for
Human Equivalent Concentration \[HEC\]), which is slightly higher than
the value recommended by SLR. If EPA used the UF of 2 or 3 incorporated
into the OEL by Doull and Rozman, their recommended AEL would range
between 55 and 85 ppm, very consistent with their recommended range of
60 to 90 ppm. As is evident from these values, all three approaches
yield similar AELs when appropriate uncertainty factors are applied. All
of these values are more than twice the 25 ppm concentration recommended
by EPA in their proposed rule.

[Conclusions]{.underline}

To summarize, we agree with the approach, endpoint, and BMDL identified
in the Proposed Rule. However, we strongly disagree with EPA's
application of uncertainty factors consistent with those used to develop
RfCs. RfC methods are neither pertinent nor applicable to OEL
development, as stated in EPA's own guidance documents. In addition, EPA
does not have the regulatory authority to develop workplace
concentrations. Therefore, we strongly urge EPA to eliminate the AEL
portion of the proposed rule. At the least, use of uncertainty factors
should be modified consistent with the goals of an OEL. Using EPA's own
words, OELs are "established to protect the average healthy
worker...against the adverse effects of inhaled pollutants to which they
are exposed only a fraction of a day". Unlike EPA, SLR incorporated this
goal into derivation of the OEL discussed in the Proposed Rule.
Therefore, we stand behind our original recommendation.

## References

ClinTrials BioResearch (ClinTrials). 1997b. A 13-Week Inhalation
Toxicity Study of a Vapor Formulation of ALBTA1 in the Albino Rat.
Project No. 91190. Bio-Research Laboratories Ltd, Senneville, Quebec,
Canada. Sponsored by Albemarle Corporation, Baton Rouge, LA. February
28.

U.S. Environmental Protection Agency (EPA). 1994. Methods for Derivation
of Inhalation Reference Concentrations and Application of Inhalation
Dosimetry. EPA/600/8-90/066F. Office of Health and Environmental
Assessment, Washington, D.C.

WIL Research Laboratories, Inc. 2001. An Inhalation Two-Generation
Reproductive Toxicity Study of 1-Bromopropane in Rats. Study No.
WIL-380001. Ashland, Ohio. May 24. Sponsored by Brominated Solvents
Consortium, Washington D.C.