Document ID: EPA-HQ-OAR-2002-0064-0224
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-14T04:00Z

Review of ACGIH’s Proposed Threshold Limit Value for 1-Bromopropane
(n-Propyl Bromide, nPB) 

Introduction and Conclusions

At the request of EPA, ICF has reviewed ACGIH’s proposed TLV on nPB
(ACGIH 2004).  In their report, it appears that ACGIH used the decrease
in fetal body weight observed in the developmental study performed by
Rodwell et al. (2001) as the point of departure (POD) for deriving the
Threshold Limit Value (TLV) for nPB.  ICF and the authors of this
developmental study believe the decrease in fetal weight to be an
artifact of study design and conduct and not a treatment-related effect.
 In addition, the expert panel of The Center for the Evaluation of Risks
to Human Reproduction (CERHR) conducted a benchmark dose analysis on the
data and found that reduced fetal weight was not the most sensitive
endpoint for this chemical.  The ACGIH’s TLV-TWA of 10 ppm is lower
than ICF’s acceptable exposure limit (AEL) (17 ppm) for occupational
exposure and may be based on an effect not considered of toxicological
significance by ICF.  It is ICF’s belief that reproductive toxicity is
a more appropriate endpoint for development of a TLV. 

Additionally, ACGIH’s development of the TLV for nPB lacks
transparency.  They did not discuss or identify the uncertainty, and/or
safety factors applied in the development of the TLV, nor did they
articulate whether the NOEL (No Observed Effect Level) was adjusted or
calculated for an equivalent human exposure concentration (e.g.,
adjusted for exposure duration).  It is possible that ACGIH did not use
any one study to develop the TLV, but instead asserted a TLV of 10 ppm
to be protective of all endpoints of toxicity.  This is problematic if
EPA were to consider reduced fetal body weight to be the critical
effect, as it provides only a 10-fold margin of exposure from an effect
level of 100 ppm (Rodwell et al. 2001) to its recommended exposure limit
of 10 ppm, as compared to the same margin of exposure from a
no-effect-level to the exposure limit.

Background 

ACGIH identified several critical endpoints pertaining to neurotoxicity,
hepatotoxicity, developmental, and reproductive toxicity of nPB.  The
critical threshold values in animal toxicity tests were as follows:
neurotoxicity NOEL was 200 ppm (Ichihara et al. 2000a); hepatotoxicity
NOEL was 200 ppm (ClinTrials 1997b); reproductive NOEL was 100 ppm
(Stump, 2001); and the developmental NOEL was <100 ppm (Rodwell et al.
2001). 

Selection of Points of Departure

It appears from the TLV documentation that ACGIH identified the POD to
be the decreased fetal weight observed in the developmental toxicity
study by Rodwell et al. (2001).  This study involved the exposure of 25
pregnant rats (Crl:CD® [SD] IGS BR strain) via whole body inhalation to
the following exposure concentrations of nPB for 6 hours/day from
gestation day 6 to gestation day 19 (0 (air control), 100, 498, and 996
ppm).  Developmental effects observed were reduced ossification (mid and
high dose) of the fetus and an increased incidence of bent ribs (high
dose); the NOEL for these endpoints was 100 ppm.  Maternal toxicity
effects were treatment-related decreases in body weight, body weight
gain, and feed consumption in the mid- and high-dose groups. ACGIH
mentions statistically-significant decreases in fetal body weight
observed in all dose groups as a treatment- related effect and
identifies a NOEL of <100 ppm.  ICF and the study authors believe the
decrease observed in fetal weight to be an artifact of sampling
procedure (specifically, the difference in timeframe of measurement of
the treated versus control animals).  Thus, the decrease in fetal body
weight was not considered a direct toxic effect.  If it is assumed that
the decreased fetal body weight is not a sampling effect, then the
endpoint should be considered a secondary effect of reduced maternal
weight; therefore, this endpoint should not inform a developmental NOEL.
 

The reduced ossification of the ribs and skull seen in the mid- and
high-concentration fetuses is secondary to reduced fetal body weight and
is a common effect in the offspring of dams that exhibit maternal
toxicity (i.e., decreased food consumption, and decreased body weight
and/or body weight gain). Delayed ossification is reversible and is
generally not considered by developmental toxicologists to be a
significant adverse effect (Manson and Kang 1994).  The CERHR panel was
concerned with whether the reduced fetal body weight was a result of
sampling error as indicated by the study authors or if it represented a
LOAEL.  The CERHR conducted a BMD analysis and found that the BMD5 (5%
change from control mean value) for reduced fetal body weight was 561
ppm and the BMDL5 was 305 ppm.  The CERHR noted that the BMD was
consistent with the LOAEL of 500 ppm for skeletal variations.  This
result provides further evidence that skeletal variations are secondary
to reduced fetal weight gain in this study.  Further, the BMDL5 of 305
ppm is higher than the NOAEL observed for other endpoints, making it an
inappropriate choice for development of the TLV.

  

  SEQ CHAPTER \h \r 1 The brevity of the dosing in this developmental
study is of particular concern in the development of an occupational
exposure limit.  When available, longer-term studies are recommended to
instruct occupational exposure limits.  By contrast, it appears that
ACGIH based the development of their occupational exposure limit
primarily on the Rodwell et. al (2002) study that was used to determine
the dose range for the 2-generation study performed by Stump (2001). 
The Stump (2001) study produced the POD that was the basis of ICF’s
Acceptable Exposure Limit.  ICF finds that this 2-generation study
identifies the most sensitive endpoints of sperm motility in the F1
generation and hepatic effects in the parental generation with a NOAEL
of 100 ppm.  ICF utilized Benchmark Dose Analysis to better identify the
threshold limit for this study and to inform the AEL.  This study was
best suited for determining an occupational exposure limit because the
large sample sizes of 25 animals/dose provide the greatest statistical
power compared to other studies.  The exposures covered sensitive
life-stages (dosing occurred during preconception, gestation, and
preweaning periods) over two generations.  Multiple toxicological
endpoints (including potential developmental effects) were assessed.

Choice of Uncertainty Factors

ACGIH reported a TLV-TWA for nPB to be 10 ppm without defining or
identifying the method used to determine this value.  ACGIH stated that
the TLV may protect sufficiently against potential neurotoxicity,
hepatotoxicity, reproductive, and developmental toxicity.  The method
utilized to derive the TLV-TWA, including application of safety factors,
was not reported in the draft; therefore, no statement or calculations
were presented on adjustments of the dose to human equivalency.  The
uncertainty factors or safety factors utilized were not discussed. 
Because the proposed TLV is roughly a factor of 10 lower than the lowest
NOEL cited, ICF can only assume ACGIH utilized a combination of UFs
totaling 10.  This is consistent with using UFs of 3 to account for both
animal to human extrapolation (i.e., differences in pharmacodynamics and
pharmacokinetics) and variation within the working population.  ICF
performed sample calculations that ACGIH may have used based on current
risk assessment practices.

POD: 	Fetal weight decrease

Study: 	A Developmental Toxicity Study in Rat Via Whole Body Inhalation
Exposure.  Conducted by Huntingdon Life Sciences, Study No. 98-4141. 
Sponsored by Brominated Solvents Consortium.  August 23, 2001. (Rodwell
D.E.  2001)

Protocol: Whole-body inhalation, 6 hours/day, gestation days 6-19

Concentrations: 	0, 100, 498, or 996 ppm

NOEL:		<100 ppm

LOEL:		100 ppm (reduced fetal body weight)

HEC [adj]:  	100 ppm × 6 hours / 8 hours × 7 days / 5 days  = 105 ppm 

Uncertainty Factors:	3  - animal to human extrapolation

			3 - sensitive individuals

TLV-TWA:		~10 ppm

Conclusion

ICF believes that the ACGIH approach for setting an occupational
exposure limit should be revised in its final TLV, or EPA should not use
the same approach in setting an AEL, for several reasons:

Firstly, the developmental effect of decreased fetal weight in the
Rodwell et al. (2001) study was possibly a product of sampling
techniques and very likely secondary to maternal toxicity (particularly
decreased maternal weight gain).  ICF, supported by the CERHR Expert
Panel, believes that reduced fetal weight does not represent a direct
toxic effect of nPB exposure nor does it represent the most sensitive
toxicological endpoint in the database because other studies have not
found reduced pup weight to be the most sensitive endpoint.  There are
other, more sensitive and toxicologically relevant endpoints identified
from the database for nPB, including reduced sperm motility in the F1
generation of the 2-generation study (Stump 2001) and decreased number
of estrous cycles in a three-week period in the F0 generation of the
same study.  

Secondly, ICF is concerned by the lack of transparency of the TLV-TWA
determination, particularly the lack of discussion of uncertainty
factors.  

Lastly, the calculations used to arrive at the TLV were not presented in
the draft documentation.

References

ACGIH 2004.  Draft TLV-TWA for 1-Bromopropane. 
NIC\CS\2004\1-Bromopropane_2003-10-26.  

Center for the Evaluation of Risks to Human Reproduction (CERHR) Expert
Panel Report on the Reproductive and Developmental Toxicity of
1-Bromopropane.  October 2003. National Toxicology Program, U.S.
Department of Health and Human Services.

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

  SEQ CHAPTER \h \r 1 U.S. Environmental Protection Agency (US 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, DC. October 1994.

Ichihara G., Yu X., Kitoh J., et al. 2000a. Reproductive toxicity of
1-bromopropane, a newly introduced alternative to ozone layer depleting
solvents, in male rats.  Toxicol Sciences 54:416-423.

Manson JM and Kang YJ. 1994. Test Methods for Assessing Female
Reproductive and Developmental Toxicology. In: Principles and Methods of
Toxicology, 3rd Edition. Ed.: A. Wallace Hayes. Raven Press, 

Ltd., New York.

Rodwell D.E.  2001.  A Developmental Toxicity Study in Rat Via Whole
Body Inhalation Exposure.  Conducted by Huntingdon Life Sciences, Study
No. 98-4141.  Sponsored by Brominated Solvents Consortium.  August 23,
2001.

Stump D.G.  2001.  An Inhalation Two-Generation Reproductive Toxicity
Study of 1-Bromopropane in Rats.  Conducted by WIL Research
Laboratories, Inc., Sponsored by Brominated Solvents Consortium.  May
24, 2001.

***DRAFT (March 29, 2007) - DO NOT CITE OR QUOTE***

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