Public Information and Records Integrity Branch (PIRB)

Office of Pesticide Programs (OPP)

Environmental Protection Agency

Room 119, Crystal Mall #2

1801 South Bell Street

Arlington, Virginia

RE: Para-tertiary Amylphenol Risk Assessment Docket ID Number 2005-0181

To Whom It May Concern:

The following comments are submitted on behalf of Clariant Corporation,
the sole registrant for technical para-tertiary amylphenol (PTAP). These
comments are intended to supplement those previously made during the
error-only comment period.

**Comments on PTAP Toxicology Test Requirements**

General Comments

-   EPAs review of existing literature should include the large existing
    database on para-substituted mono alkylphenols.

-   A tiered testing strategy should be used to fill data gaps.

-   EPAs test requirements need to incorporate the best available
    science to determine the need for testing as well as appropriate
    test methods if testing is needed.

-   PTAP does not meet the criteria for additional developmental or
    reproductive toxicity testing as described in the draft 40 C.F.R.
    §158 Subpart W testing requirements.

-   Adequate Margins of Exposure exist for inhalation, and a 28-day
    inhalation study should not be required.

-   The requested ecotoxicity tests may be of little or no practical
    value.

-   EPA appears to have created a new "Indirect Food Use" category

**EPAs review of existing literature should include the large existing
database on para-substituted mono alkylphenols**

The para substituted mono alkylphenols class of chemicals, i.e.,
nonylphenol (NPh), octylphenol (OPh), and para tert-butyl phenol has
been the subject of many recent reviews and studies under a number of
EPA and international programs. These data should be used in EPA's
evaluations of the toxicology and environmental database, gap analysis
as well as in its toxicology endpoint selections.

EPA's assessment of estrogenic potential cites several screening studies
as a basis for heightened concern for reproductive and developmental
effects. Data generated on similar alkylphenols, the recent Nonylphenol
and Octylphenol multigeneration studies and the conclusions, general
principles, and strategy laid out in the Endocrine Disruptor Screening
Program (EDSP) were not considered in the assessment.

A large number of studies have been published on alkylphenols in the
last 5 to 10 years. While many of these studies focus on the octyl- and
nonylphenols, a number of studies have included longer and shorter chain
para-substituted mono alkylphenols including tert-amyl phenol. Results
of in vitro and other screening studies have indicated that many
alkylphenols can interact with the estrogen receptor and therefore have
the potential to cause endocrine disrupting effects. Many of the studies
conclude that the alkylphenols interact with the estrogen receptor only
at very high doses. The potency of the alkyl phenols is estimated to be
several orders of magnitude less than 17-β-estradiol. Relative potency
among the alkylphenols is estimated to be nonylphenol \> octylphenol \>
tert-amylphenol with NPh and OPh estimated to be 1000-10,000 fold less
potent than 17-β-estradiol, and tert-amylphenol estimated to be 100,000
fold less potent than 17-β-estradiol.

These screening studies were followed up with in vivo studies. NIEHS
conducted a 3-generation rat feeding study with nonylphenol. NPh was
administered in the diet at concentrations of 0, 200, 650, and 2000 ppm
to groups of Sprague-Dawley rats over three generations. Effects
observed at higher doses in females, were consistent with NPhs known
weak estrogenic action. However, no effect fertility or reproductive
performance was observed at any of the doses tested. The NIEHS study
found no consistent effect on fertility from all levels of exposure to
nonylphenol. Consistent with exposure to very high doses of nonylphenol,
the study found effects including male and female reproductive changes
in rats at doses of 650 ppm and above, based on decreased epididymal
sperm density and testicular spermatid head counts in males (F2
generation only), and increased estrous cycle length and decreased
ovarian weights observed in females. However, these changes in
reproductive parameters were not linked to alterations in fertility.
(Since the effects on sperm were observed in only one generation and
were not associated with adverse effects, the study\'s author questioned
whether this represents random chance, or real biological effects.)
There were no adverse reproductive effects at doses of 200 ppm, which
translates to a No Observable Effect Level (NOEL) for reproductive
toxicity of 15 mg/kg/day. This NOEL for rats is several multiples of 10
higher than an estimated, maximal daily human intake of NPh. In
addition, there were no adverse effects on fertility at doses of 2000
ppm, which means the No Observable Adverse Effects Level (NOAEL) is
greater than 150 milligrams of nonylphenol per kilogram of body weight
in rats. (NTP Report \# RACB94021)

RTI conducted a rat 2-generation study on octylphenol (870.3800 with
additions). Dietary exposure to octylphenol for two generations one
litter per generation, at 0, 0.2, 20, 200 and 2000 ppm, resulted in:
decreased body weights and weight gains at 2000 ppm, offspring toxicity
(reduced body weight during lactation at 2000 ppm, delayed vaginal
opening and preputial sepation at 2000 ppm, which was considered related
to body weight decreases, no effects on reproductive parameters or
developmental effects were observed. (Two-Generation Reproductive
Toxicity Evaluation of Para-tert Octylphenol Administered in the Feed to
CD (Sprague-Dawley Rats) RTI Project No.:  65C-6569-200  The study
results are expected to be published in an upcoming edition of
*Regulatory Toxicology and Pharmacology*. The results also were reported
at a recent Society of Toxicologists (SOT) meeting in Washington, DC. A
copy of the abstract may be found at:
<http://www.aperc.org/docs/abstract-sd.pdf>.

A combined Repeat Dose Reproductive/Develomental Toxicity Screening Test
(OECD TG 422) was completed on para tert-butylphenol. Male rats were
dosed for 44 days, and females were dosed 14-days prior to mating to day
4 of lactation with 20, 60 or 200 mg/kg/day pTBP by gavage. No treatment
related toxic effects on pregnant and lactating females or their
offspring were seen.

The EDSP describes a tiered testing approach for the evaluation of
endocrine disrupting potential. Tier 1 recommends in vitro or low animal
use screening studies similar to the literature studies cited for PTAP.
The purpose of the Tier 1 studies is largely to provide fast,
inexpensive, low or no animal use studies that serve as a screen to
identify compounds that should be tested in more robust studies. The
EDSP recognizes that the tier 1 screening studies are likely to result
in false positive results. Furthermore, the screening studies cited for
PTAP have not been validated, and during validation testing, many of the
results have not been able to be reproduced, nor have the methods
yielded consistent results. Positive results in Tier 1 studies should be
confirmed with more robust in vivo studies.

The EDSP's "weight-of-evidence" approach makes explicit the assumption
that results of some assays/tests, in some taxa, at some level of
severity, are intrinsically "worth" more than others and should,
therefore, carry more weight in decisions following Tier 1 and Tier 2.
For example, positive results showing reproducible, high levels of
effects at low doses (near the doses produced by environmental or human
exposures) are likely of greater weight than weak effects observed only
at very high, perhaps excessively toxic, levels of exposure.

Using the weight of evidence approach, tert-amylphenol has been shown to
have potential to interact with the estrogen receptor in screening
studies at relatively high doses. In the rat gavage developmental
toxicity study, maternal toxicity (mucoid/soft stools, urine stains
rales, hair loss, salivation) was observed at 200 and 500 mg/kg/day. No
adverse maternal effects were observed at 50 mg/kg/day. Fetal effects
(skeletal abnormalities, decreased body weight gain) were observed at
500 mg/kg/day. No effects were observed at 200 mg/kg/day. A number of
screening studies have shown that both NPh and OPh are likely to be at
least 10 to 100 fold more potent in interacting with the estrogen
receptor than tert-amyl phenol. Since multi generation studies with both
NPh and OPh did not demonstrate adverse developmental or reproductive
effects at environmentally relevant concentrations, and since both NPh
and OPh were estimated to be 10-100 times more potent in interacting
with the estrogen receptor, and given the lack of effects seen in the
reproductive/developmental screening study with pTBP and in the oral
developmental study or subchronic dermal study with PTAP, and low
anticipated exposures outlined in the dietary, occupational and
residential assessments heightened concern for endocrine disrupting
effects does not appear to be warranted.

For additional details concerning the many pertinent studies on NPh and
OPh, see, for example: Van Miller, J.P., and Staples, C.A. (2005).
Review of the potential environmental and human health-related hazards
and risks from long-term exposure to p-tert-octylphenol. [Human and
Ecological Risk Assessment]{.underline}, 11, 319-351; Tyl, R.W., Myers,
C.B., and Marr, M.C. (2004, February 12). Three-Generation,
Endpoint-Specific Evaluation of para-Nonylphenol (NP; CAS RN 84852-15-3)
Toxicity in Rats. [Unpublished Report 65C-07946-000]{.underline}. RTI
International, Center for Life Sciences and Toxicology, Health Science
Group, Research Triangle Park, NC, USA; Chapin, R.E., Delaney, J., Wang,
Y., Lanning, L., Davis, B., Collins, B., Mintz, N., and Wolfe, G.
(1999). The Effects of 4-Nonylphenol in Rats: A Multigeneration
Reproduction Study. [Toxicological Sciences]{.underline},
[52]{.underline}, 80-91; Latendresse, J.R., Weis, C.C., Mellick, P.W.,
Newbold, R.R., and Delclos, K.B. (2004). A Five Generation Reproductive
Toxicity Assessment of p-Nonylphenol (NP) In CD Sprague-Dawley Rats.
[Toxicologist]{.underline}, 1066, 219; Nagao, T., Wada, K., Marumo, H.,
Yoshimura, S., and Ono, H. (2001). Reproductive Effects of Nonylphenol
in Rats after Gavage Administration: A Two-Generation Study.
[Reproductive Toxicology]{.underline}, [15]{.underline}, 293-315; Odum,
J., and Ashby, J. (2000). Neonatal Exposure of Male Rats to Nonylphenol
Has No Effect on the Reproductive Tract. [Toxicological
Sciences]{.underline}, [56]{.underline}, 400-404; Odum, J., Pyrah,
I.T.G., Soames, A.R., Foster, J.R., Van Miller, J.P., Joiner, R.L., and
Ashby, J. (1999). Effects of p-Nonylphenol (NP) and Diethylstilboestrol
(DES) on the Alderly Park (Alpk) Rat: Comparison of Mammary Gland and
Uterus Sensitivity Following Oral Gavage or Implanted Mini-pumps.
[Journal of Applied Toxicology]{.underline}, [19]{.underline},
367-378.^\
9^ Odum, J., Pyrah, I.T.G., Foster, J.R., Van Miller, J.P., Joiner,
R.L., and Ashby, J. (1999). Comparative Activities of p-Nonylphenol and
Diethylstilbestrol in Noble Rat Mammary Gland and Uterotrophic Assays.
[Regulatory Toxicology and Pharmacology]{.underline}, [29]{.underline},
184-195.^\
10^ Cunny, H.C., Mayes, B.A., Rosica, K.A., Trutter, J.A., and Van
Miller, J.P. (1997). Subchronic Toxicity (90-Day) Study with
*para*-Nonylphenol in Rats. [Regulatory Toxicology and
Pharmacology]{.underline}, [26]{.underline}, 172-178.

**A tiered testing strategy should be used to fill data gaps and prevent
duplicative studies**

In the toxicology endpoint selection document EPA requests a 90-oral
toxicity study with modifications to assess endocrine disruptor effects
and uterotropic effects, a second developmental study and a reproductive
study based on the in vitro screening studies. In some cases, the same
test procedure is being duplicated in two or more species (e.g.,
developmental dosing studies in rats and rabbits). In other places, EPA
is proposing to conditionally require a second species because the data
will provide "some assurance" that EPA is not basing its assessment on a
single species that may be highly sensitive. However, "some assurance"
is not a sufficient rationale for requiring testing of another species.
EPA should not require testing on additional animals when the value of
the testing requirement has not been established through tiered testing
and full assessment of the available database on PTAP and structurally
similar compounds.

Any concerns regarding potential endocrine disruptor effects and
uterotropic effects can likely be resolved by the results of the 90-day
oral study if the protocol is modified as requested by the ADTC.
Accordingly, any requirement for additional developmental and
reproductive studies should be held in reserve pending completion and
review of the new 90-day oral study being requested. Any requirement to
perform either the additional developmental or a 2-generation
reproductive study prior to receipt of the 90-day study, risks
unnecessarily increasing the number of animals tested and providing
little or no useful additional information that would affect the overall
risk assessment.

**EPAs test requirements need to incorporate the best available science
in terms of determining the need for testing as well as appropriate test
methods if testing is needed.**

As mentioned above, a tiered testing strategy and weight of evidence
approach to testing requirements has not been applied. The EDSP is
currently evaluating and validating the models available to study
potential endocrine disrupting effects. Clariant is willing to work with
EPA to ensure that these principles are incorporated into the design of
the 90-day oral study.

**PTAP does not meet the criteria for additional developmental or
reproductive toxicity testing as described in the Draft 158 w testing
requirements.**

Testing in two species if one of two conditions is met.

a.  Significant exposure to females of childbearing age may reasonably
    be expected. In EPA's current dietary risk assessment, a
    conservative target MOE of 3000 was chosen. EPA's dietary risk
    assessment concluded that none of the exposure scenarios approach
    the target MOE.

b.  Significant developmental toxicity is observed after testing in the
    first species. Significant developmental effects were not observed
    in the rat developmental study.

**PTAP does not meet the criteria for a 2-generation reproductive study
laid out in the draft 158w guideline.**

A 2-generation test is required if:

Adverse effects on organs of the reproductive system are observed in
90-day or other studies or if developmental toxicity is demonstrated in
available data. In the 90-day dermal toxicity no systemic toxicity was
observed at the highest dose tested, 25 mg/kg/day. In the rat
developmental toxicity study fetal effects were limited to skeletal
abnormalities and decreased body weight gain at 500 mg/kg/day. In this
study maternal toxicity was observed at 200 and 500 mg/kg/day.

**The requested ecotoxicity tests may be of little or no practical
value.**

The environmental assessment cites a number of ecotoxicity and
environmental studies on PTAP, but fails to cite the significant number
of studies and environmental assessments on similar para substituted
mono alkylphenols. EPA states that since there are no outdoor uses of
PTAP, significant exposure is unlikely to occur. Despite the
availability of literature data on PTAP and structurally similar
substances, and the fact that there are no outdoor uses for PTAP, EPA
has requested an acute ecotoxicity battery. (See, for example, the
recently published manuscript in the [Human and Ecological Risk
Assessment]{.underline} journal (Staples, C., Mihaich, E., Carbone, J.,
Woodburn, K., and Klecka, G. (2004). A Weight of Evidence Analysis of
the Chronic Ecotoxicity of Nonylphenol Ethoxylates, Nonylphenol Ether
Carboxylates, and Nonylphenol. [Human and Ecological Risk
Assessment]{.underline}, [10]{.underline}, 999-1017) which provided a
weight of evidence hazard assessment using a robust statistical
technique known as Species Sensitivities Distribution (SSD). About 90
chronic toxicity values from high quality peer-reviewed studies were
evaluated. Using the SSD analysis for nonylphenol (NP) the authors
calculated a chronic safe level of 5.7 ug/L, which supports the draft US
EPA criteria for NP of 5.9 ug/L.)

Given the limited exposure and EPA's conclusion that an environmental
risk assessment was unnecessary, new studies are of little or no
practical value. Requiring such tests places unnecessary burdens on
registrants, misallocates scientific expertise and technical resources
that could be more productively used for other purposes, leads to
unnecessary animal testing, and is directly contrary to EPA's stated
goals of increasing the quality of the data and the efficiency of the
registration program. A study should not be required unless it can
clearly be linked to a registration decision.

**Adequate Margins of Exposure exist for inhalation, and a 28-day
inhalation study should not be required.**

The ADTC states "inhalation exposure is expected from use as an air
sanitizer". (It should be noted that while there are uses for PTAP in
air deodorizers, it is not registered for use as an air sanitizer.)
Although it is not discussed by the ADTC, the other use that may result
in post-application inhalation exposure occurs as a result of its use in
fogging agricultural premises.

All residential and institutional handler/applicator inhalation
exposures are considerably greater than the target MOE. Post-application
exposure in residential settings is also considerably greater than the
very conservative target MOE. The only calculated post-application
exposure below the target MOE results from exposure following a two-hour
reentry period in fogged barns. The ventilation rate assumed by EPA in
its model is too conservative and it severely overestimates the exposure
to PTAP.

**Model takes no account of the application time**

The model calculates a peak concentration (total mass applied/volume of
building) to give a peak concentration. In reality, this peak
concentration will not be achieved because the fog is not applied
instantaneously, nor will instantaneous mixing occur.

**Ventilation rate is too low**

Barns such as stables, poultry and livestock buildings have extensive
guidance available issued by various state agencies on the need for
correct ventilation to maintain animal welfare and prevent disease. For
example, the according to the Ontario State Department of Food and Rural
Affairs
(<http://www.omafra.gov.on.ca/english/engineer/facts/96-031.htm>) a
minimum ventilation rate of 1 air change per house (ACH) is recommended
for a stable. The U.S. Humane Society
(<http://www.eap.mcgill.ca/LPAW_1.htm>) recommends a minimum of 4 air
changes per hour in winter and 40 air changes per hour in summer as
necessary to keep the air in swine facilities reasonably clean and
fresh. These rates are much larger than the default hourly air exchange
rate (ACH) of 0.18 used by the Agency in the calculation. An ACH of 0.18
is only apt to be found in the highly energy efficient new homes.
Indeed, the EPA exposure factors handbook (EPA, 1997) recommends values
of 0.45 ACH as the central tendency and 0.18 ACH as the conservative
defaults for residential risk assessment. Using a more realistic
ventilation rate of 1 ACH results in a MOE of \>1000, above the Agency's
level of concern.

Should the Agency still have concerns over the MOE at 2-hour reentry,
Clariant is willing to work with the Agency to modify the label language
to change the reentry interval or make other modifications to alleviate
any concerns. If the inhalation MOEs are all above the target, requiring
that the registrant conduct a 28-day day inhalation study would have no
affect on the risk assessment, and this requirement should be
eliminated.

**EPA appears to have created a new "Indirect Food Use" category.**

Finally, EPA seems to have created a new \"indirect food\" contact
category. Historically, the Agency has made a distinction between food
uses and non-food indoor uses. For most non-food uses (wood preservation
being a notable exception) the toxicology data requirements were those
enunciated in the 1987 Antimicrobial Data Call-In (AMDCI). Specifically,
the standard AMDCI tier 1 requirements for those uses have been exposure
data plus acute toxicity data, mutagenic data, and developmental
toxicity (one species), and one 90-day subchronic performed using the
route of most likely exposure (In the case of PTAP the principal route
of exposure was dermal.) Food contact uses typically required additional
data including developmental toxicity in a second species, reproductive
toxicity, chronic toxicity, and oncogenicity. This distinction between
these two basic categories of use and the data required to support those
uses have continued until very recently. In point of fact, the
distinction was apparent in the \"error only\" drafts that were provided
to Clariant for comment in May 2005. See, for example, the data
requirements table on page 2 of the RED Toxicology Chapter dated May 21,
2005. Requirements for a developmental toxicity study in a second
species, a reproduction study, chronic toxicity and oncogenicity data
are all data requirements that typically apply only to food contact or
direct food uses.

The July 12, 2005 draft Dietary Exposure Assessments indicates that
general agricultural premise use \"would be an indirect food use\",
which could require additional data including "livestock and poultry
metabolism studies, analytical methods for livestock and poultry tissues
and residues for livestock and poultry. (As it typically appears on most
labels these general agricultural premise uses involve application of
PTAP to hard interior surfaces of barns and poultry houses followed by
potable water rinses or soap/detergent scrubbing.) It is suggested that
such uses could represent an indirect food use premised on an assumption
that residues could remain on the hard surface following rinsing or
scrubbing and that an animal in the barn cribbing on the wood might
consume that residue, which could eventually find its way into food;
however, the argument is hypothetical at best. Historically both FDA and
EPA have viewed these as non-food uses.

End-use registrations for phenolic compounds typically contain two or
three different phenolic compounds formulated together, as you have
probably noted in reviewing the labels. These combinations often include
PTAP combined with ortho-benzyl-para-chlorophenol (BCP) and/or
ortho-phenylphenol (OPP). In this particular instance the issue of how
to handle uses such as the agricultural premises was addressed in the
BCP RED. The RED required a number of changes to the label directions
\"for farm premises to permit their classification as non-food use
products.\" The label changes required to enable EPA to classify these
uses of BCP as non-food uses have already been made for many of the
end-use PTAP products when new labels were submitted to comply with the
BCP RED. Clariant believes that these changes are appropriate in this
instance also, and recommends adoption of these in lieu of classifying
such uses as food contact uses. To the extent that the Agency believes
that further changes in the labeling may be necessary, Clariant would be
willing to discuss such further modifications.

As you know, the issues related to so-called indirect food uses apply to
many active ingredients. The Biocides Panel of the American Chemistry
Council has been carrying on a dialogue with AD trying to resolve these
issues and the data requirements. Clariant is a member of that Panel,
and, along with the other Panel members, it is committed to developing
whatever data may eventually be required to support the continued
registration of these uses. This includes confirmatory exposure data if
required. Clariant believes further that imposition of these data
requirements on PTAP without similarly imposing them on all active
ingredients registered for the same uses would create an unfair playing
field. If appropriate, these data requirements can be included in the
Part 158 Subpart W when the regulations are finalized. At that point in
time, the Agency may choose to issue a DCI requesting these data from
all registrants. Until then, however, it is appropriate for EPA to be
consistent in how it handles similar compounds and uses.

Sincerely,

E. David Lewis

for, Clariant Corporation

EDL/d