**APERC Comments on 59th Report of the**

**Interagency Testing Committee**

**Docket ID Number EPA-HQ-OPPT-2006-0961**

**FR Vol. 72, No. 13, January 22, 2007**

The 59^th^ Report of the Interagency Testing Committee (ITC) to the EPA
Administrator (FR Vol. 72, No. 13, January 22, 2007) states that Phenol,
4-(1,1-dimethylethyl) (CAS 98-54-4) also known as
*para-tert*-butylphenol (*pt*BP) was removed from the TSCA Section 4(3)
Priority Testing List (PTL) based on the submission of a reproductive
effects study on this compound conducted in rats. The Report also states
that Phenol, 4-nonyl-, branched (CAS 84852-15-3) also known as
nonylphenol (NP) and Phenol, 4-(1,1,3,3-tetramethylbutyl) (CAS 140-66-9)
also known as octylphenol (OP) will remain on the PTL to determine if
existing fish reproductive effects data are sufficient to meet the ITC's
data needs as well as to determine if these two compounds should be
tested for avian reproductive effects. Additionally, the Report notes
the ITC's interest in reviewing the Safer Detergent Stewardship
Initiative, which has been proposed by the EPA Design for Environment
Program. Following are the Alkylphenols & Ethoxylates Research Council's
(APERC's) comments on the ITC's decisions and data interests regarding
the above mentioned alkylphenol compounds.

**I. Support Removal of Phenol, 4-(1,1-dimethylethyl) from the PTL**

APERC supports the ITC's removal of Phenol, 4-(1,1-dimethylethyl), more
commonly referred to as *para-tert*-butylphenol (*pt*BP), from the TSCA
Section 4(3) Priority Testing List based on the submission of a
reproductive effects study on this compound conducted in rats. The study
was conducted according to Good Laboratory Practices using a protocol
consistent with OECD Method 422, a two-generation rat study that
measures reproductive endpoints, and the delisting of this compound is
well founded. No adverse effects on reproduction were found in the
absence of maternal toxicity in this study and the No Observed Effect
Level (NOEL) for *pt*BP was determined to be 800 ppm (dietary).[^1]

**II. Existing Fish Reproductive Effects Studies Should Be Sufficient to
Address ITC's Data Interests**

EPA's Water Quality Criteria (WQC) for NP are based on a comprehensive
review of the available literature related to the aquatic toxicity of
this compound.[^2] In addition, studies used in the development of WQC
were reviewed to ensure that they meet data acceptability requirements
outlined by EPA.[^3] The chronic toxicity studies used in deriving the
NP WQC included the assessment of effects on reproduction endpoints in
fish and other aquatic organisms. Two life cycle studies on NP by Yokoto
*et al.*, 2001[^4] and Schwaiger *et al.*, 2002[^5] are cited and
considered in the NP WQC document. Also considered in the NP WQC are
early life-stage studies with embryos and fry of rainbow trout
(*Oncorhynchus mykiss*) by Brooke *et al*. (1993)[^6] and fathead minnow
(*Pimephales promelas*) by Ward and Boeri, 1991.[^7] Also included in
the WQC document is a one-year flow-through exposure during the
embryonic, larval and juvenile stages in juvenile rainbow trout
(*Oncorhynchus mykiss*) by Ackermann *et al.,* 2002[^8] that measured
endpoints of survival, hatch rate, weight and sex ratio and found no
effects up to measured concentrations of 10.17 µg/L for any endpoint.

Staples *et al*., 2004[^9] provides another useful weight of evidence
review of the chronic effects of NP in aquatic species. As in the NP WQC
document, these authors also found that reproductive effects in fish and
aquatic species are not as sensitive as other chronic endpoints.

Van Miller and Staples[^10] published a "Review of the Potential
Environmental and Human Health-Related Hazards and Risks from Long-Term
Exposure to p-tert-Octylphenol" in 2005, which included a comprehensive
review of the chronic effects, including reproductive and developmental,
for this compound in fish and other aquatic species.

These existing reviews and chronic and reproductive effects studies
should be sufficient to address the ITC's interest in reproductive
effects of NP and OP in fish.

**III. Use and Exposure of NP and OP Do Not Warrant Avian Reproductive
Effects Testing**

NP and OP are not used in applications that would result in any
significant exposure to birds; they are not used in pesticide or
fertilizer products that are dispersed directly into the terrestrial or
aquatic environment. Therefore avian reproductive effects testing does
not seem to be warranted for these two compounds. Rattner *et al.*
(2004) concluded that findings of their study, which monitored
contaminants in the eggs from oprey nests in Chesapeake Bay regions of
concern, did not clearly and completely resolve the question of whether
contaminants are affecting osprey reproduction.[^11] NP and OP were
among the numerous analytes tested. Since NP was detected in the eggs
but with the exception of a few of the samples levels were not
quantifiable, these compounds do not appear to warrant further concern
regarding avian reproductive toxicity. Since OP was not detected in any
of the egg samples in this study, it clearly does not warrant any
additional avian testing.

**IV. Amphibian Studies**

The 59^th^ ITC Report notes that there are two amphibian toxicity
studies available for OP, which may be sufficient to meet the ITC's
amphibian toxicity data needs for both NP and OP. Since APERC's last
correspondence with the ITC, two additional amphibian studies have been
identified.

An amphibian study on NP in bullfrog tadpoles (*Rana catesbetana*) was
recently published by Christensen *et al.* (2005).[^12] However, based
on the authors' own cautions the study was determined to be not valid.
The test substance did not dissolve homogeneously in the water column,
even with the presence of methanol solvent and in some cases NP
concentrations resulted in the formation of an oily residue on the
surface of the water. This could result in varying degrees of exposure
to the tadpoles and may have resulted in physical/chemical effects such
as smothering the tadpoles. The author also cautioned that the highest
tested concentration of NP, which affected tail resorption and the rate
of metamorphosis, is generally greater than what is found in the
environment. Also, the author cites his own unpublished data on NP that
determined a 24 hour LC50 \> 3.43 mg/L in Bullfrog tadpoles (*Rana
catesbetana)* and for the Red-legged frog (*Rana aurora*) determined a
24 hour LC50 of 310 ug/L and a 48 hour LC50 of 250 µg/L, which indicate
that the effect levels found in this study occurred at concentrations
(936 µg/L) known to be in the lethal range.

Another recently published study by Hogan *et al.* (2006)[^13] assessed
the toxicity of OP using a 2 week LC50 assay in the Northern Leopard
frog (*Ranid pipiens*) and the Wood frog (*Ranid sylvatica*). The LC50
for OP was reported as 1.36 - 1.42 µM in stage 26 tadpoles. The authors
report that OP was detected in water at concentrations of up to 13 µg/L
(\~63 nM) in an estruary in the UK but note that concentrations of
approximately 1-10 µg/L (\~ 5-50 nM) are more common.

Results from a statistical analysis of OP concentrations in US surface
waters, which included two large nationwide monitoring studies and 17
additional investigations conducted between 1995 and 2005, are more
relevant to the ITC's purposes. Based on the frequency of detection in
surface waters, 67% of all alkylphenol related analytes were below their
detection limits. In those samples were OP was detected, the average OP
concentration was found to be 0.46 µg/L (\~2.3 nM) and the maximum
concentration for OP was 1.10µg/L (\~ 5nM).[^14]

**V. EPA's Safer Detergent Stewardship Initiative Not Relevant to ITC
Activities**

The ITC is likely already aware that EPA's Design for Environment (DfE)
office proposed a program called the Safer Detergent Stewardship
Initiative (SDSI) that encourages companies to deselect nonylphenol
ethoxylates (NPEs) as ingredients in detergents.[^15] According to EPA,
SDSI is intended to reduce the amount of NPE surfactants and NP in
streams and "assist in attainment of the Aquatic Life Criteria for
nonylphenol." Since concentrations of NP found in US surface waters
are - with only a few exceptions - already below the final NP WQC^14^
APERC believes that a national program, even one that is voluntary,
promoting deselection of NPEs is not warranted. Instead, APERC advocates
that local risk management mechanisms should be used to manage the
infrequent situations where exceedances might occur. Since SDSI is not
based on scientific risk assessment, it should not influence the ITC's
judgment regarding the need for additional studies.

[^1]: Charles Rivers Laboratories, Edinburgh, Scotland, Final Report:
    p-tert-butylphenol Two Generation Reproduction Study in Rats. Study
    No. 493595. Report No. 24804. Unpublished Report sponsored by SASOL
    GmbH (Germany) and SI Group-Switzerland GmbH (Formerly Schenectady
    Pratteln GmbH, Switzerland), February 2006.

[^2]: US EPA. (2005, December). Final NP WQC document
    (EPA-822-R-05-055).
    http://www.epa.gov/waterscience/criteria/nonylphenol/.

[^3]: Stephen, C.E. *et al*. (1985). Guidelines for Deriving Numerical
    National Water Quality Criteria for the Protection of Aquatic
    Organisms and Their Uses.
    <http://www.epa.gove/waterscience/criteria/85guidelines.pdf>.

[^4]: Yokota, H., Seki, M., Maeda, M., Oshima, Y., Tadokoro, H., Honjo,
    T., and Kobayshi, K. (2001). Life-cycle Toxicity of 4-nonylphenol to
    Medaka (*Oryzias latipes*). Environ. Toxicol. Chem., 20, 2552-2560.

[^5]: Schwaiger, J., Mallow, U., Ferling, H., Knoerr, S., Braunbeck, T.,
    Kalbfus, W., and Negele, R.D. (2002). How estrogenic is nonylphenol:
    A transgenerational studying using rainbow trout (Oncorhynchus
    mykiss) as a test organism. Aquat. Toxicol., 59, 177-189.

[^6]: Brooke, L.T. (1993a). Acute and chronic toxicity of nonylphenol to
    ten species of aquatic organisms. Report to US EPA for Work
    Assignment No. 02 of Contract No. 68-C1-0034. Lake Superior Research
    Institute, University of Wisconsin- Superior, Superior, WI. 30 pp.
    Amended 18 October 2005, 34 pp.

[^7]: Ward, T.J., and Boeri, R.L. (1991). Early life stage toxicity of
    nonylphenol to the fathead minnow, Pimephales promelas. Study Number
    8979 CMA. EnviroSystems, Hampton, NH. 59 pp.

[^8]: Ackermann, G.E., Schwaiger, J., Negele, R.D., *et al*. (2002).
    Effects of long-term nonylphenol exposure on gonadal development and
    biomarkers of estrogenicity in juvenile rainbow trout (*Oncorhynchus
    mykiss*). Aquatic Toxicol, 60, 203-21.

[^9]: Staples, C., Mihaich, E., Carbone, J., Woodburn, K., and Klecka,
    G. (2004). A Weight of Evidence Analysis of the Chronic Exotoxicity
    of Nonylphenol Ethoxylates, Nonylphenol Ether Carboxylates and
    Nonylphenol, Human and Ecological Risk Assessments, 10, 999-1017.

[^10]: Van Miller, J., and Staples, C. (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, 15, 17.

[^11]: Rattner, B.A., McGowan P.C., Golden, N.H., Hatfield, J.S.,
    Toschik, P.C., Lukei, R.F. Jr., Hale, C. Schmitz-Alfonzo, I., and
    Rice, C.P. (2004). Contaminant Exposure and Reproductive Success of
    Ospreys (*Pandion haliaetus*) Nesting in Chesapeake Bay Regions of
    Concern. Arch. Environ. Contam. Toxicol., 47, 126-140.

[^12]: Christensen, *et al.* (2005). Effects of Nonylphenol on Rates of
    Tail Respoption and Metamorphosis in Rana catesbeiana tadpoles.
    Journal of Toxicology and Environmental Health Part A-Current
    Issues, 68, 557-572.

[^13]: Hogan, N.S., Lean, D.R.S., and Trudeau, V.L. (2006). Exposures to
    estradiol, ethinylestradiol and octylphenol affects survival and
    growth of Rana pipiens and Rana sylvatica tadpoles. Journal of
    Toxicology and Environmental Health-Part A-Current Issues, 69,
    1555-1569.

[^14]: Klečka, G. *et al.* (2007). Exposure Analysis of C8- and
    C9-Alkylphenol, Alkylphenol Ethoxylates, and their Metabolites in
    Surface Water Systems within the United States. Water Environment
    Research. (In press)

[^15]: EPA Design for Environment Program. (2006). Safer Detergent
    Stewardship Initiative.
    <http://www.epa.gov/dfe/pubs/projects/formulat/sdsi.htm>.