![](media/image1.wmf)

Ben Chambliss February 13, 2004

Office of Pesticide Programs (7504C)

U.S. Environmental Protection Agency

Crystal Mall 2, 3^rd^ Floor

1921 Jefferson Davis Highway

Arlington, VA 22202

Subject: Preliminary Risk Assessment for the Reregistration Eligibility
Decision on Zinc OMADINE.

Dear Mr. Chambliss,

Following are our error correction comments to the Zinc OMADINE
Preliminary Risk Assessment.

While the agency evaluators have done a commendable job in putting
together this Preliminary Risk Assessment after an extensive review of
most of the Zinc OMADINE data submissions, Arch is very concerned that
agency\'s environmental risk assessment uses unrealistic PEC values
(Agency calculated PEC of 21.66 ppb vs. Arch calculated PEC of 0.12 ppb)
using an inadequate computer model.   Since a realistic PEC is crucial
to conducting a realistic risk assessment, it is imperative that all
efforts be exerted to calculate a PEC which is well supported by
experimental evidence and established by comprehensive modeling
programs. We believe that the PEC calculated by EPA is not based on the
best available and full body of scientific evidence, and that the
assessments of risk based on that PEC is therefore not realistic. We
believe further that it would not be fair to use the risk assessment in
its current form to determine reregistration status of zinc OMADINE. We
have provided our own PEC calculations and those done for and approved
by other regulatory agencies.^ ^

 

We look forward to working with the Agency on this matter.

If you have further questions, please contact me.

Sincerely,

Garrett B. Schifilliti

Manager, Regulatory Services

\(203\) 229-3510

\(203\) 229-3288 Fax

<gbschifilliti@archchemicals.com>

1.  **CBI Claims:**

# **None**

2.  **Additional Data in Development:**

> a\. Zinc Pyrithione: Terrestrial Plant Toxicity, Tier II Seedling
> Emergence using Rice, Oryzea oryza sativa, Guideline: OPPTS 850.4225
>
> b\. Zinc Pyrithione: Terrestrial Plant Toxicity, Tier II Vegetative
> Vigor using Rice, Oryzea oryza sative, Guideline: OPPTS 850.4250
>
> c\. Zinc Pyrithione: Influence on Growth and Growth Rate of the Marine
> Diatom, Skeletonema costatum, Guideline: 123-2

d.  Sediment Toxicity Test with Zinc Pyrithione and, the Freshwater
    Amphipod, Hyalella azteca, Guideline OPPTS 850.1735.

e.  Sediment Toxicity Test with Zinc Pyrithione and the Marine Amphipod,
    Leptocheirus plumulosu, Guideline OPPTS 850.1735.

f.  Assessment of Potential Inhalation and Dermal Exposure to Zinc
    Pyrithione During Outdoor Painting of Ship Hulls with Intersmooth
    360 or 460 Ecoloflex SPC Antifouling, Guidelines: 875.1100 &
    875.1300.

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3.  **Error Corrections:**

> (We will point out errors by Heading, page number, and paragraph and
> will indicate in bold the correction to that section. Discussion of
> the correction will follow, if appropriate, i.e., if not just a
> "typo". )

A. Executive Summary, page 1, 2nd paragraph reads "...for use in
dandruff shampoos."

> Should read "...for use in **Anti**-dandruff shampoos."
>
> Further, the following statement would provide a complete description
> of its use in this FDA approved application: "**It is considered safe
> ands effective (considered both GRAS and GRAE and Category I by USFDA)
> for the treatment of dandruff and seborrheic dermatitis with a history
> of over 40 years of human use.**"
>
> B. Hazard, page 1, 2nd paragraph, 1st sentence states: "The oral LD 50
> range from 460-630 mg/kg"
>
> **Should read**: **The combined oral LD50 in rats is 269 mg/kg ranging
> from 221 -- 302 mg/kg.**
>
> C. Hazard, page 1, 2nd paragraph, 2nd sentence: "Acute Toxicity by the
> inhalation route is also relatively low (0.61 mg/L; Toxicity Category
> III)."

**Should read**: **"...relatively low (\>0.61 mg/L;..." needs insertion
of a "greater than" symbol.\
**\
Comment: Acute Inhalation LC50 for zinc pyrithione a.i. 100% powder is
\>0.61 mg/L (only 1 out of 10 deaths at 0.24 mg/L and 3 out of 10 deaths
at 0.61 mg/L, but in the interest in saving animals no further doses
were tested and the Toxicity Category III classification for inhalation
was accepted) and recent testing of the 48% zinc OMADINE aqueous
dispersion the acute inhalation LC50 was 5.08 mg/L for the dispersion
following a 4-hr. nose-only exposure.

> D. Hazard, page 1, last paragraph, last sentence, "Developmental
> toxicity using the oral route of administration show zinc OMADINE to
> produce significant developmental effects which are greater in
> severity (of developmental toxicity) at doses of 1.5 and 3.0 mg/kg/day
> than toxicity observed in maternal animals at these same dose levels".
>
> **Should read**: **"Developmental toxicity studies using the oral
> route, produced developmental toxicity at doses that produced
> significant maternal toxicity during sensitive times of
> development."**
>
> Comment: Based on the Data Evaluation Report (DER); EPA Reviewer John
> E. Whalen in 1996, "A decrease in body weight gain (p≤0.01) during the
> dosing period for the mid (1.5 mg/kg/day) and high-dosed (3.0
> mg/kg/day) (41% and 99%, respectively) cannot be considered to be
> biologically significant since the absolute body weight changes were
> only \~4% and \~6%\..."
>
> The reference of 4 and 6% relates to the changes in absolute body
> weight over the entire gestation period days 0-29 and the 41% and 99%
> decrease in body weight gains were observed over gestation days 0-19,
> dosing ceased on gestation day 19 and yes there was a rebound in body
> weight after cessation of treatment. In addition, the DER stated that
> there was no corresponding decrease in food consumption. However, in
> the same DER report of the zinc OMADINE Developmental Toxicity Study
> in the Rabbit Table 3.0 Food Consumption shows a statistically
> significant decrease in food consumption for gestation days 6-19. Body
> weight gains from gestation days 6-19 achieved statistical
> significance of p ≤0.01 that corresponded precisely to a decrease in
> food consumption of 16% (mid-dose, 1.5 mg/kg/day) and 23% (high-dose,
> 3.0 mg/kg/day). Therefore it should be concluded that severe maternal
> toxicity was observed in the mid and high-dosed animals during a very
> sensitive time for development. The NOEL for maternal and
> developmental effects was 0.5 mg/kg/day based on severe maternal
> toxicity at 1.5 and 3.0 mg/kg/day.
>
> E. Hazard, page 2, 1st paragraph, 2nd & 3rd sentences, "Intravenous
> administration of 5mg/kg zinc OMADINE to female Yorkshire pigs
> produced cholinergic effects lasting for 30-60 minutes post-dose (HED
> document 003933). Increased salivation was reported immediately after
> dosing in the rat developmental toxicity study at a dose of 3
> mg/kg/day (MRID#4287904)".
>
> Should read: "Intravenous administration of 5mg/kg zinc OMADINE to
> female Yorkshire pigs produced **symptoms similar to** cholinergic
> effects lasting for 30-60 minutes post-dose. Increased salivation was
> reported immediately after dosing in the rat developmental toxicity
> study at a dose of 3 mg/kg/day (MRID#4287904) (**possibly due to the
> fact that zinc pyrithione causes significant irritation to mucosal
> membranes and it is not uncommon to observe increased salivation
> following oral administration from such compounds).**"
>
> [Comment:]{.underline} Another explanation for the observation of an
> increase in salivation could be the fact that zinc OMADINE is
> severely irritating to mucosal membranes and it is not uncommon to
> observe increased salivation following oral gavage of such compounds.
> Reference to hindlimb weakness in the same paragraph seems suggestive
> that such an effect possibly is indicative of cholinergic effects. We
> would like to reiterate the fact that hindlimb weakness has only been
> observed in rats and rabbits and has never been observed in dogs or
> primates when tested at much higher concentrations for up to one year
> of exposure.
>
> F. Toxicity Endpoints, page 2, 1st sentence reads "...to assessment
> potential risks..."
>
> Should read "...to **assess** potential risks..."

G.  Water Exposure & Risk, page 4, 1^st^ sentence "AD has considered the
    registered uses of zinc OMADINE and the available data on
    persistence and mobility"

> Should read: "AD has considered the registered uses of zinc OMADINE
> and **used** the available data **on only abiotic hydrolysis conducted
> in the dark with sterile water**"
>
> Comment: Regarding mobility and potential impact on surface and ground
> water resources, it does not appear that the Agency has considered the
> available data on mobility (Abs/Des, Soil Column Leaching MRID#'s
> 44010402 & 45565201). Zinc OMADINE is classified as immobile in
> sediments and soils and is not likely to get into ground water. Since
> recreational boating in seawater will not impact drinking water, only
> the implication of surface freshwater should be considered as it
> pertains to untreated drinking water. Arch disagrees with the
> statements made in the Water Exposure and risk section and further
> comments follow.

H.  Water Exposure and Risk, page 4, 3rd sentence "...PEC of 21.66 ppb
    zinc OMADINE was estimated using the Luttik Johnson model".

> Should read "....PEC of 21.66 ppb zinc OMADINE was estimated by using
> the Luttik Johnson model **that used a leach rate input of 12.5
> μg/cm2/day and abiotic hydrolysis (conducted in the dark with sterile
> water) half life of 123 days**. **Other models that allow use of
> relevant environmental parameters provide a PEC value of 0.12 ppb
> (EXAMS). Luttik-Johnson model using a composite degradation rate from
> multiple degradation pathways gives a PEC value of 0.16 ppb "**
>
> []{.mark}
>
> Comment: Arch strongly disagrees with agency's approach to calculation
> of the predicted environmental concentration (PEC) of 21.66 ppb using
> the Luttik Johnson model. It is clear from the PEC calculation that
> the agency has not considered all available data on degradation and
> persistence. For assessing persistence, only hydrolysis in dark,
> sterile fresh water was considered by the agency. Accepted guideline
> studies on photolysis and aerobic and anaerobic metabolism (MRIDs
> 44011501, 44010401, 44850002) show that zinc pyrithione has a short
> half-life in the environment and these studies are more relevant to
> environmental fate than abiotic hydrolysis. (On page 11 of the RED
> document, the Agency does take these studies into account and states
> that zinc OMADINE has a "fairly short half-life, ranging from hours
> to days"). Because incorrect parameters were used in the modeling, the
> resulting PEC of 21.66 ppb is ten-fold higher than the highest
> measured concentration reported for a persistent co-biocide (the
> highest measured concentrations are 1.7 -- 2.1 μg/L for Irgarol,
> MRID#46101101). Since zinc pyrithone is short-lived, logic dictates
> that its measured concentrations will be even lower. Although there
> have been attempts to measure zinc OMADINE in the environment, it has
> not been detected yet (detection limit = 0.02 μg/L; MRID#46101101).
>
> The Luttik-Johnson model used is inadequate for generating
> environmentally relevant PECs. Refinement of modeling by the Agency is
> suggested as other International Government Agencies are using models
> (MAM-PEC, EXAMS, REMA) that are better predictors of realistic PECs.
> Some of the shortcomings of the Luttik-Johnson model are:

a)  No hydrodynamic water exchange component

b)  No consideration for effects of temp, salinity, pH

c)  Only one degradation pathway is input

> The key parameters that impact the PEC are the leach rate and the
> degradation rate. Arch has evaluated all the widely used models for
> risk assessment for antifoulant biocides and submitted a comprehensive
> document for agency to review (MRID 46101101). That document has not
> been reviewed for the RED. (see Calculation of Predicted Environmental
> Concentrations of Zinc Pyrithione in Antifouling Applications (MRID
> 46101101). The input value of 12.5 μg/cm2/day for the leach rate in
> the Luttik-Johnson model is an abnormal value based on one paint that
> is not a commercial paint. Subsequent MRID submissions show actual
> data on commercial paints (see range in following Table 1). MAM-PEC
> which is a widely recognized model used for risk assessment of
> antifoulant paints uses 2.5 μg/cm2/day for different biocides in
> assessing risk. The 2.5 μg/cm2/day is based on mass balance and
> coating lifetime calculations. The leach rate of 12.5 μg/cm2/day would
> mean a coating lifetime of 20% of that guaranteed by the paint company
> (normally 5 yrs) -- and therefore an impossibly high leach rate. The
> risks are directly proportional to the environmental concentrations,
> which are in turn directly proportional to biocide release rates and
> inversely proportional to biocide degradation and environmental
> transport rates.
>
> Also the PEC derived from Luttik-Johnson model should not be used for
> comparison to drinking water level of comparison (DWLOC) as the model
> only relates to a marina or a harbor. Given the fast degradation
> through multiple pathways, it is unlikely that the PEC of 21.66 ppb
> could be a valid number for DWLOC. It is not realistic to assume that
> water from the marina can be used as potable water without treatment.
>
> Because of the limitations of the Luttik-Johnson model, European
> regulatory bodies have used more appropriate models like MAM-PEC,
> EXAMS or REMA which all give lower PEC values for zinc OMADINE in a
> marine paint application (\<0.1 ppb) 
>
> With a realistic PEC, which should be 100-1000 times lower, there is
> no risk.
>
> The leach rate of 12.5 μg/cm2/day is an impossibly high leach rate for
> commercial AF paints leading to an improbable PEC of 21.66 ppb and it
> is simply incorrect to call this a "conservative" leach rate or call
> the PEC a "conservative" PEC.
>
> The use of refined PEC values was discussed in July 2003 at a meeting
> between Arch and EPA personnel. At that meeting, EPA's Antimicrobial
> Division environmental and regulatory reviewers suggested that Arch
> submit a discussion, explanation and rationale for the refined PEC
> values and a justification for not relying on the ASTM release rate
> and for not using the present PEC values in the assessment of zinc
> pyrithione. Arch believes that this report (MRID 46101101) fully
> satisfies that request and provides a definitive basis for use of a
> redefined PEC value.
>
> Additionally, in an outdoor Microcosm Study (2003, MRID 45876501) it
> was shown that ZPT degraded rapidly with a half-life of 36 minutes.
> This is similar to the half-life seen in photolysis study (half-life
> of 13 -17 minutes at 250C). At 4hr., no ZPT was detected in the water
> (det. limit = 0.02 ppb). In the sediment, ZPT reached a maximum of
> 0.46% at day 1 and was not detected at and after day 7. The amount of
> bound residues was 5.6 -6.9% at the end of the study. In a dark
> microcosm study, ZPT decreased to 4% of the starting dose at day 1 and
> was not detectable by day 7. The half-life in this dark study is
> estimated to be 20 hr. In the sediment, ZPT was not detectable at day
> 7. The only significant degradation product after 30 days was
> 2-pyridine sulfonic acid accounting for 69-76% of the total
> radioactivity. Amount of bound residues ranged from 5-7% of the total
> radioactivity in the end of the study. This outdoor study simulating
> environmental conditions provides multiple environmental degradation
> pathways that show that zinc OMADINE rapidly degrades in the
> environment.
>
> Whereas the Agency assumed a release rate of 12.5 μg/cm2/day, Arch
> used a value of 2.5 μg/cm2/day which is in the range of leach rates
> obtained from commercially registered paint leach rate studies. The
> Agency release rate appears to be biased by the ASTM release rate of
> an early, experimental paint that was never commercialized and is not
> representative of commercial antifouling paints containing zinc
> pyrithione.
>
> For the degradation rate of zinc pyrithione, the Agency used a
> half-life of 123 days, which is extrapolated from a 30 day hydrolysis
> study carried out in sterile, synthetic seawater in the absence of
> light. The corresponding rate constant was entered into the
> Luttik-Johnson emission model to obtain the PEC. In comparison, Arch
> input rate data from several environmental fate studies -- hydrolysis,
> photolysis, aerobic and anaerobic aquatic metabolism, die-away,
> adsorption/desorption -- into chemical fate models capable of
> integrating multiple degradation processes (including the
> Luttik-Johnson model) to give an overall degradation rate for a
> particular environmental scenario (see **Table 2**). Because
> pyrithione undergoes biolysis, photolysis and sediment-catalyzed
> degradations, it is necessary to use multi-fate exposure models such
> as EXAMS and MAM-PEC. EXAMS, with its extensive photolysis algorithms,
> was found to be the most suitable modeling program for zinc
> pyrithione. EXAMS calculates a half-life of \<12 hours for the EPA
> scenario. Arch, using the same environmental scenario as the agency
> uses, but with more current data on release rates and degradation
> rates as input in different exposure models, **calculated a PEC of
> 0.12ppb for zinc pyrithione vs. the agency value of 21.66 ppb.** When
> appropriate release rates and degradation rates are input into the
> Luttik-Johnson model, it gives a PEC of **0.16** **ppb , which is
> orders of magnitude lower than the 21.66 ppb.**
>
> Arch requests that RASSB of the AD refine the PEC calculations using
> models that allow incorporation of relevant multiple environmental
> parameters (e.g. EXAMS, MAM-PEC). Arch modelers have done this
> exercise and the data are presented below (**Table 3**) for
> consideration.
>
> Validation of exposure modeling may only be done by comparison of PEC
> values with measured environmental concentrations. Despite some
> monitoring activity, zinc pyrithione has not been detected in the
> environment. For this reason, methods used to calculate the PEC of
> zinc pyrithione cannot be corroborated by measured concentrations. As
> an alternative, Arch has applied the zinc pyrithione modeling approach
> to calculate the PEC of a widely used, persistent antifouling biocide
> Irgaol), for which extensive monitoring data is available. Using
> MAM-PEC and EXAMS, PEC values for Irgarol 1051 were calculated to be
> 1.3 and 3.4 μg/L, respectively. These are in agreement with the
> highest measured Irgarol concentrations of 2.1 μg/L (Danish marinas).
> We are therefore confident that our modeling approach provides
> realistic PEC values.
>
> The Agency PEC value of 21.66 μg/L for zinc pyrithione is 10-fold
> higher than the highest measured environmental concentration (2.1
> μg/L) of Irgarol in a real worst-case marina. It is difficult to
> rationalize a scenario where the concentration of a biocide with a
> short half-life could exceed the concentration of a persistent biocide
> having comparable market share. Arch's method not only generates PEC
> values that are more consistent with the relative persistence of
> Irgarol and pyrithione, but it is also consistent with measured
> environmental concentrations of Irgarol.
>
> Therefore, Arch requests the Agency to refine or redefine its modeling
> approach and PEC calculations for zinc pyrithione recognizing that

-   in the absence of validated laboratory methods (since the ASTM leach
    rate method over-estimates the leach rates), release rates can be
    calculated from mass balance/service life data for current,
    commercial paints

-   biocides like other chemicals undergo abiotic and biotic
    transformations in the environment - biodegradation and photolysis
    data from guideline studies that have been reviewed and accepted
    should be considered.

-   more sophisticated multi-fate models such as EXAMS, MAM-PEC or REMA
    are more appropriate for modeling biocides that degrade by multiple
    pathways.

-   calculated PEC values should be compared with measured environmental
    concentrations as a reality check, using a surrogate antifoulant if
    necessary. If the PEC values are significantly higher than actual
    environmental concentrations, it should be realized that there is a
    strong bias in the modeling approach and the resulting PEC should
    not be used to carry out risk assessments of either persistent or
    non-persistent antifouling biocides.

> The significance of using the appropriate leach rate and appropriate
> degradation rate are highlighted in the tables below.

###  Significance of Leach rate data

> **Table 1. ASTM laboratory leach rates from paints formulated with
> zinc pyrithione**
>
> **[(from MRID 45821001, Table VII, p. 56)]{.underline}**

+--------------------+-------------+------------+-----------+---------+
| Paint              | Leach Rate  | Period     | \% ZnPT   | MRID    |
|                    |             |            |           |         |
|                    | (           |            |           |         |
|                    | μg/cm2/day) |            |           |         |
+--------------------+-------------+------------+-----------+---------+
| Ecoloflex BEA369   | 6.5 ± 0.9   | days 21-49 | 3.8       | 4       |
|                    |             |            |           | 4877104 |
| Self-polishing     | 5.1         | day 49     |           |         |
| cuprous oxide      |             |            |           |         |
| based large vessel |             |            |           |         |
+--------------------+-------------+------------+-----------+---------+
| Ecoloflex BEA468   | 5.4 ± 0.8   | days 21-49 | 3.8       | 4       |
|                    |             |            |           | 4877105 |
| Self-polishing     | 3.9         | day 49     |           |         |
| cuprous oxide      |             |            |           |         |
| based large vessel |             |            |           |         |
+--------------------+-------------+------------+-----------+---------+
| Ecoloflex BEA469 - | 4.3 ± 0.7   | days 21-49 | 3.8       | 4       |
| Self-polishing     |             |            |           | 4877106 |
| cuprous oxide      | 3.2         | day 49     |           |         |
| based large vessel |             |            |           |         |
+--------------------+-------------+------------+-----------+---------+
| Ecoloflex BEA368   | 7.2 ± 1.1   | days 21-49 | 3.8       | 4       |
|                    |             |            |           | 4877103 |
| Self-polishing     | 5.9         | day 49     |           |         |
| cuprous oxide      |             |            |           |         |
| based paint for    |             |            |           |         |
| large vessels      |             |            |           |         |
+--------------------+-------------+------------+-----------+---------+
| Ablative zinc      | 7.2 ± 1.1   | days 21-45 | 2.4       | 4       |
| oxide based        |             |            |           | 3864603 |
| resin/wood rosin   | 5.4         | day 45     |           |         |
| paint for aluminum |             |            |           |         |
| hulls              |             |            |           |         |
+--------------------+-------------+------------+-----------+---------+
| Long-life cuprous  | 2.3 ± 0.5   | days 21-45 | 5.9       | 4       |
| oxide based paint, |             |            |           | 3864603 |
| Vinyl Red naval    | 1.9         | day 45     |           |         |
| formula 121        |             |            |           |         |
+--------------------+-------------+------------+-----------+---------+
| E. Paint SN-1      | 1.24 ± 0.23 | days 22-49 | 2         | 4       |
|                    |             |            |           | 4833310 |
| Ablative zinc      | 1.01        | day 49     |           |         |
| oxide              |             |            |           |         |
| solvent-based      |             |            |           |         |
| paint              |             |            |           |         |
+--------------------+-------------+------------+-----------+---------+
| E.Paint EP2000     | 2.02 ± 0.72 | days 22-49 | 4.7       | 4       |
|                    |             |            |           | 4833310 |
| Ablative zinc      | 1.12        | day 49     |           |         |
| oxide water-based  |             |            |           |         |
| paint              |             |            |           |         |
+--------------------+-------------+------------+-----------+---------+

## 

## Table 2. Environmental rate constants for zinc pyrithione MRID 45821001

+--------------------+---------+----------+----------+---------+------+
| Degradation        | Rate    | H        | G        | MRID    | S    |
| Pathway            | C       | alf-life | uideline |         | tatu |
|                    | onstant |          |          |         | s^a^ |
|                    |         |          |          |         |      |
|                    | day-1   |          |          |         |      |
+--------------------+---------+----------+----------+---------+------+
| Abiotic            | \       | \>90 d   | 161-1    | 4       | A    |
|                    | <0.0072 |          |          | 3864602 |      |
| Hydrolysis         |         |          |          |         |      |
+--------------------+---------+----------+----------+---------+------+
| Photolysis         | 57.0    | 13 --    | 161-2    | 4       | A    |
|                    | --76.8  | 17.5     |          | 4011501 |      |
| Indoor             |         |          | supp     |         | NR   |
|                    | 266 -   | min      | lemental | 4       |      |
| Outdoor            | 561     |          |          | 5821001 |      |
|                    |         | 1.8 --   |          |         |      |
|                    |         | 3.8 min  |          |         |      |
+--------------------+---------+----------+----------+---------+------+
| ### Biotic         | 0.17 -- | 7.2 --   | supp     | 4       | NR   |
|                    | 2.3     | 96 hr    | lemental | 5821001 |      |
| Water column       |         |          |          |         |      |
| biolysis           |         |          |          |         |      |
+--------------------+---------+----------+----------+---------+------+
| Sediment-catalyzed | 28 - 33 | 0.5 --   | 162-3    | 4       | A    |
| deg                |         | 0.6 hr   |          | 4850003 |      |
|                    |         |          | 162-3    |         | A    |
|                    |         |          |          | 4       |      |
|                    |         |          |          | 4850004 |      |
+--------------------+---------+----------+----------+---------+------+
| Sediment-sorbed    | 0.17 -  | 18 -- 96 | 162-3    | > 44    | A    |
| deg                | 0.87    | hr       |          | 8500014 |      |
|                    |         |          | 162-4    | 4850002 | A    |
+--------------------+---------+----------+----------+---------+------+
| Microcosm          | \>1.4   | \<12 hr  | supp     | #### 4  | NR   |
|                    |         |          | lemental | 5876501 |      |
| Dark-dosed         | 28      | 0.6 hr   |          |         | NR   |
|                    |         |          | supp     | > 4     |      |
| Light-dosed        |         |          | lemental | 5876501 |      |
+--------------------+---------+----------+----------+---------+------+

a\. A is accepted; NR is not reviewed

## Table 3. PECs for EPA marina scenario calculated by 4 aquatic exposure models for zinc pyrithione and Irgarol 1051 vs. monitored concentrations, MRID 45821001

+-------------+--------+------+-------+----------+-------+---------+
| Co-biocide  | Pre    |      |       |          | Monit |         |
|             | dicted |      |       |          | ored, |         |
|             | e      |      |       |          | μg/L  |         |
|             | nviron |      |       |          | conce |         |
|             | mental |      |       |          | ntrat |         |
|             | con    |      |       |          | ions, |         |
|             | centra |      |       |          | ug/L  |         |
|             | tions, |      |       |          |       |         |
|             | μg/L   |      |       |          |       |         |
+-------------+--------+------+-------+----------+-------+---------+
|             | EXAMS  | MAM  | Lu    | Tidal    | Hi    | Country |
|             |        | -PEC | ttik- |          | ghest |         |
|             |        |      | Jo    | Prism    | rep   |         |
|             |        |      | hnson |          | orted |         |
+-------------+--------+------+-------+----------+-------+---------+
| Zinc        | 0.12   | 0.11 | 0.16  | 0.099    | \<    | U.K.^a^ |
| Pyrithione  |        |      |       |          | 0.020 |         |
|             | 0.12   |      | 0.16  |          | nd    |         |
+-------------+--------+------+-------+----------+-------+---------+
|             |        |      |       |          | \<2.0 | J       |
|             |        |      |       |          | nd    | apan^b^ |
+-------------+--------+------+-------+----------+-------+---------+
|             |        |      |       |          |       |         |
+-------------+--------+------+-------+----------+-------+---------+
| Irgarol     | 3.4    | 1.3  | 3.7   | 3.7      | 2.1   | Den     |
| 1051        |        |      |       |          |       | mark^c^ |
+-------------+--------+------+-------+----------+-------+---------+
|             |        |      |       |          | 1.42  | U.K.^a^ |
+-------------+--------+------+-------+----------+-------+---------+
|             |        |      |       |          | 1.7   | Fr      |
|             |        |      |       |          |       | ance^d^ |
+-------------+--------+------+-------+----------+-------+---------+
|             |        |      |       |          | 0.64  | Fr      |
|             |        |      |       |          |       | ance^e^ |
+-------------+--------+------+-------+----------+-------+---------+

a Thomas et al, 2001; Appendix A in MRID 45821001;b Yasuba, 2000;
Morita, 2001;c Århus A., 1997;d Readman et al, 1993; e Tolosa et al,
1996

Arch has also supplied PEC values using either EXAMS or MAM-PEC to
various international regulatory bodies and registrations have been
approved for several countries. The modeling approach in Table 4 used
realistic environmental scenarios and lab leach rate data generated from
several commercial antifoulant paints and the PEC values (0.001 to 0.06
ppb) generated from such realistic scenarios are orders of magnitude
lower than 21.66 ppb.

Zinc OMADINE is now registered for antifoulant use in UK, Malta,
Ireland, Hong Kong, Australia, New Zealand, Sweden, Switzerland,
Finland, Holland, Belgium, Japan, S. Korea, and China.

**Table 4. Arch submission to other Regulatory Bodies:\
Calculated PECs (μg/L; ppb) using EXAMS or MAM-PEC**

  ------------------------- ------------------------- -------------------
  **Agency**                **Scenario**              **PEC, (μg/L;
                                                      ppb)**

  Finland -- SYKE           Spring, Summer,Fall       

                            Typical Finnish Marina    0.045

                            Typical Finnish Harbor    0.0002

                            Worst Case Harbor         0.011

                                                      

  Sweden -- KemI            June- July                0.001

                            Fiskebackskil marina      0.021, 0.061

                                                      

  Australia                 Harbor                    0.007

                            Lake Geneva               0.001

                                                      

  Switzerland               Feb, - Nov.               

                            Swiss Marina              0.027

                                                      

  Netherlands --CTB         Fiskebackskil parameters  0.06
  ------------------------- ------------------------- -------------------

> I. Residential (Non-Occupational) Exposure & Risk, page 5, 2nd bullet
> states "residential handlers that paint using a brush (antifoulant
> paint use for all boat sizes: Dermal MOE = 22-120)."
>
> **This statement should be stricken and the following should be
> considered.**
>
> Comment: Since 1994, the Health and Safety Executive (HSE) of the UK
> has gathered information on human exposure to antifouling products in
> the professional and amateur (residential; non-occupational)
> sectors...the surveys and studies were as follows:
>
> 9 surveys applying copper-based antifoulant to ships (40 exposure
> data; 1994)
>
> 5 surveys applying tin-based antifoulants to ships (20 exposure data;
> 1996)
>
> 4 surveys applying various antifoulant to ships (10 exposure data; IOM
> 1996)
>
> 8 surveys applying various antifoulant to leisure craft (9 exposure
> data; 1997-99)
>
> This information was utilized in providing exposure data for HSE to
> conduct a risk assessment that covered professional and amateur
> applicators of antifoulant paint that contained zinc OMADINE. The
> assumptions that were used were: 4% active substance in the product;
> 1% dermal penetration value; and 4% or 1% clothing penetration.
>
> Based on this assessment, HSE came up with a central tendency and
> worst case exposure for each application i.e., professional
> application with brush/roller and amateur application with
> brush/roller. The HSE uses Toxicity Exposure Ratios (TERs) which are
> analogous to USEPAs MOEs. For amateur application using a brush/roller
> the central tendency for systemic exposure (excluding inhalation) was
> 500 and for inhalation the TER was 17500. The worst case exposure for
> amateur using brush/roller for systemic exposure was TER of 6.
> However, the central tendency represents the mean exposures and is
> based on actual field data for applying antifoulant paints and may
> prove useful for the USEPA. Especially, since the USEPA has indicated
> that data was extrapolated from the PHED database and has indicated
> that the confidence in the PHED data is C and is not based on actual
> application of antifoulant paints. Reference for some of the HSE
> Surveys: Garrod, A.N.I., Guiver, R., and Rimmer, D.A. Potential
> Exposure of Amateurs (Consumers) Through Painting Wood Preservative
> and Antifoulant Preparations. Am. Occup. Hyg. Vol 44, No. 6:421-426,
> (2000)
>
> J. Residential (Non-Occupational) Exposure & Risk, page 5, last
> sentence before "Aggregate Exposure and Risk", states, "The estimated
> dermal MOE is 3,300 based on conservative assumptions, and the results
> of a study that measured concentrations of zinc OMADINE in the urine
> for 5 days following a single shampoo application.
>
> Should read, "The estimated dermal MOE is 3,300 based on conservative
> assumptions, and the results of a study that measured
> **radioactivity** **associated with metabolized zinc OMADINE** in the
> urine for 5 days following a single shampoo application **containing
> radiolabelled zinc OMADINE.**
>
> Comment: Radioactivity was measured, not the zinc OMADINE. The
> radioactivity was from metabolized zinc OMADINE.
>
> K. Aggregate Exposure & Risk, Acute, Page 5, last sentence "...acute
> PEC of 21.66 ppb":

##### Should read "...acute PEC of 0.12 ppb..."

> Comment: See discussion under "H" above.
>
> L. Aggregate Exposure & Risk, Oral, Page 6, states "The short- and
> intermediate-term oral aggregate risk for adult males and females do
> not exceed the Agency's level of concern. However, the DWLOC for
> infants/children of 17 ppb is slightly less than the PEC of 21.66 ppb,
> indicating a potential for adverse risks of concern...".

Should read "The short- and intermediate-term oral aggregate risks for
all population groups do not exceed the Agency's level of concern with a
lower PEC of 0.12 ppb."

> Comment: See discussion under "H" above.
>
> M. Aggregate Exposure & Risk, Dermal & Inhalation, Page 6, in both of
> the Dermal and Inhalation sections the author indicates that due to
> the fact that the dosing for the Dermal 90-day study were log doses
> and the MOEs exceeded the level of concern (LOC) and these MOEs were
> based on subchronic toxicity and doses were based on whole body
> exposures and a large gap between the NOEL and LOEL existed for the
> Dermal study indicated that the evaluation was very conservative.
>
> [Guidance requested:]{.underline} This verbiage suggested the need for
> shorter exposures etc. e.g. 5-day dermal study with evaluation of
> doses between 100 and 1000 mg/kg/day and the same for Inhalation
> toxicity looking at higher doses for a nose-only 5-day exposure period
> instead of a 90-day whole body subchronic exposure. We request
> verification that conducting 5-day dermal and 5-day inhalation studies
> would be useful for assessing the hazard for paints.
>
> N. Aggregate Exposure & Risk, Chronic, Page 7, 3nd sentence "However
> for infants/children, the DWLOC of 15 ppb is slightly less than the
> PEC of 21.66 ppb, indicating the potential for aggregate chronic risks
> of concern"

##### Should be stricken or modified to have no potential for concern because the acute PEC is 0.12 ppb..."

> Comment: See discussion under "H" above.
>
> O. Occupational Exposure and Risk, page 8, third bullet reads,
> "handling zinc OMADINE-containing paint products using an airless
> sprayer application method (inhalation MOEs = 4.4 and 44 with and
> without the use of a respirator as PPE, respectively, and dermal MOE =
> 74 without the use of gloves as PPE)."
>
> Should read: **"handling zinc OMADINE-containing paint products using
> an airless sprayer application method (inhalation MOEs = 44 and 4.4
> with and without the use of a dust mask as PPE, respectively, and
> dermal MOE = 74 without the use of gloves as PPE)."**
>
> Comment: For professional applicators, use of NIOSH/MSHA approved
> respirator (half or full face) commonly provide 50 to 100% reduction
> in exposures.
>
> P. Environmental Risk, Environmental Fate page 9, 3rd sentence,
> "Half-lives in buffered water were measured at 99, 120 and 123 days at
> pHs 5,7, and 9 respectively. In sea water, the half life was 96 days"
>
> Should read: "Half-lives in buffered water were **extrapolated** from
> 30 day studies to give 99, 120 and 123 days at pHs 5,7, and 9
> respectively. In sea water, the extrapolated half life was 96 days".
>
> Q. Environmental Risk, Environmental Fate, page 9, 4th sentence,
> "These half-lives indicate that zinc OMADINE can be persistent in
> water under conditions of low microbial activity."
>
> **This sentence should be omitted since it incorrectly implies that
> the degradation of zinc pyrithione is solely dependent upon microbial
> activity. Degradation also occurs by photolysis and sediment-catalyzed
> chemical reactions.**
>
> R. Environmental Risk, Environmental Fate page 9, 7th and 8th
> sentence, "In aerobic aquatic media, the half-lives of zinc OMADINE
> were 12.4 and 15 days for fresh water and sea water respectively. In
> the same media, the half-lives under anaerobic conditions are 25 and
> 13.3 hours, respectively".
>
> Should read, **"In aerobic aquatic media, degradation was biphasic
> with t½α = 30-90 min for freshwater and seawater and t½β = 4-15 days
> for seawater and 15 days for freshwater. In the same media,
> degradation under anaerobic conditions was also biphasic with t½α = 30
> min for freshwater and seawater and t½β = 25 hours for fresh water and
> 13.3-19 hours for seawater."**
>
> Comment: Data from accepted guideline studies was omitted so that
> range of half- lives is not accurate (MRID#s 44850002, 44010401). The
> half-life values given are from aerobic and anaerobic aquatic
> metabolism studies done in water/sediment at 3-ppm (MRID# 44010403).
> These studies showed degradation in two distinct phases: an initial
> rapid rate of decline, during which \~50% (aerobic) to \~80%
> (anaerobic) of the pyrithione degraded over a period of 1-2 hours,
> followed by a slower rate of decline in the sediment. Only the longer
> second phase half-lives are cited. However, the second phase
> half-lives were shown to be largely the result of the conversion of
> zinc pyrithione to copper pyrithione by reaction with copper in the
> sediment. Degradation of the sequestered copper pyrithione, which is
> soluble only to the extent of 0.1 ppm, is inhibited by its
> precipitation from solution at the high dose level.
>
> It is therefore not appropriate to use the second-phase half lives
> from these studies.
>
> Subsequent aerobic and anaerobic studies done with zinc pyrithione and
> copper pyrithione at lower concentrations have been submitted and
> accepted by the agency (MRID#s 44850002). These studies were conducted
> at a concentration of 50 ppb (this concentration was chosen to allow
> detection of pyrithione with the existing analytical methods; even
> though the expected environmental concentrations are still orders of
> magnitude lower), which is below the solubility of copper pyrithione.
> Degradation was biphasic in these studies as well; however, the second
> phase of decline was much faster. The biphasic degradation at the
> lower concentration is attributed to the high affinity of pyrithione
> for sediment. In the aerobic system, the half lives for removal of
> pyrithione from water and from sediment was 0.024 days and 4.0 days,
> respectively. In the anaerobic system, the corresponding values were
> 0.020 days and 0.79 days. For the water and sediment combined,
> dissipation times were 0.89 days for 50% and 34 days for 90% in the
> aerobic system and 0.02 days for 50% and 0.79 days for 90% in the
> aerobic system. The degradation of zinc pyrithione and copper
> pyrithione, as well as the formation and decline of the metabolites,
> is identical. Based on the more recent studies done at 50 ppb, the
> half lives for pyrithione is 1-2 hours in water and 1-4 days in
> sediment.
>
> S. Environmental Risk, page 9, 6th sentence, "Photolytic measurements
> showed that zinc OMADINE dissociates in 13 minutes in buffered
> medium..."
>
> Should read, "Photolytic measurements showed that zinc OMADINE
> **degrades** in 13 minutes in buffered medium..."
>
> T. Environmental Risk, page 9, 2nd paragraph, 2nd sentence, "The
> octanol/water partition coefficient is less than 1000, which makes it
> unlikely to bioaccumulate, although with its high Kds for sediments
> and a long hydrolytic half-life, it can be persistent in soils and
> sediments containing little or no microbial population".

Should read "The octanol/water partition coefficient is less than 1000 (
**log Kow = 0.97**, which makes it unlikely to bioaccumulate."

**The remainder of the sentence referring to persistence in soils and
sediments containing little or no microbial population is not correct
and should be omitted.**

> U. Environmental modeling/Exposure, page 10 states " The boat
> antifoulant use, however, is expected to produce significant exposure
> to aquatic organisms, and environmental modeling was conducted to
> assess the exposure and risk from this use"

**Should read**: **"The boat antifoulant use, however, is expected to
produce low exposure to aquatic organisms, and appropriate and refined
environmental modeling should be conducted to assess the exposure and
risk from this use"**

Comment: Refer to the previous discussion in section H of the refined
modeling that includes more accurate leach rate data and multiple
degradation rates that clearly demonstrates significantly lower PEC
values than what AD generated using the Luttik-Johnson model.

> V. Ecological Hazard and Risk, page 10, 1st paragraph states " The
> antifoulant use of zinc OMADINE is likely to result in adverse acute
> and chronic effects to fish and aquatic invertebrates, including
> endangered species. It also causes adverse impacts on freshwater and
> marine invertebrate reproduction and growth at very low levels. These
> reproductive impacts indicate that zinc OMADINE is a potential
> endocrine disruptor."
>
> **Arch respectfully disagrees with these statements. and recommends
> that they be and be replaced with .** **"The anitfoulant use of zinc
> OMADINE** **is unlikely to result in adverse effects to fish and
> aquatic invertebrates based on the refined PEC values of 0.12 ppb.
> Zinc OMADINE** **at near lethal concentrations (i.e. at or near the
> LC50 values reported for fish and invertebrates) was observed to
> produce limited effects to reproduction and minor effects to growth
> thus diminishing the concern for potential endocrine disruption."**
>
> Comment: a) If the phrase 'likely to result' is based on a PEC of
> 21.66 ppb, then it should be recognized that this number came from a
> preliminary risk assessment that needs further refinement,
> particularly since it is ten-fold higher than measured concentrations
> of widely used antifouling biocides that are persistent as discussed
> in earlier comments (in section H). Efforts to detect zinc pyrithione
> in marinas have been unsuccessful to date (MRID#45821001; Table 3).
> The detectabilities of the monitoring methods were well below aquatic
> toxicity levels. Therefore the above conclusion of "likely to result
> in adverse acute and chronic effects" would appear to be based on a
> hazard assessment from erroneous data rather than a refined risk
> assessment.
>
> [Comment b):]{.underline} The results from testing zinc OMADINE in
> the Early Life Stage Study of the fathead minnow resulted in a NOEC of
> 1.22 µg/L following 32-days of exposure with a LOEC of 2.82 µg/L. The
> sensitive toxic endpoints were survival and sublethal effects at hatch
> and days 7, 14, 21, and 28 post hatch. There was no apparent effect on
> reproduction but in the AD Preliminary Risk Assessment there is
> mention of developmental effects to the fish i.e. bent bodies. This
> effect only was observed at concentrations above 1.22 µg/L (≥2.82
> µg/L) and only became visible on days 5-10 and again on days 17-32
> post hatching, strongly suggesting that repeated exposures to near
> lethal concentrations of zinc OMADINE was responsible for this effect
> and not developmental toxicity. NOTE: The Acute LC50 in fathead minnow
> for zinc Omadine® is 2.68 µg/L (see table 13 page 42 of the AD
> Preliminary Risk Assessment). The results from testing zinc OMADINE
> in the Chronic Toxicity to the Daphnid, Daphnia magna with Zinc
> OMADINE demonstrated that the NOEC is 2.7 µg/L and the LOEC is 5.8
> µg/L. Doses tested were 0, 2.7, 5.8, 12, 22, and 49 µg/L. The LC50 for
> Daphnid reported in the AD Preliminary Risk Assessment is 8.25 µg/L.
> The mean day to the first brood was delayed at 22 and 49 µg/L,
> concentrations that clearly produce significant toxicity to the
> Daphnid. At concentrations of 12 and 22 µg/L lengths were affected
> (however, differences in length never achieved statistical
> significance; no animals survived to day 32 at 49 µg/L), again
> concentrations of zinc OMADINE causing an effect to length also are
> producing significant toxicity i.e. LC50 8.25 µg/L (significant
> mortality was observed at 49 µg/L starting on day 2 with near 100%
> mortality by day 6).\
> \
> The Chronic Toxicity of Zinc OMADINE to the Mysid, Americamysis bahia
> resulted in a NOEC of 2.28 µg/L and a LOEC of 4.20 µg/L. The LC50 for
> Mysid is 4.7 µg/L as reported in the AD Preliminary Risk Assessment.
> At concentrations of zinc OMADINE that allowed survival equal or
> similar to control values, no reproductive effects were observed.\
> Zinc OMADINE appears to be more of an acute hazard over a chronic
> hazard, based on review of the acute LC50/NOEC and chronic LOEC/NOEC
> values. The chronic NOEC values are in every case similar to the acute
> NOEC values. The fact that only doses of zinc OMADINE that were near
> or greater than the corresponding LC50 were resulting in effects in
> reproduction etc. strongly argues against any chronic hazard and
> definitely confounds any interpretation of possible endocrine
> disruption.
>
> We agree that as the agency states, \"when appropriate screening
> methods have been developed, ZPT will be tested against those
> protocols\". 
>
> W. Ecological Hazard and Risk, page 10, 3rd paragraph, entire
> paragraph -- acute and chronic LOCs have been exceeded"
>
> **This paragraph should be stricken because** **this is an incorrect
> conclusion based on an incorrect PEC calculation (see section H).**
>
> Comment: As discussed previously in section H, the exposure modeling
> was a preliminary risk assessment that needs further refinement,
> particularly since it is ten-fold higher than measured concentrations
> of widely-used antifouling biocide, e.g. Irgarol, that is persistent.
> If the modeling is refined using the proper parameters for leach rate
> and degradation (see section H, Table 3 and 4), the PEC will be a
> factor of 10 to a 1000 less than the NOEC of the most sensitive
> aquatic organisms. These refined PECs will not exceed the LOCs.
>
> X. Section 2.0, Physical & Chemical Properties, page 11 listing of
> properties,
>
> "Kow 0.97 \@25 deg. C": **Should read "log K~ow~ 0.97"**
>
> "Koc 2000-3500" **Should read "log K~oc~ 2.9-4.0"**
>
> Y. Section 2.0, Physical & Chemical Properties, page 11, 2nd sentence,
> "However, it is fairly stable in fresh water and sea water under
> conditions of low microbial activity."
>
> **Should read, "However, it is fairly stable in filtered sterile fresh
> water and sterile sea water in the absence of light."**
>
> Comment: There are no instances of marinas and harbors that we are
> aware of that have little to no microbial activity . The marinas and
> harbors are very rich in microbial populations that would readily
> degrade any leached zinc OMADINE.
>
> Z. Section 2.0, Physical & Chemical Properties, page 11, last
> sentence,
>
> "...it can be persistent in soils and sediments containing little or
> no microbial population."
>
> **Should read**: **"...it is not persistent in soils containing little
> or no microbial population, since it is degraded by sediment as well
> as by redox pathways"**
>
> Comment: The Agency makes an incorrect conclusion about degradation
> depending solely on the presence of microbes. The aerobic and
> anaerobic aquatic metabolism studies both showed biphasic degradation
> with a sediment-catalyzed term that has a 30 minute half-life,
> consistent with a chemical reaction and inconsistent with microbial
> degradation. The N-oxide of zinc pyrithione is cleaved by reducing
> agents (anaerobic sediment). Also the thiol group is readily oxidized
> by trace metals. It should also be noted that extensive degradation
> was observed in other guideline studies with sediment and soil
> (ads/des, soil leach). These studies were all conducted in the absence
> of light. If light is present, photolysis becomes an additional
> important degradation pathway.
>
> []{.mark}
>
> AA. Section 3.0, Hazard Characterization, Developmental Toxicity, page
> 12, 1st paragraph, "Developmental toxicity studies using the oral
> route of administration show zinc OMADINE to produce significant
> developmental effect in rabbits which are greater in severity at doses
> of 1.5 and 3.0 mg/kg/day than toxicity observed in maternal animals at
> these same dose levels."
>
> **Should read**: **"No developmental effects were observed at
> concentrations below 1.5 mg/kg/day and severe maternal toxicity was
> observed at 1.5 and 3.0 mg/kg/day**
>
> Comment: In section 3.0 Hazard Characterization the reference to
> endocrine disruption is associated with the agencies concern for the
> potential of zinc OMADINE to cause developmental effects based on the
> Developmental Toxicity study carried out in Rabbits with zinc
> OMADINE. As mentioned under number 2.0 comment, the DER for the
> rabbit study indicates that the significant decrease in body weight
> gain in the does at the mid and high dose levels (44% and 99%) was not
> biologically relevant as the evaluation of the absolute body weights
> demonstrated only a modest \~4% and \~6% change in body weight over
> the entire gestation period days 0-29. In addition, the DER stated
> that there was no corresponding decrease in food consumption. However,
> in the same DER report of the zinc OMADINE Developmental Toxicity
> Study in the Rabbit Table 3.0 Food Consumption shows a statistically
> significant decrease in food consumption for gestation days 6-19. Body
> weight gains from gestation days 6-19 achieved statistical
> significance of p ≤0.01 that corresponded to a decrease in food
> consumption of 16% (mid-dose, 1.5 mg/kg/day) and 23% (high-dose, 3.0
> mg/kg/day).\
> \
> This clearly indicates that severe maternal toxicity was present at
> the mid- and high-dosed levels and the developmental toxicity observed
> in this study was a result of the significant maternal toxicity and
> significant decrease in food consumption.
>
> BB. Section 3.0, Hazard Characterization, Developmental Toxicity, page
> 13, 2^nd^ paragraph reference to Developmental Toxicity
>
> See Comment in section AA
>
> CC\. Section 3.0, Hazard Characterization, Chronic Toxicity and
> Carcinogenicity, page 14, "Data on the carcinogenic potential of
> sodium OMADINE showed no evidence of carcinogenicity, but one study
> was not tested to an adequate dose."
>
> []{.mark}
>
> **Should read:** "**The only study available to evaluate the
> carcinogenicity of zinc OMADINE was a non-guideline dietary
> oncogenicity study carried out with zinc OMADINE that showed no
> evidence of carcinogenicity. Data from two guideline studies
> evaluating the potential of sodium OMADINE showed no evidence of
> carcinogenicity, with one study failing to achieve significant
> toxicity at the high dose, other than irritation at the site of
> administration (study considered unacceptable, but useful for risk
> assessment)"**.\
> \
> [Comment:]{.underline} The Agency's comment is misleading and suggests
> that only one study was carried out with sodium OMADINEwhen in fact
> two cancer studies were carried out, one Chronic Carcinogenicity study
> in the rat via oral gavage and one Carcinogenicity study in the mouse
> via dermal exposure. The Chronic carcinogenicity study was accepted as
> core but the dermal carcinogenicity study in the mouse was considered
> inadequate due to not achieving a maximally tolerated dose. In
> addition, a two-year dietary carcinogenicity study in rats was carried
> out with zinc OMADINE, this study was carried out in the late 1950's
> and would not be considered acceptable under today's standards.
> However, this study was negative for any increase in tumors over
> control animals. This study along with the two sodium OMADINE studies
> provide additional confidence that the pyrithione's are not
> carcinogenic.
>
> DD. Section 3.0 Hazard Characterization, Metabolism, page 14, last two
> sentences "**The above data do not adequately characterize the
> disposition of zinc OMADINE**, **as no dual labeled test material was
> studied .** The data do suggest less in vivo dissociation of zinc
> OMADINE vs. sodium OMADINE and greater retention of zinc in tissues
> vs. the pyrithione moiety.

####### Remove both sentences, based on comments below 

> **Should read:** "Klaasan utilized ^14^C-ZPT and isotopic ^65^-zinc-PT
> to study zinc OMADINE. Klaasan's conclusions indicate that zinc and
> pyrithione go to different locations in the body and are eliminated at
> different rates and different routes,"
>
> Comment: The work by Klaassan demonstrates that when zinc pyrithione
> is administered via oral, dermal, or intravenous routes, the
> pyrithione moiety separates from zinc and distributes differently in
> the body. In fact when it is administered orally, a majority of the
> zinc is excreted in the feces (Klaassan, C. D. (1976). Absorption,
> distribution, and excretion of zinc pyridinethione in rabbits.
> Toxicology and Applied Pharmacology, 35, pp. 581-587.\
> \
> Following oral gavage of ^14^C- or ^65^Zn-ZPT, the percentage of
> administered dose in each of the tissues analyzed was about one-tenth
> of those concentrations seen following i.v. administration. The
> concentration of ^14^C was observed to be higher than ^65^Zn levels in
> liver, kidney, spleen, heart, lung, pancreas, intestine, stomach, and
> spinal cord but only by a small percentage in most cases. The
> concentration of ^65^Zn was observed to be higher in blood and plasma,
> as well as in eye and muscle. Six hours after oral administration of
> ZPT 1.35% of the ^14^C and 4.4% of the ^65^Zn was found in the major
> organs. The ^14^C levels in the blood were observed to decrease
> between 2 and 6 hours where levels of ^65^Zn were observed to be on
> the increase. Urinary excretion data showed that the ^14^C portion was
> excreted in the urine from 5% at 1 hr. to 50% at 6 hours with less
> than 1% of the ^65^Zn portion being excreted in the urine over 6
> hours.\
> \
> Klaassan concluded that based on the results from these experiments,
> it is apparent that the inorganic (zinc) and organic (pyrithione)
> portion of zinc pyrithione separate. He points to two facts that
> strongly demonstrate this point and they are the differences in zinc
> and pyrithione distribution in the major organs and the differences in
> their excretion profiles.
>
> EE. Section 3.2 FQPA Considerations, page 17, last sentence to page
> 18, 1st sentence "...the developmental toxicity database for zinc
> OMADINE shows effects in offspring at similar dose levels as effects
> in adults, .....".
>
> Should say: **"No developmental effects were observed at
> concentrations below 1.5 mg/kg/day and severe maternal toxicity was
> observed at 1.5 and 3.0 mg/kg/day for zinc OMADINE,...."**
>
> See comments under section AA
>
> FF.Section 3.3 Dose-Response Assessment Table 3 Toxicological
> end-points top of page 19 row Incidental oral... under column
> referring to toxicological effects"

###### Correction: Study reference should be for "Rats" and not Rabbits

> GG. Dietary Exposure and Risk 4.2, pg. 21, Table 4.
>
> C**orrection: Table 4, 3^rd^ column value should be 2.1 instead of
> 1.3**
>
> Comment: Footnote b does not include the aPAD values for females
> listed in Table 3, 0.0016 mg/kg/day, and this value was not used in
> the calculation, where the %aPAD for females would be 2.1 if the lower
> aPAD is used.
>
> This error has a ripple effect into the DWLOC calculation for females
> and the aggregate risk calculations. The respective corrections would
> be in Section 5.1,Table 8 where the aPAD for females would be 0.00016,
> the Max Acute Water Exposure for Females would be 0.000157 mg/kg/day
> and the resulting DWLOC would be 47 μg/l
>
> HH. Section 4.3 Drinking Water Exposure and Risk, page 22, 1^st^
> paragraph "Therefore, the Agency is presently relying on computer
> models (PECs) of pesticides in surface water to estimate drinking
> water exposure to zinc OMADINE"

**This statement should be stricken.**

Comment: Does the Agency mean that an individual may drink untreated
surface water from a freshwater marina as opposed to the untreated water
from a freshwater marina being an individual's main source of drinking
water? In our experience all surface waters are treated prior to being
used for drinking water.

> II\. Section 4.3 Drinking Water Exposure and Risk, page 22, 2^nd^
> paragraph, "..... (PEC) is 21.66 ppb zinc OMADINE based on
> Luttik-Johnson Model."

##### Should read "...acute PEC of 0.12 ppb..."

> Comment: The Agency calculated PEC value is erroneous. See discussion
> under "H" above. Refined modeling with appropriate parameters is
> suggested to obtain realistic PECs
>
> JJ. Section 4.3 Drinking Water Exposure and Risk, page 22, 2nd
> paragraph, 5th sentence, "The primary use of this model by the agency
> at this stage is to provide a course screen..."
>
> Should read, "The primary use of this model by the agency at this
> stage is to provide a **coarse** screen..."
>
> KK. Section 4.3 Drinking Water Exposure and Risk, page 22, 3rd
> paragraph, last sentence, "A DWLOC may vary with drinking water
> consumption patterns ane body weight..."
>
> Should read, "A DWLOC may vary with drinking water consumption
> patterns **and** body weight..."
>
> LL. Section 4.4.2, Dandruff Shampoo Exposure, page 25 and top of page
> 26, all references to "Dandruff" shampoo should be "Anti-Dandruff"
> shampoo.
>
> Typographical error in last line of 2nd paragraph referring to "zine
> OMADINE", should be "**zinc** OMADINE".
>
> MM\. Section 4.4.2, Dandruff Shampoo Exposure, page 25, 2^nd^
> paragraph last sentence..."....rather than from soluble zinc OMADINE
> complexed with detergent in the commercial shampoo"
>
> **This part should be stricken because the zinc** OMADINE **does not
> complex with detergent in the shampoo.**
>
> NN. Section 5.1.1. Acute Aggregate Risk Assessment page 29, 3^rd^
> sentence "Drinking water\...could occur from the antifoulant paint
> use"
>
> **This statement is incorrect. See comments under section H and HH.**
>
> OO. Section 5.1.2 Acute DWLOC Calculations, page 30, 2^nd^ full
> paragraph "Using a conservative screening-level model, the acute
> (maximum) PEC for zinc OMADINE in sea water is 21.66 ppb"

**Should read: ".....acute PEC of 0.12ppb.**

> **Also Table 8 on page 30, Table 9 on page 33 and Table 11 on page 36
> contain erroneous PEC and should be replaced with 0.12 ppb**

Comment: See discussion on PEC under H above

> PP. Section 5.2 Short- and Intermediate- Term Aggregate Risk, Oral
> Aggregate Risk Results, full paragraph 2 "However, the DWLOC for
> infants/children of 17 μg/L is slightly less than the PEC of 21.66
> μg/L"
>
> **This statement is incorrect when one considers a PEC of 0.12 ppb. In
> addition to the fact that surface water are routinely treated prior to
> use as drinking water.**
>
> Comments: See H and HH sections.
>
> QQ. Section 5.3.2, Chronic (non-Cancer) DWLOC Calculations, page 35,
> last paragraph, "PEC for Zinc OMADINE in sea water is 21.66 ppb"

##### Should read "...acute PEC of 0.12 ppb..."

> Comment: The erroneous PEC value should be replaced. See discussion on
> PEC under "H" above and DWLOC discussion under "HH" above .
>
> RR.Section 9, Environmental Risk, Environmental Fate, page 41, 1st
> paragraph, 6th sentence, "Photolytic measurements showed that zinc
> OMADINE dissociates in 13 minutes..."
>
> Should read "Photolytic measurements showed that zinc OMADINE
> **degrades** in 13 minutes..."
>
> SS. Section 9, Environmental Risk, Ecological Hazard and Risk, page
> 42, 1st paragraph, "Zinc OMADINE is very highly toxic on an acute
> basis to freshwater and marine fish and invertebrates, as well as to
> aquatic plant species".
>
> [Comment:]{.underline} Request that a sentence following the above
> sentence describing the conditions and measures taken to meet
> guidelines in maintaining test substance concentrations throughout the
> aquatic toxicity tests. The results are highly conservative based on
> the fact that under normal lighting in a laboratory greatly diminishes
> the concentration of zinc OMADINE (through photolysis) and
> consequently would reduce the "real-life" toxicity to fish and aquatic
> plants.
>
> Even though Zinc OMADINE LC50 values for fish and aquatic plants are
> less than 1.0 mg/L and in many cases goes down to single digits of the
> µg/L; we want to point out that these values are highly conservative
> as in all of the fish and most of the aquatic plant studies light
> intensity was reduced by 75% and the use of filters to block the
> 350-355 nm wavelength (sensitive wavelength of zinc OMADINE) were
> utilized and the diluters were run at maximal capacity in an attempt
> to maintain test article concentration throughout the test period.
> Without these measures pyrithione levels drop dramatically and
> constant levels of zinc OMADINE cannot be maintained over 6 hours let
> alone the usual 96-120 hours for acute toxicity tests.
>
> TT. In section 9.0 Environmental Risk subsection Ecological Hazard and
> Risk, page 42, a statement indicating that "..zinc OMADINE causes
> adverse impacts on freshwater and marine invertebrate reproduction and
> growth at very low levels. Thus, these reproductive impacts indicate
> that zinc OMADINE is a potential endocrine disruptor."
>
> **Should read: "Zinc OMADINE** **at near lethal concentrations i.e.
> at or near the LC50 values reported for fish and invertebrates was
> observed to produce limited effects to reproduction and minor effects
> to growth. However, at doses at or near the NOEC for zinc OMADINE**
> **no effects to reproduction or growth was observed in any aquatic
> species tested, fish or invertebrate thus diminishing any concern for
> the potential of endocrine disruption."**
>
> Comment:\
> [Ecological Toxicity:]{.underline} The results from testing zinc
> OMADINE in the Early Life Stage Study of the fathead minnow resulted
> in a NOEC of 1.22 µg/L following 32-days of exposure with a LOEC of
> 2.82 µg/L. The sensitive toxic endpoints were survival and sublethal
> effects at hatch and days 7, 14, 21, and 28 post hatch. There was no
> apparent effect on reproduction but in the AD Preliminary Risk
> Assessment there is mention of developmental effects to the fish i.e.
> bent bodies. This effect only was observed at concentrations above
> 1.22 µg/L (≥2.82 µg/L) and only became visible on days 5-10 and again
> on days 17-32 post hatching, strongly suggesting that repeated
> exposures to near lethal concentrations of zinc Omadine® was
> responsible for this effect and not developmental toxicity. NOTE: The
> Acute LC50 in fathead minnow for zinc OMADINE is 2.68 µg/L (see table
> 13 page 42 of the AD Preliminary Risk Assessment).\
> \
> The results from testing zinc OMADINE in the Chronic Toxicity to the
> Daphnid, Daphnia magna with Zinc OMADINE demonstrated that the NOEC
> is 2.7 µg/L and the LOEC is 5.8 µg/L. Doses tested were 0, 2.7, 5.8,
> 12, 22, and 49 µg/L. The LC50 for Daphnid reported in the AD
> Preliminary Risk Assessment is 8.25 µg/L. The mean day to the first
> brood was delayed at 22 and 49 µg/L, concentrations that clearly
> produce significant toxicity to the Daphnid. At concentrations of 12
> and 22 µg/L lengths were affected (however, differences in length
> never achieved statistical significance; no animals survived to day 32
> at 49 µg/L), again concentrations of zinc OMADINE causing an effect
> to length also are producing significant toxicity i.e. LC50 8.25 µg/L
> (significant mortality was observed at 49 µg/L starting on day 2 with
> near 100% mortality by day 6).\
> The Chronic Toxicity of Zinc OMADINE to the Mysid, Americamysis bahia
> resulted in a NOEC of 2.28 µg/L and a LOEC of 4.20 µg/L. The LC50 for
> Mysid is 4.7 µg/L as reported in the AD Preliminary Risk Assessment.
> At concentrations of zinc OMADINE that allowed survival equal or
> similar to control values, no reproductive effects were observed.\
> \
> [Conclusion:]{.underline} Zinc OMADINE appears to be more of an acute
> hazard over a chronic hazard, based on review of the acute LC50/NOEC
> and chronic LOEC/NOEC values. The chronic NOEC values are in every
> case similar to the acute NOEC values. The fact that only doses of
> zinc Omadine® that were near or greater than the corresponding LC50
> were resulting in effects in reproduction etc. strongly argues against
> any chronic hazard and definitely confounds any interpretation of
> possible endocrine disruption.
>
> UU.Section 9.0, page 42, Table 13,
>
> **Corrections to Table. Waterflea LC~50~ should be 34 ppb and 95%
> confidence intervals should read 28 -- 41 (MRID 44921801). NOAEC
> should be 13 ppb.**
>
> VV.Section 9.0, page 43, Table 13,
>
> **Corrections to Table. Algae and aquatic plants. Freshwater algae
> NOAEC should be 7.8 ppb (MRID# 43864609); Anabaena NOAEC should be 3.8
> ppb (MRID# 45564901); Navicula NOAEC should be 2.4 ppb (MRID#
> 45565001); Lemna gibba NOAEC should be 4.0 ppb (MRID# 45204104).**
>
> WW.Section 9.0, page 43, Table 14, Freshwater fish early life stage
> toxicity data
>
> **Correction to Table. Fathead minnow EC~50~ should be 1.9 ppb (MRID#
> 44591204); NOAEC should be 1.22 ppb and the LOAEC is 2.82 ppb (Table
> indicated 282 ppb for NOAEC)**
>
> XX.Section 9.0, page 44, Table 14 Freshwater Invertebrate Life Cycle
> Toxicity Data
>
> Correction to Table Waterflea EC~50~ should be 29 ppb (MRID#
> 44535401); and NOAEC should be 2.7 ppb and the LOAEC should be 5.8
> ppb.; Mysid EC50 should be 5.2 ppb and NOAEC should be 2.3 ppb; LOAEC
> should be 4.2 ppb.

Y.  Section 9.0, page 46, 1st paragraph " Environmental.......
    invertebrates. The antifoulant use of zinc OMADINE is likely to
    result in adverse effects to fish, aquatic plants and aquatic
    invertebrates, including endangered species.

> **This paragraph should be stricken because** **this is an incorrect
> conclusion based on an incorrect PEC calculation (see section H).**
>
> Comment: As discussed previously in section H, the exposure modeling
> was a preliminary risk assessment that needs further refinement,
> particularly since it is ten-fold higher than measured concentrations
> of widely-used antifouling biocide, e.g. Irgarol, that is persistent.
> If the modeling is refined using the proper parameters for leach rate
> and degradation (see section H, Table 3 and 4), the PEC will be a
> factor of 10 to a 1000 less than the NOEC of the most sensitive
> aquatic organisms. These refined PECs will not exceed the LOCs.

Z.  Section 10.0, page 46 Data Deficiencies /Data Needs:

> Comment: We have generated data on aquatic plants and whole sediment
> toxicity study to support our antifoulant use of zinc OMADINE.