2 

2009) associated with the California data from the California Department of Pesticide 

Regulation. 

Monitoring Data 

The Agency greatly appreciates receiving relevant monitoring data and the associated report 

(Ensminger and Kelley, 2011) and analytical method (California Department of Food and 

Agriculture, 2009). The Agency typically has access to a vast array of toxicology data through 

the Ecotoxicology (ECOTOX) database maintained by the Agency but does not have ready 

access to environmental fate studies and pesticide usage and monitoring data summarized in 

proprietary or state and local agency reports/databases. 

Comments by MANA 

Comment: EFED noted that residential uses were to be cancelled; thus, their recommendations 

for environmental fate and ecological effects studies reflect this reduced usage. The initial basis 

for some studies, however, cited risks identified in the 2008 RED as the basis for requiring 

studies. Lower use patterns, now in effect, may affect how these risks are currently perceived. 

EPA Response: The Agency agrees that mitigation measures (e.g., reduced application rates and 

elimination of residential use) as a result of the 2008 RED have reduced risk. EFED cited risks 

identified in the 2008 RED as part of the basis for requiring the passerine acute oral toxicity test 

and aquatic plant toxicity tests during Registration Review. The ecological risk assessment for 

the 2008 RED was based on “information contained in the currently existing labels that the 

registrant has indicated they will support for re-registration” and application rates “supported by 

the registrant and documented in the Prometon Use Closure Memo (1/22/07).”2

 In particular, 

estimated exposure concentrations (EECs) were based on a maximum single application rate of 

0.23 lb a.i./ 500 ft2 which is equivalent to 20.04 lb a.i./A. This application rate is very close to 

the current, highest maximum application rate of 18 lb a.i./A which is applicable for all use sites 

except right-of-way specifically for utility poles. As a result, EFED does not anticipate EECs 

modeled in the 2008 RED assessment to change substantially. For example, a preliminary 

analysis of risk to birds via T-REX modeling using the reduced single maximum application rate 

of 18 lb a.i./A indicates that there is still potential for avian risk from acute and chronic exposure 

to prometon (i.e., acute and chronic level of concern exceedances). Therefore, recommendations 

for submission of data in the Registration Review problem formulation are based on perceived 

risk as a result of the current, registered uses of prometon. 

Comment: Table 4 lists triazine-related herbicides. Prometon is in the methoxytriazine class. 

There are five other methoxytriazine products in this class. The Food Quality Protection Act 

obligated the Agency to evaluate pesticides with a common mechanism of toxicity (US 

Congress, 1996). FQPA notes: 

 

2 DP 335303, 335305. Error Correction: Drinking Water Assessment and Ecological Risk Assessment for Prometon 

RED. October 24, 2007.
3 

"(D) FACTORS -In establishing, modifying, leaving in effect, or revoking a tolerance or 

exemption for a pesticide chemical residue, the Administrator shall consider, among other 

relevant factors-... 

"(v) available information concerning the cumulative effects of such residues and other 

substances that have a common mechanism of toxicity; ... " 

While the Agency has concluded a cumulative risk assessment for chlorinated triazine 

herbicides, prometon is not chlorinated and was not considered to share a common mechanism of 

toxicity (US EPA, 2002, 2006). The weight of evidence used cited a specific endpoint: the 

disruption of the hypothalamic-pituitary-gonadal (HPG) axis. Included in this assessment were 

three chlorinated degradants: Desethyl atrazine (DEA), Desisopropyl atrazine (DIA) and 

diaminochlorotriazine (DACT). 

It is likely that some of the triazine herbicides, thirty-four of which are noted in Table 4, share 

commonality other than disruption of the HPG and thus share similar mammalian and ecological 

effects. While prometon is not chlorinated, it does have some common degradants with atrazine, 

specifically GS-17791, GS-17794. We suspect sufficient data may be available, including data 

for triazines not currently registered by EPA, which effectively speak to the issues identified by 

the Agency. 

We ask that all relevant effects of the triazine group be considered during the Registration 

Review of prometon. Integrating such data into the review process does not require that a formal 

common mechanism of toxicity be established for every endpoint considered. 

EPA Response: In the absence of toxicity data that are specific to prometon for a particular 

taxon, EFED will consider data from surrogate triazine herbicides. For example, as stated in the 

Registration Review problem formulation, in the absence of acceptable/quantitative toxicity data 

for Lemna, EFED may use the most conservative Lemna toxicity endpoints (i.e., EC50 and 

NOEC) among the triazines to characterize the toxicity of prometon to aquatic vascular plants; in 

the absence of acceptable/quantitative data for a freshwater diatom, marine diatom, and 

cyanobacterium, EFED may adjust the most conservative aquatic non-vascular plant endpoints 

(i.e., EC50 and NOEC) for atrazine to characterize the toxicity of prometon to aquatic nonvascular plants; and in the absence of toxicity data for a passerine species, passerine toxicity data 

for surrogate pesticides – starting with data for triazines and proceeding to data for less related 

chemicals – may be used to characterize the toxicity of prometon to passerine species.

Comment: Prometon' s MOA interferes with photosynthesis. Based on the current acute toxicity 

to both freshwater and saltwater plant species, additional endpoints of toxicity can be predicted 

with some measure of confidence. 

EPA Response: The registrant is welcome to submit an analysis that predicts the toxicity of 

prometon “with some measure of confidence” to Lemna, freshwater diatoms, marine diatoms, 

and cyanobacteria based on what is currently known about the toxicity of prometon to freshwater 

plant and saltwater plant species. Such an analysis will be considered by EFED at the time of 

submission. As stated in the Registration Review problem formulation, in the absence of 
4 

acceptable/quantitative toxicity data for Lemna, EFED may use the most conservative Lemna

toxicity endpoints (i.e., EC50 and NOEC) among the triazines to characterize quantitatively the 

toxicity of prometon to aquatic vascular plants; and in the absence of acceptable/quantitative data 

for a freshwater diatom, marine diatom, and cyanobacterium, EFED may adjust the most 

conservative aquatic non-vascular plant endpoints (i.e., EC50 and NOEC) for atrazine to 

characterize the toxicity of prometon to aquatic non-vascular plants. 

Comment: We note that the Agency recently completed a retrospective analysis for the 

immunotoxicity requirement (Rowland, 2013). This analysis led to the conclusion that data from 

the immunotoxicity study was generally unlikely to impact regulatory decisions. Accordingly, 

where sufficient data on immune-related endpoints were available, the Agency indicated it would 

consider waivers based on a weight of evidence evaluation. Since generation of additional data is 

resource intensive on both registrant and Agency, we ask that basis for issuing DCIs be 

thoughtfully evaluated, considering each study's potential for affecting regulatory decisions and 

whether collective data from a variety of other triazines can speak to these needs. We note that 

EFED's Registration Review Problem Formulation for prometon characterized the series of 

ecological studies as having a high potential to add value to the Registration Review risk 

assessment (Sternberg et al., 2013). Generating additional data in the absence of valid regulatory 

questions may add to prometon’s database, yet provide minimal regulatory return. 

EPA Response: In the Registration Review problem formulation, EFED prioritized data gaps: 

low potential studies are unlikely to change risk determinations because alternate methods and 

weight of evidence may possibly be used in the absence of data whereas high potential studies 

would enable the Agency to better characterize potential risks by eliminating uncertainties that 

cannot be accounted for using alternate methods or weight of evidence. In addition, EFED 

detailed a path forward in the absence of data for studies considered data gaps. The registrant is 

welcome to submit waivers based on a weight of evidence evaluation. Such waivers will be 

considered by EFED at the time of submission. 

Comment: Guideline: 835.4300/ Aerobic aquatic metabolism 

MANA will address this data gap if this is requested in the Data Call-In. 

The Agency notes prometon is persistent in soil and does not readily undergo abiotic hydrolysis. 

Expected metabolites have been identified and the toxicities of these are assigned "as toxic as the 

parent." (Mana Crop Protection, p. 4). 

EPA Response: Previous risk assessments conducted by the Agency used twice the half-life 

calculated for the aerobic soil metabolism as a conservative estimate of the aerobic aquatic

metabolism half-life. EFED will use the same method in the Registration Review risk assessment 

if an aerobic aquatic metabolism is not provided. 

Potentially, conducting an aerobic aquatic metabolism study for prometon might produce a 

shorter half-life than twice the aerobic soil metabolism half-life, which would decrease EFED’s 

estimates of risk from prometon uses. As noted in the Registration Review problem formulation, 
5 

fulfilling this data requirement has a high potential to add value to the Registration Review 

ecological risk assessment. 

Comment: Guideline: 835.4400/ Anaerobic aquatic metabolism 

MANA will address this data gap if this is requested in the Data Call-In. 

An anaerobic aquatic study was cited by the Agency (MRID 40145501) in the 2008 RED (cited 

also as an aerobic soil metabolism study). This study will be reviewed for its relevance to this 

anticipated data need. 

EPA Response: The ecological risk assessment in support of the Reregistration Eligibility 

Decision (RED) used the half-life calculated for the anaerobic soil metabolism as the anaerobic 

aquatic metabolism half-life. However the study is conducted with both an aerobic and anaerobic 

phases in the same study. In the anaerobic phase the parent and degradates were stable (did not 

degrade). The anaerobic soil metabolism half-life was calculated across both the aerobic and 

anaerobic phases of the same study. Therefore in the RED, the anaerobic soil metabolism halflife actually refers to degradation that only occurred under aerobic conditions. Under current 

EFED guidance, prometon would be considered stable to anaerobic soil metabolism, and 

therefore stable to anaerobic aquatic metabolism, if EFED used this study to estimate an 

anaerobic aquatic metabolism half-life. 

Potentially, conducting an anaerobic aquatic metabolism study for prometon would show some 

degradation, which would decrease EFED’s estimates of risk from prometon uses (compared to 

an assumption of stable for anaerobic aquatic metabolism). However, if the registrant believes 

that the result of an anaerobic aquatic metabolism study would only show that prometon does not 

degrade by anaerobic aquatic metabolism, then the registrant could submit a waiver request that 

states that the registrant believes that prometon will not degrade under anaerobic aquatic 

conditions. In that case, EFED would consider prometon stable to anaerobic aquatic metabolism 

and the registrant would be spared the expense of this study. As noted in the Registration Review 

problem formulation, fulfilling this data requirement has a high potential to add value to the 

Registration Review ecological risk assessment. 

Comment: Guideline: 835.1400/ Fish Early Life Stage Toxicity Test, Rainbow Trout 

MANA will address this data gap if this is requested in the Data Call-In. 

We note MRID 41810902 (Fish Early Life Stage) was cited as data supporting the re-registration 

of prometon. This study was conducted with fathead minnow (Pimephales promelas). This study 

will be reviewed for its relevance to this anticipated data need. 

EPA Response: The registrant is welcome to review MRID 41810902 for its relevance to the 

anticipated data need. Such a review will be considered by EFED at the time of submission. 

As noted in the Registration Review problem formulation, the chronic, early life stage endpoint 

of 19.7 mg/L for freshwater fish (fathead minnow; MRIDs 41810902, 42318202) is 

approximately equal to the most sensitive acute endpoint of 19.6 mg/L for freshwater fish 

(rainbow trout; MRID 41609108). This discrepancy is probably due to the different species used 

in the tests (i.e., fathead minnow in the chronic test and rainbow trout in the acute test). Making 
6 

extrapolations from chronic data to acute data or vice versa to establish the sensitivity of another 

fish species (e.g., the acute toxicity of prometon to a more sensitive freshwater fish such as the 

fathead minnow; the chronic toxicity of prometon to estuarine/marine fish) requires at least one 

set of paired tests (acute and chronic) with a common species. This can involve the performance 

of either an acute toxicity test with fathead minnow or a chronic test (e.g., early life stage 

toxicity test) with rainbow trout. 

Comment: Guideline: 850.4400/ Aquatic Plant Toxicity Test using Lemna spp.

MANA will address this data gap if this is requested in the Data Call-In. 

Acute toxicity to plants (SW diatom) is 0.25 mg/L (LC50). The citation, ECOTOX 9211 refers to 

a study (judged qualitative) of the effect of herbicides on photosynthesis and growth of marine 

unicellular algae. The Agency also notes that the LC50 for freshwater non-vascular aquatic plants 

(e.g., green alga) is 0.098 mg/L, significantly more toxic than to diatoms. Prometon’s mode of 

action (interfering with photosynthesis by disrupting carbon dioxide fixation and other actions) is 

consistent with its marked aquatic plant toxicity. 

EPA Response: The Agency conducts assessments on unicellular and aquatic macrophytes (i.e., 

aquatic non-vascular and vascular plants, respectively). Algae and duckweed (Lemna spp.) 

represent distinct taxonomic groups in the risk assessment, and as such, duckweed data are preferred 

over algae data to represent aquatic vascular plants. In previous risk assessments, an ECOTOX 

open literature study (E081431) was referenced for characterizing the toxicity of prometon to 

aquatic vascular plants (i.e., Lemna spp.). However, this study has been classified as qualitative 

for use in the Registration Review ecological risk assessment because of the lack of experimental 

details (e.g., replication, test concentrations). Therefore, there are currently no 

acceptable/quantitative data available for use in characterizing the toxicity of prometon to 

aquatic vascular plants. In the absence of this data, the most conservative Lemna toxicity 

endpoints (i.e., EC50 and NOEC) among the triazines may be used to characterize the toxicity of 

prometon to aquatic vascular plants. 

Comment: Guideline: 850.2100/ Avian Oral Toxicity, passerine species 

MANA will address this data gap if this is requested in the Data Call-In. 

Avian acute toxicity and dietary toxicity studies have been conducted on the quail, as well as 

reproduction study in the duck. The Agency notes the greatest prometon residues and exposure 

levels are likely to occur in the surface soil and on plant foliage, seeds and insects on treated 

areas immediately following applications. Bioaccumulation is not expected. 

EPA Response: In addition to acute oral toxicity data for either a waterfowl or upland game 

species (e.g., mallard duck or bobwhite quail, respectively), acute oral toxicity data for a 

passerine species are now required under the new 40 CFR Part 158. As noted above, a 

preliminary analysis of risk to birds via T-REX modeling using the reduced single maximum 

application rate of 18 lb a.i./A indicates that there is still potential for avian risk from acute and 

chronic exposure to prometon (i.e., acute and chronic level of concern exceedances). Passerine 

birds may utilize metabolic pathways that are different from larger birds and therefore be more 

sensitive to prometon. Furthermore, passerines exhibit behavioral responses to pesticide dosing 
7 

that are potential indicators of reduced fitness in the field (e.g., regurgitation of contaminated 

diet) even when direct biochemically-mediated lethal toxicity is not apparent. Therefore, 

fulfilling this data requirement has a high potential to add value to the Registration Review 

ecological risk assessment as the generated data will allow the Agency to be protective of 

passerine species. 

Comment: Guideline: 850.4550/ Cyanobacteria (Anabaena flosaqua) toxicity 

MANA will address this data gap if this is requested in the Data Call-In. 

This data gap is based on the 2008 RED identifying a risk concern for aquatic non-vascular 

plants. We note there is an array of both freshwater and saltwater aquatic plant studies (Table 16 

of the 2008 RED). We will integrate these data with other data on triazines in considering this 

data gap. 

EPA Response: The registrant is welcome to submit an analysis that integrates existing 

prometon toxicity data for freshwater and saltwater aquatic plant studies in considering this data 

gap. Such an analysis will be considered by EFED at the time of submission. 

References 

Ensminger, M. and K. Kelley. 2011. Monitoring Urban Pesticide Runoff in Northern California, 

2008-2009. California Environmental Protection Agency, Department of Pesticide 

Regulation, Environmental Monitoring Branch, Surface Water Protection Program. 

Report 249. March 2011. 53 pp. 

California Department of Food and Agriculture. 2009. Determination of Atrazine, Bromacil, 

Cyanazine, Diuron, Hexazinone, Metribuzin, Norflurazon, Prometon, Prometryn, 

Simazine, Deethyl Atrazine (DEA), Deisopropyl Atrazine (ACET), Diamino 

Chlorotraizine ( DACT), Tebuthiuron and the metabolites Tebuthiuron-104, Tebuthiuron106, Tebuthiuron-107 and Tebuthiuron-108 in Well Water and River Water By Liquid 

Chromatography- Atmospheric Pressure Chemical Ionization Mass Spectrometry.” 

Center for Analytical Chemistry. Environmental Analysis Section. EM 62.9. Revision 2. 

Revision Date: 1/09/09. 26 pp.