## U.S. EPA

High Production Volume Chemical Challenge Program

Robust Summaries and Test Plan

for C4 3

- thiophenamine, N

- [ ( 1S )

- 2

- methoxy

- 1

- methylethyl ]

- 2,4

- dimethyl

-

(CAS No. 170373

- 17

- 8 )

Revised Submission

Submitted by: Exponent, Inc. 1800 Diagonal Ro ad, Suite 500 Alexandria, VA 22314

On behalf of: BASF Corporation 3150 Highway JJ Palmyra, MO 63641

Date of submission: February 1 6 , 201 2HPV Robust Summaries and Test Plan

– C4

- This page intentionally blank

-HPV Robust Summaries and Test Plan

– C4

ii Table of Contents

1.0 Executive Summary 1
2.0 Introduction 5
2.1 Overview 5
2.2 Methods for Data Review 5
3.0 Substance information for C4 7
3.1 Substance description 7
3.2 Use and Exposure Information 7
4.0 Analogs for C4 8
4.1 EPA guidance for use of analogs 8
4.2 Structural Similarity and Comparison of Data for C4 and Dimethenamid 9
5.0 Data Analysis 12
5.1 Physico

- chemical Properties 12
5.2 Environmental Fate and Pathways 13 5.2.1 Photodegradation, Volatilization, and Hydrolysis 14 5.2.2 Bioaccumulation, Fugacity, and Biodegradation 14
5.3 Eco toxicity 15
5.4 Health Effects 17 5.4.1 Absorption, Distribution, Metabolism and Excretion 17 5.4.2 Acute Toxicity 18 5.4.3 Repeated Dose Toxicity 18 5.4.4 Genetic Toxicity 19 5.4.5 Reproductive Toxicity 20 5.4.6 Developmental Toxicity 21 5.4.7 Summary of health effects data 23
6.0 Conclusions and Recommendations 25
7.0 SIDS Data Matrix 26
8.0 References 28HPV Robust Summaries and Test Plan

– C4

iii

List of Figures Page Figure 1. Structure of C4 7 Figure 2. Comparison of structures of C4 and Dimethenamid 10

List of Tables Page Table 1. Testing plan and rationale 4 Table 2. Comparison of available data for C4 and dimethenamid 11 Table 3. Physico

- chemical properties of C4 and dimethenamid 13 Table 4. Environmental fate and pathways information for C4 and dimethenamid 15 Table 5. Ecotoxicity information for C4 and dimethenamid 17
Table 6. Health effects information for C4 and dimethenamid 24HPV Robust Summaries and Test Plan

– C4

1



## 1.0 Executive Summary

3

- Thiophenamine, N

- [(1S)

- 2

- methoxy

- 1

- methylethyl ]

- 2,4

- dimethyl

- , (CAS No. 170373

- 17

- 8 ), also k nown as C4, is an amber liquid with a molecular weight of 199.3 g/mole. (Note that the test plan for this substance previously referred to CAS No. 87676

- 07

- 1). The available data for C4 (measured and estimated) were supplemented with data on a structurally related chemical, dimethenamid (CAS No. 163515

- 14

- 8), which was used as an analog. Because C 4 is an intermediate in the production of dimethenamid, the compounds are very similar in structure, the primary difference being the addition of chloroacetamide t o the nitrogen in C4. Reliable data from studies conducted according to acceptable guidelines were available for nearly all of the SIDS endpoints for dimethenamid, improving the utility of the analog in read

- across.

C4 is a closed

- system intermediate in th e manufacturing process for the herbicide dimethenamid

. Potential exposures are thought to be extremely limited, because of the low volatility of C4 , which limits inhalation exposures , and because personal protective equipment is used during sampling event s when any dermal contact might occur. Environmental exposures are expected to be extremely rare, because any spills would be handled in an appropriate manner to minimize release to the environment.

EQC Level III fugacity modeling predicts that, if releas ed to the environment, C4 is expected to partition primarily to soil (7 8.6 %) and water (2 1.1 %). Vapor

- phase C4 , which is expected to be limited because of its low volatility, will be degraded in the atmosphere by reaction with hydroxyl radicals, with a pre dicted half

- life of 1.1 hours. C4 is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions. Because of its low octanol

- water partition coefficient, C4 is not expected to bio accumulate. C4 was not biodegradable in 28 days in a ready bio degradability test conducted according to OECD Guideline 310.

The toxicity of C4 to aquatic plants was determined in a study conducted with the green alga, Pseudokirchneriella subcapitata , acc ording to OECD Guideline 201. The resulting 72

- hour EC50 for C4, based upon yield, was 58.9 mg/L

. There are no studies available on toxicity of C4HPV Robust Summaries and Test Plan

– C4

2

to fish or invertebrates

. Based upon structure

- activity relationships , C4 is expected to be slightly
to mode rately toxic to these species, with LC50 or EC50 values of 12.0 and 8.7 mg/L for fish and invertebrates, respectively. A full complement of reliable ecotoxicity data is available for dimethenamid. These data agree well with the ECOSAR values for C4 for fis h and invertebrates (dimethenamid LC50 values of 6.3 and 10 mg/L for fish, 12 mg/L for Daphnia ), and can be used in a read

- across manner to fulfill these endpoints.

Reliable data from guideline studies conducted under Good Laboratory Practices ( GLP ) are

a vailable to fulfill most of the SIDS Level 1 endpoints for health effects for C4. The acute oral LD50 for C4 in rats was 1 , 038 mg/kg, while the acute dermal LD5 0 in rats was greater than 4,153 mg/kg. Supporting data for dimethenamid consist of an acute ora l LD50 for rats of 466 mg/kg, an acute dermal LD50 for rabbits of > 2 , 000 mg/kg, and an acute inhalation LC50 for rats of > 2.2 mg/L. In a 90

- day repeated dose oral study with rats, the NOAEL for C4 was 300 ppm (ca. 18.2 mg/kg bw/day in males and 20.7 mg/k g bw/day in females). This is comparable to the NOAEL of 39 mg/kg bw/day for a 90

- day repeated oral dose study in rats for dimethenamid. In both studies, decrements in body weight were seen at the ne xt highest dose level (58

– 66 mg/kg bw/day for C4 and 118 mg/kg bw/day for dimethenamid). In the 90

- day study with C4, there was no evidence of gross or histopathological effects in the reproductive organs of male or female rats up to and including the highest dose, 1 , 000 ppm (ca. 58 mg/kg bw/day for males and 66 mg/kg bw/day for females). Similarly, in the 90

- day study with dimethenamid, there were no effects upon the reproductive organs of rats of either sex up to and including the highest dose of 239 mg/kg bw/day. These results are consistent with the findings of a two

- generation study in rats with dimethenamid, which provided a NOAEL for reproductive function of 150 mg/kg bw/day.

The two

- generation study in rats with dimethenamid reported a NOAEL for developmental toxicity of 50 mg/kg bw/day based upon decreas ed pup body weight gain. When administered to rats during pregnancy in another study, dimethenamid produced a NOAEL for maternal and developmental toxicity of 25 mg/kg bw/day, with the developmental effects consisting of slight but significant increases in the incidence of incomplete ossification in fetuses at higher doses

. When administered to rabbits during pregnancy, the NOAEL was 37.5 mg/kg bw/day forHPV Robust Summaries and Test Plan

– C4

3

maternal toxicity and 75 mg/kg bw/day for developmental toxicity. Although there are no developmental t oxicity studies for C4, the results for the studies with dimethenamid can be used to estimate the developmental effects of C4.

In the bacterial reverse mutation assay, C4 was positive in only one of five strains, and only in the absence of metabolic activ ation, where a 1.6

- to 2.5

- fold increase in revertants per plate was observed. Dimethenamid was not mutagenic in any tested strain in the bacterial reverse mutation
assay, n or in the CHO/HGPRT assay, and was not clastogenic in the mouse micronucleus assay.

The original test plan submitted by BASF to EPA for C4 in September 2008 identified several data gaps for HPV elements. This revised test plan incorporates the results of testing conducted on C4 since that date by the sponsor to determine water solubili ty, biodegradability, and acute toxicity to algae. Including these new data, and considering the existing data and the data available for dimethenamid which can be used in a read

- across manner, the overall conclusions and recommendations are that adequate information exists for all HPV elements for C4. This information is summarized in Table 1

.HPV Robust Summaries and Test Plan

– C4

4 Table 1. Testing plan and rationale

CAS # 170373

- 17

- 8 C4

Information Available?

OECD Study?

GLP Study?

Supporting Information?

Estimation Method?

Acceptable?

Testing Recommended?

HPV Endpoint Physico

- chemical Properties
Melting Point Y N N Y Y Y N Boiling Point Y N N Y N Y N
Vapor Pressure Y N N Y Y Y N

Partition Coefficient Y N N Y Y Y N Water Solubility Y Y N Y N N N

Environmental F ate

Photo

- Degradation Y N N Y Y Y N Water Stability Y N N Y Y Y N Fugacity Y N N Y Y Y N
Biodegradation Y Y Y Y Y N N Ecotoxicity

96

- Hour Fish Y N N Y Y Y N

48

- Hour Invertebrate Y N N Y Y Y N

96

- Hour Algae Y Y Y Y N N N

Health Effects

Acute Y Y N Y N N N Genetic Toxicology in vitro Y Y N Y N N N Genetic Toxicology in vivo Y N N Y N N N Repeated Dose Y Y Y Y N N N Reproductive Y Y Y Y N N N Developmental Y N N Y N N NHPV Robust Summaries and Test Plan

– C4

5



## 2.0 Introduction

2.1 Overview

Ex ponent, Inc., on behalf of BASF Corporation, has prepared the revised robust summaries and revised test plan for 3

- thiophenamine, N

- [(1S)

- (2

- methoxy

- 1

- methylethyl ]

- 2,4

- dimethyl

- , also referred to as C4 (CAS No. 170373

- 17

- 8 ), under the United States Environ mental Protection Agency’s (U.S. EPA) Extended High Production Volume (eHPV) Chemical Challenge Program. Note that the previously submitted test plan and robust summaries for C4 referred to CAS No. 87676

- 07

- 1, which is the racemic C4 , 3

- thiophenamine, N

- (2

- methoxy

- 1

- methylethyl)

- 2,4

- dimethyl

- . The current test plan and robust summaries correctly reflect the chiral S molecule of C4 , CAS No. 170373

- 17

- 8.

The purpose of this plan is to develop physicochemical data, environmental fate and effects data, and mammalian health effects data for C4 consistent with the Screen ing Information Data Set (SIDS). Therefore, this plan summarizes the existing SIDS data for C4 and an analog, dimethenamid , and evaluates the need for testing to fill any data gaps in the SIDS endpoints.



### 2.2 Methods for Data Review

A review of the scienti fic literature and BASF Corporation’s company data was conducted on the physicochemical properties, environmental fate and effects, and mammalian toxicity endpoints for C4 and the analog , dimethenamid. In addition, searches were conducted on the CAS numbe r and chemical name for C4 using the following databases and web sites: ATSDR, CICAD, ESIS, HPVIS, HERA, IARC, IPCS INTOX Databank, IRIS, Japanese Chemicals Evaluation and Research Institute, NTP, OECD, EFDB, ECOTOX, and TOXNET (including TOXLINE, MEDLINE, CCRIS, HSDB, DART, GENETOX, and CHEMIDPlus). In addition to these databases and web sites, a literature search was performed and standard handbooks (CRC Handbook on Chemicals, Hawley’s Condensed Chemical Dictionary, Merck Index, etc.) were consulted for p hysicochemical properties.HPV Robust Summaries and Test Plan

– C4

6

This document addresses a single eHPV sponsored chemical; however, data for a closely related compound, dimethenamid (CAS No. 163515

- 14

- 8) have been used to support the data set for the sponsored chemical through a read

- across a pproach. Data read

- across means that physicochemical property and toxicological data from one chemical are used to estimate those same characteristics for another chemical

. This approach is appropriate only when the two chemicals are deemed sufficiently si milar in structure that they are likely to have similar chemical and toxicological properties. Typically, the more data

- based information there is to support this assumption, the stronger the foundation for the read

- across approach will be. The use of stru ctural analogs is consistent with EPA guidance for use of structure

- activity relationships (SAR) in the HPV Chemical Challenge Program ( U.S. EPA, 1999 a ).

In accordance with U.S. EPA guidance, in those instances where measured physicochemical parameters and environmental fate data were not available, these properties were developed using EPIWIN (EPISuite version 4.00 ) modeling. EPIWIN is an acronym for the Estimation Programs Interface for Microsoft Windows, and is a package of computer programs developed by the U.S. EPA Office of Pollution Prevention and Toxic Substances (OPPTS) , which uses computational methods and structure

- activity relationships (SAR) in estimating chemical properties, environmental fate, and aquatic toxicity of organic chemicals. Because of the inherent limitations of SAR approaches, EPIWIN modeling may produce non

- realistic estimates; therefore, EPIWIN data are evaluated for reasonableness prior to use as data surrogates . In accordance with U.S. EPA guidance, environmental fate and trans port estimates were developed using the Level III Equilibrium Criteria Model (EQC) in EPIWIN v4.0 0 as described by Mackay et al. (1996).

Robust summaries were prepared for C4 and dimethenamid in EPA’s High Production Volume Information System (HPVIS) for key studies to provide a detailed summary of the test methods and results. Though several studies may have been evaluated for a particular SIDS endpoint, in general robust summaries were prepared only for the critical study that represented the best avail able data. Selection of the critical study was based on a review of all studies using the ranking system developed by Klimisch et al. (1997), as well as the criteria outlined in the U.S.HPV Robust Summaries and Test Plan

– C4

7

EPA’s (1999b) methods for determining the adequacy of existing data. Reliable studies that provided supporting data were also included

. 

## 3.0 Substance information for C4

3.1 Substance description

C4 (CAS No. 170373

- 17

- 8 ), also known as 3

- thiophenamine, N

- (2

- methoxy

- 1

- methylethyl)

- 2,4

- dimethyl

- , is used in the manufacture o f the herbicide dimethenamid. It is an amber liquid with a molecular weight of 199.3 g/mole. The structure of the racemic C4 is shown in Figure 1.

Figure 1. Structure of C4



### 3.2 Use and Exposure Information

C4 is a site

- limited closed

- system intermediate used in the manufacture of the herbicide dimethenamid. It is produced at only one site in the U.S. The production volume is between 5 and 15 million pounds per year; hence C4 is an HPV chemical. Processing occurs in closed systems with no routine exposure possible except for QC sampling. S amples are handled in lab oratory settings according to a chemical hygiene plan and using engineering controls such as fume hoods. C4 is a relatively non

- volatile liquid, so the probability of inhalation exposure is quite low and air monitoring is not warranted. Dermal exposures that might be associated with sampling the materials (and waste streams) during the manufacturing process are preventedHPV Robust Summaries and Test Plan

– C4

8

through worker training regarding proper health and safety procedures , the us e of proper personal protective equipment ( PPE ) , and engineering controls.

The vast majority of C4 is converted to the desired product and the inventory of C4 onsite at any one time is small, i.e., less than 250,000 pounds in a single storage tank. Any sm all amount of C4 that might end up in the final product is regulated by the active ingredient registration. All organic and aqueous waste streams from the processes that use C4 are incinerated or disposed of via an onsite deep well. Potential environmenta l exposures are limited to spills onsite, which are handled in accordance with recognized emergency response and safety procedures to minimize potential exposures. The use of secondary containment at the manufacturing site further limits potential environ mental release. In summary, C4 poses a minimal exposure threat to workers or the environment.



## 4.0 Analog s for C4

4.1 EPA guidance for use of analogs

In its SAR guidance for the HPV Chemical Challenge Program, the U.S. EPA states that the most likely analo gs for an HPV chemical are those that resemble the candidate chemical in terms of the following:

1. Molecul ar structure/size;

2. Some substructure that may play a critical functional role;

3. Some molecular property (e.g., lipophilicity, electronic and steric para meters); and/or

4. Some precursor, metabolite, or breakdown product.
In general, valid analogs should have close structural similarity and the same functional groups as the HPV chemical. In addition, a high correlation is desired between the HPV chemical and the putative analog for the following parameters:HPV Robust Summaries and Test Plan

– C4

9

 Physico

- chemical properties (e.g., physical state, molecular weight, log Kow, water solubility);

 Absorption potential;

 Mechanism of action of biological activity; and

 Metabolic pathways/kinetics of metabol ism.



### 4.2 Structural S imilarity and C omparison of D ata for C4 and D imethenamid

The selected analog is dimethenamid (CAS No. 163515

- 14

- 8), or S

- 2

- chloro

- N

- (2,4

- dimethyl

- 3

- thienyl)

- N

- (2

- methoxy

- 1

- methylethyl)

- acetamide. As C4 is a precursor of dimethenamid, t he two compounds are structurally similar. The molecular weights have a difference of 76.5 g/mol owing primarily to the addition of one oxygen and chlorine atom in dimethenamid. The primary difference between the two molecules is that the nitrogen in C4 i s part of a secondary amine while in dimethenamid a tertiary amide (in the form of chloroacetamide) exists. In addition, both C4 and dimethenamid possess chiral stereocenters, as shown in Figure 2. Dimethenamid occurs as a racemic 50/50 mixture of the M and P isomers. When dimethenamid was originally registered, all toxicology studies were conducted with the 50/50 racemic mixture (also known as SAN 582 H). More recently, it was discovered that only the P isomer (referred to in some reports

as s

- dimethenam id or SAN 1289 H) has useful herbicidal activity. A number of studies were conducted to compare the toxicities of the P

- isomer and the racemic dimethenamid. These studies concluded that the mammalian toxicity of racemic dimethenamid and dimethenamid

- P

were remarkably similar and therefore studies of the racemic mixture could be used to support the registration of dimethenamid

- P. All of the robust summaries submitted with this test plan are for studies conducted using dimethenamid

- P, with the following exce ptions: toxicokinetics data are for the racemic mixture, and several of the environmental fate studies were conducted using both the racemic and P

- isomer, although no differences between them were observed. The data presented in the tables thus refer to d imethenamid

- P unless otherwise noted.HPV Robust Summaries and Test Plan

– C4

10

Similarly, all of the studies conducted in the past three years that have been performed with C4 have been with the chiral S molecule, as it is the precursor currently produced for the manufacture of dimethenamid

- P. Older studies were conducted with the racemic C4; however, as with dimethenamid, the toxicity of the chiral S molecule is expected to be highly similar to that of the racemic C4. The structures of the two chemicals , showing the chiral stereocenters, are pr esented in Figure 2.

C4

Dimethen a mid

Figure 2. Comparison of structures of C4 and DimethenamidHPV Robust Summaries and Test Plan

– C4

11

Table 2 compares the available information for C4 and dimethenamid where experimental data exist for both compounds. (Further details on t hese data are given in subsequent sections of this test plan). Experimental data have been recently generated for C4 for the following fate and ecotoxicity endpoints: water solubility, biodegradability, and algal toxicity. In addition, reliable data exist for C4 for nearly all of the human health endpoints. Although the herbicide dimethenamid is much more toxic to algae than C4, it is apparent that the two compounds have very similar toxicity for the human health endpoints . The absorption, distribution, me tabolism, elimination and toxicity of these compounds in mammalian systems are also expected to be similar. Dimethenamid is thus believed to possess most of the desired properties for an analog as described in U.S. EPA guidance. Therefore, data read

- across is used for those instances where valid and reliable data are available for dimethenamid but not C4.

Table 2. Comparison of available data for C4 and d imethenamid

Substance Information and Properties C4 ( 170373

- 17

- 8 ) Dimethenamid (163515

- 14

- 8)

Synonym 3

- thiophenamine, N [(1S)

- 2

- methoxy

- 1

- methylethyl ]

- 2,4

- dimethyl

S

- 2

- chloro

- N

- (2,4

- dimethyl

- 3

- thienyl)

- N

- (2

- methoxy

- 1

- methylethyl)

- acetamide Molecular Formula C 10 H 17 NOS C 12 H 18 ClNO 2 S Molecular weight 199.3 275.79
Water solubility 472.5 mg/L 1449 mg/L
Algal t oxicity EC50 58.9 mg/L 1 0.017 mg/L 2

Acute oral LD50 1038 mg/kg 466 mg/kg Acute dermal LD50 > 4153 mg/kg > 2000 mg/kg Repeated dose NOAEL ca. 18.2 (males) and 20.7 (females) mg/kg/day 39 mg/kg/day

Genetic tox

– in vitro Generally negative Negative

Rep roductive toxicity

NOAEL ca. 58

- 66 mg/kg/day (highest dose

tested in 90

- day study) 239 mg/kg/day (highest dose tested in 90 day study) 150 mg/kg/day (highest dose tested in 2

-

generation study)

1 72

- hour value based upon yield
2 96

- hour value based upon cell densityHPV Robust Summaries and Test Plan

– C4

12



## 5.0 Data Analysis

A summary of the available data for C4 and dimethenamid is shown, along with information on the reliability of the data, in the completed SIDS data matrix provided in Section 7 . These data are discussed below, while details are provided in the Robust Summaries submitted concurrently with this Test Plan.



### 5.1 Physico
- chemical P roperties

Data on the physico

- chemical properties of C4 and dimethenamid are presented in Table 3. The source of the information is classified as “esti mated” or “measured

. ” Estimated data were obtained through structure

- activity correlations (EPIWIN). Measured data were obtained through experimental procedures. Complete details on the sources of information for each data element are provided in the Robu st Summaries submitted with this Test Plan.

BASF conducted testing to determine the water solubility study of C4 . Water solubility is a key property because of its potential relevance for human and environmental risk assessment. This study followed the fl ask method in OECD Guideline 105, although it was not performed under GLP. The resulting water solubility at 22 °C was 472.5 mg/L (Rachmalla, 2009). A report by Wilson (1989) provided measured vapor pressure data for racemic C4 over a temper ature range of approximately 81

– 190 oC. These data were used to extrapolate the vapor pressure at 25 oC as 0.015 hPa and to calculate a boiling point (the temperature at which the vapor pressure equals atmospheric pressure) of 260.3 oC. The study by Wilson did not provid e sufficient methodological details upon which to base its reliability, however it is supportive of the estimations of boiling point (277.8 °C) and vapor pressure (0.00296 hPa) provided by EPIWIN , which are tabulated below. The estimated melting point fro m EPIWIN appears to be inaccurate, given that C4 is a liquid at room temperature. A complete set of GLP studies conducted according to appropriate guidelines was available for dimethenamid. These measured data align well with the measured and estimated da ta on physico

- chemical properties for C4.HPV Robust Summaries and Test Plan

– C4

1 3 Table 3. Physico
- chemical properties of C4 and d imethenamid

Substance Information and Properties C4 ( 170373

- 17

- 8 ) Dimethenamid (163515

- 14

- 8)

Synonym 3

- thiophenamine, N [(1S )

- 2

- methoxy

- 1

- methylethyl ]

- 2,4

- dimethyl

S

- 2

- chloro

- N

- (2,4

- dimethyl

- 3

- thienyl)

- N

- (2

- methoxy

- 1

- methylethyl)

- acetamide Molecular Formula C 10 H 17 NOS C 12 H 18 ClNO 2 S Molecular weight 199.3 275.79

Melting point 72.7 °C (estimated). Note that substance is a liquid. ≥

- 50 °C (measured) 2 ( Guideline study, valid without restriction )
Boiling point 277.8 °C (estimated) ≥ 280 oC (measured) 2 ( Guideline study, valid without restriction )
Vapor pressure 0.00 296 hPa (estimated) 0.0000251 hPa (measured) 3 ( Guideline study, val id without restriction )

Water solubility 472.5 mg/L (measured) 1 (Guideline study, valid without

restriction) 1449 mg/L (measured) 4 ( Guideline study, valid without restriction )

Partition coefficient (log Kow) 2.68 (estimated) 1.89 (measured) 5 ( Guideline s tudy, valid without restriction ) Note: estimated values are from EPIWIN 1 Rachmalla, 2009 2 Kroehl, 1999 3 Chen and Laster, 1996 4 Laster, 1996 5 Lam, 1988
Recommendation: No additional physico

- chemical property studies are necessary. The availa ble data fill the HPV required data elements with sufficient precision to define the potential hazards of C4

.


### 5.2 Environmental Fate a nd Pathwa ys
The environmental fate data for C4 and dimethenamid are summarized in Table 4 along with identification of the sources of information (measured or estimated). Additional information is tabulated in Section 7 and more fully described in the Robust Summaries.HPV Robust Summaries and Test Plan

– C4

14



### 5.2.1 Photodegradation , Volatilization, and Hydrolysis
Indirect photodegradation in air was calculated for C 4 using AOPWIN v1.92. The resulting half

life was approximately 1.1 hours. A similar estimation was made for dimethenamid, resulting in a predicted atmospheric half

- life of 2.5 hours. In experiments to determine photolysis of dimethenamid in aqueous soluti on, the ph otodegradation half

- life was 24

– 26 days (Guirguis, 1997a; Sabat, 1992). The predicted Henry’s Law Constant for C4 is ( 5.71 x10 - 8 atm

- m 3 /mole ; HENRYWIN v3.20) is very low and indicates a lack of volatility. A guideline study demonstrated that dim ethenamid is hydrolytically stable at pH 5, 7 and 9 for 31 days (Guirguis, 1997b). C4 is also expected to be stable to hydrolysis because it lack s functional groups that hydrolyze under environmental conditions

.



### 5.2.2 Bioaccumulation, Fugacity, and Biode gradation
C4 is not expected to bioaccumulate to any extent, as its estimated log Kow value (2.68) and log BCF (1.44) are relatively low ( U.S. EPA, 2011 ). This corresponds well to measured data for dimethenamid (log Kow value of 1.89). If released to the environment, C4 is expected to partition primarily to soil ( 7 8.6 %) and water (2 1.1 %), as predicted by EQC (equilibrium criterion) Level III fugacity modeling. Dimethenamid is also predicted to partition primarily to soil ( 80.8 %) and water ( 18.9 %).

A study to determine the biodegradability of C4 in the carbon dioxide headspace test (OECD 310) was performed, under GLP, by Schwarz (2009). The test substance, mixed with mineral salts and a non

- adapted inoculum of municipal activated sludge, was incubated in se aled vessels with a headspace of air for 28 days. The extent of biodegradation was expressed as a percentage of the total inorganic carbon formed , based on the amount of the total organic carbon initially added. The results (biodegradation of 1.8%) indicat ed that C4 was not readily biodegradable under the conditions of the test. Ready biodegradability studies have not been performed in an aqueous matrix with dimethenamid, as it is not expected to be readily biodegradable. In aerobic soil metabolism studies conducted according to acceptable guidelines and under GLP, it was demonstrated that dimethenamid was completely degraded in soil with half

- lives of approximately 7 days (Wendt, 1997) or 35 days (Kruger and Bade, 1990). In studies conducted using sediment and water from a river and pond system, the ha lf

- life of dimethenamid wasHPV Robust Summaries and Test Plan

– C4

15

20

− 28 days in the water phase and 23

– 33 days for the whole system (Wyss

- Benz and Vokel, 1994).

Recommendation : No additional studies on environmental fate and pathways are necessary. The HPV required endpoints are fulfilled by a combination of test results and estimation using acceptable methods.

Table 4. Environmental fate and pathways information for C4 and dimethenamid

Environmental Fate Endpoint C4 ( 170373

- 17

- 8 ) Dimethenamid (163515

- 14

- 8)

Photodegradation half

- life 1.1 hours (estimated) 1 2.5 hours (es timated) 1 Aqueous photolysis 24

- 26 days (measured) 4 ( Guideline study, valid without restriction )

Hydrolysis Expected to be stable to hydrolysis Stable at pH 5, 7 and 9 for 31 days (measured) 5 ( Guideline study, valid without restriction ) Fugacity (percent distribution over time assuming equal emissions to air, water and soil) Air: < 0. 1%; Water: 2 1.1 %; Soil: 7 8.6 %; Sediment: 0.2 % (estimated) 2 Air: 0.1 %; Water: 18.9 %; Soil: 80.8 %; Sediment: 0.2 % (estimated) 2

Biodegradation Not readily biodegradable (< 1% in 28 days) per OECD 310. (Guideline study, valid without restriction) 6 Primary biodegradation in water in days

weeks, ultimate biodegradation in months (estimated) 3

1 estimated by AOPWIN v1.92 2 estimated by EQC Level III 3 estimated by BIOWIN v4.10 4 Gui rguis, 1997a; Sabat, 1992 5 Guirguis, 1997b 6 Schwarz, 2009


### 5.3 Ecotoxicity

A cute aquatic toxicity data are summarized in Table 5 along with identification of the sources of information (measured or estimated)

. Additional information i s tabulated in Sectio n 7 and more fully described in the Robust Summaries. C4 is an intermediate in the production of an herbicide (dimethenamid), and the available data for dimethenamid (discussed below) indicate that algae were the most sensitive aquatic organisms compared t o fish and invertebrates. Therefore, an algal toxicity test was conducted with C4 according to OECD Guideline 201 and under GLP (Salinas, 2011). In this study, the green alga Pseudokirchneriella subcapitata was exposed for 72 hours to five concentrations o f C4 (10 to 220 mg/L nominal) in algal medium. TestHPV Robust Summaries and Test Plan

– C4

16

concentrations were analytically verified to be 91.0 to 102.7% of nominal at the beginning of the test and 89.0 to 93.9% of nominal at the end of the test; therefore the results were calculated on the bas is of the nominal concentrations. The EC50 for yield (final cell density minus initial cell density) was calculated to be 58.9 mg/L while the EC50 for growth rate (increase in cell density per day) was calculated to be 97.0 mg/L, indicating that C4 is slig htly toxic to algae, 1 and does not have the same phytotoxic effect as dimethenamid.
A complete set of ecotoxicity data is available for dimethenamid. In flow

- through studies, the LC50 for dimethenamid was 6.3 mg/L for rainbow trout ( Oncorhynchus mykiss ) , 10 mg/L for bluegill sunfish ( Lepomis macrochirus ) , and 12 mg/L for Daphnia magna (Graves and Swigert, 1996a; Graves and Swigert, 1996b; Graves and Smith, 1996). In a static test using Selenastrum capricornutum (new name Pseudokirchneriella subcapitata ), t he EC50 based upon cell density after 120 hours of exposure was 0.017 mg/L (Hoberg, 1997a) and in a static renewal test using Lemna gibba (duckweed), the EC50 after 14 days of exposure was 0.016 mg/L based upon frond number and 0.0089 mg/L based upon frond biomass (Hoberg, 1997b). Because dimethenamid is

a n herbicide, greater toxicity to aquatic plants than to animals is not unexpected. All of the ecotoxicity studies with dimethenamid were conducted using analytically measured test concentrations and perfor med according to EPA guidelines and under GLP.
No test results are available for fish or daphnids for C4. However, predictions made using ECOSAR v1.00 indicate that C4 is slightly toxic to fish (estimated LC50 value 12.0 mg/L) and moderately toxic to da phnids (estimated EC50 value 8.7 mg/L). P redictions for C4 are comparable to the experimental results for dimethenamid for fish and invertebrates. Therefore, these endpoints are considered fulfilled by read

- across.

Recommendation : No additional ecotoxici ty studies are necessary. The required HPV endpoints are fulfilled via a combination of test data, estimation, and read

- across from the endpoint information for dimethenamid.

1 Ecotoxicity categories are according to http://www.epa.gov/oppefed1/ecorisk_ders/toera_analysis_eco.htmHPV Robust Summaries and Test Plan

– C4

17 Table 5. Ecotoxicity information for C4 and dimethenamid

Ecotoxicity Endpoint C4 ( 170373

- 17

- 8 ) Dimethenamid (163515

- 14

- 8)
Acute fish LC50, 96

- h our (mg/L) 1 2.0 (estimated) 1 6.3 for Oncorhynchus mykiss , 10 for Lepomis macrochirus (measured) 2 (Guideline studies, valid without restriction) Acute invertebrate EC50, 48

- h our (mg/L) 8 .7 (estimated) 1 12 for D aphnia magna (measured) 3 ( Guideline study, valid without restriction )

Algal growth inhibition EC50, 72

- h our (mg/L) 58.9 based upon yield for Pseudokirchneriella subcapitata (measured) 4 (Guideline study, valid without restriction) 0.0 17 based upon cell density for Pseudokirchneriella subcapitata (120

- hour exposure) (me asured) 5 ( Guideline stud y , valid without restriction )

Aquatic vascular plant growth inhibition EC50 No data; however, not a SIDS endpoint 0.0089 based upon frond biomass , 0.016 based upon frond number for Lemna gibba (measured) 6 (Guideline study, valid without restriction)

1 estimated by ECOSAR v1.00 2 Graves and Swigert, 1996a; 1996b 3 Graves and Smith, 1996 4 Salinas, 2011 5 Hoberg, 1997a 6 Hoberg, 1997b



### 5.4 Health E f fects

5.4.1 Absorption, Distribution, Metabolis m and E xcretion
No information is available on the absorption, distribution, metabolism and excretion of C4. In a study in which rats were dosed with racemic dimethenamid by intravenous injection or oral
gavag e at doses of 10 and 1,000 mg/kg, good absorption (>90%) and rapid excretion, regardless of exposure route, were observed, with excretion primarily via bile (Vollmin, 1992). By 168 hours after treatment, an average of 90% of the administered dose was elimi nated by all routes, and there was no evidence for bioaccumulation potential. There was no significant difference in absorption, distribution, and elimination, and metabolism of dimethenamid between the sexes or between exposure routes. There was also no significant difference in percent absorption between the low dose and the high dose, or between single and multiple doses. More than 40 metabolites of dimethenamid have been detected in the excreta from rats. Metabolism was primarily throughHPV Robust Summaries and Test Plan

– C4

18

glutathione c onjugation pathways, but reductive dechlorination, oxidation, hydroxylation, O

demethylation, and cyclization were additional metabolic pathways.



### 5.4.2 Acute T oxicity

The oral LD50 of racemic C4 was determined in a study using 6 male rats dosed by ora l gavage at 519 and 2 , 077 mg/kg bw. All three animals in the high dose group died while all three animals in the low dose group survived, resulting in an LD50 of 1 , 038 mg/kg bw (Hamburger, 1988a). The dermal LD50 of racemic C4 was determined in a GLP

- compl iant study i n which C4 was administered topically to 10 rats (male and female) at a dose of 4 , 153 mg/kg bw. No mortality or dose

- related signs of toxicity were observed. The acute dermal LD50 of C4 was thus greater than 4 ,153 mg/kg bw (Hamburger, 1988b).

The oral LD50 of dimethenamid was determined to be 466 mg/kg bw for rats (combined sexes), in a GLP

- compliant guideline study using three doses (350, 400 , and 500 mg/kg bw) with 5 rats per sex per dose (Blaszcak, 1996a). This study resulted in a male LD50 of 429 mg/kg bw and a female LD50 of 531 mg/kg bw. The dermal LD50 of dimethenamid was determined in a GLP

compliant guideline study in which 5 rabbits per sex were dosed at 2 , 000 mg/kg bw. No mortality was observed, resulting in a dermal LD50 of greater t han 2 , 000 mg/kg bw (Blaszcak, 1996b). An acute inhalation study conducted with dimethenamid according to EPA guidelines and under GLP exposed five male and five female rats to 2.2 mg/L (measured concentration) of undiluted dimethenamid as a liquid aerosol. All animals survived, resulting in an acute inhalation LC50 of greater than 2.2 mg/L (Hoffman, 1996).



### 5.4.3 Repeated Dose Toxicity

In a GLP

- compliant study with racemic C4, rats (16 per sex per dose) w ere exposed via the diet for 13 weeks to 0, 100, 300 , and 1 , 000 ppm (Schaefer, 1994). ( These doses were reported to be equivalent to approximately 6.2, 18.2, and 57.7 mg/kg bw/day for males and 7.4, 20.7 , and 66.0 mg/kg bw/day for females). The NOAEL was 300 ppm (ca. 18.2 mg/kg bw/day for males and 20.7 mg/k g bw/day for females , as reported by the authors ), based upon reductions in body weight and food consumption and inhibited body weight gain in both sexes in the 1 , 000 ppm
group.HPV Robust Summaries and Test Plan

– C4

19

Ten rats per sex were exposed for 90 days to dietary concentrations of 0, 500 , 1 , 500 and 3 ,000 ppm dimethenamid in a GLP

- compliant study conducting according to EPA guidelines (Blanset, 1996). The NOAEL was 500 ppm for both sexes (ca. 39 mg/kg bw , as reported by the authors ), based upon decreased body weight gain, increased serum g amma

- glutamyltransferase, and increased cholesterol at the 3 , 000 ppm dose , and similar but lesser effects on body weight gain and serum gamma

- glutamyltransferase at the 1 , 500 ppm dose. Slight changes at 500 ppm (decrease in aspartate aminotransferase, slig ht increase in relative liver weight in males, and slight hepatocellular hypertrophy in females) were not considered adverse.



### 5.4.4 Genetic T oxicity

For racemic C4, bacterial reverse mutation tests were conducted using five strains of S. typhimurium (TA97, TA98, TA100, TA 102, TA1535), both with and without metabolic activation (Suter, 1988a; 1988b; 1988c). C4 demonstrated mutagenic effects on only one strain (TA1535) and only in the absence of metabolic activation. In the first study (Suter, 1988a), test

c oncentrations were 25, 250 , and 2 , 500 ug/plate. No toxicity was observed. Treatment at the highest concentration without metabolic activation increased the number of TA1535 revertants 2.3 times that of the control. In the second study (Suter, 1988b), usin g concentrations of 200 to 3 , 000 ug/plate, an increase in TA1535 revertants (absent metabolic activation) was 1.6 times that of the control at 1 , 000 ug/plate; the next highest dose, 3 , 000 ug/plate, was bacteriotoxic. In t he third study (Suter, 1988c), six concentrations (500 to 3 , 000 ug/plate) were tested on TA1535 without metabolic activation; toxicity was seen at the two highest concentrations, but concentrations of 500, 1 , 000, 1 , 500, and 2 , 000 ug/plate increased the number of revertants over that in the control by factors of 1.63, 2.08, 2.45, and 2.53, respectively. The induction of mutants in this strain was completely suppressed in the presence of S9. C4 had no mutagenic effects on any of the other strains, either with or without activation, up to the bacteriotoxic dose range. No in vitro studies using mammalian cell lines were available for C4, and no in vivo studies were available.

Dimethenamid showed no mutagenic effects in the bacterial reverse mutation assay, conducted under GLP and according to O ECD guidelines (Englehardt and Hoffman, 1997). Four strains of S. typhimurium (TA98, TA100, TA1535, TA1537) and one strain of E. coli (WP2 uvrA) wereHPV Robust Summaries and Test Plan

– C4

20

tested, using the standard plate test and preincubation test, both with and without metabolic activation. Bacteriotoxic effects were seen at doses ≥ 2 , 500 ug/plate in the standard plate test and doses ≥ 500 ug/plate in the preincubation test.

In a study conducted following OECD guideline 476 and performed under GLP, dimethenamid was not mutagenic in the HGPRT assay with Chinese Hamster Ovary ( CHO) cells, both with and without metabolic activation (San and Clark, 1996). Test concentrations were 100 to 450 ug/L without metabolic activation and 100 to 400 ug/L with metabolic activation. Toxicity occurred at the higher test concentrations.

Putman et al. (1996) reported the findings of a mouse micronucleus assay on dimethenamid, conducted according to OECD guideline 474 and under GLP. Dimethenamid was administered at doses of 103, 205, and 410 mg/kg bw (single intraperitoneal dose) to male and femal e mice (15 per sex per dose). Bone marrow preparations from sacrificed animals (24, 48 , and 72 hours) were examined. Even though clinical signs of toxicity were observed in both the mid

- and high

dose groups, no increase in the number of polychromatic eryt hrocytes containing micronuclei was observed at any dose group at any exposure period.



### 5.4.5 Reproductive T oxicity
In the repeated dose study conducted by Schaefer (1994), rats of both sexes were exposed via the diet to 0, 100, 300 , and 1 , 000 ppm of racemi c C4 for a period of 13 weeks (90 days). This study was a sub

- chronic toxicity/neurotoxicity study that was not designed specifically to assess toxicity to reproduction. However, the protocol included macroscopic and microscopic examination of reproductive organs and tissues (e.g., ovaries, testes with epididymides, mammary glands, prostate gland and seminal vesicle, uterus, cervix, vagina). Of the organs with reproductive function, only the ovaries and the testes were weighed. No reproductive tissue effect s were observed at any dose including the highest dose tested, 1 , 000 ppm (ca. 58 mg/kg bw/day in males and 66 mg/kg bw/day in females).

Rats of both sexes were exposed to dimethenamid in the diet (0, 500, 1500 , and 3 , 000 ppm) for 90 days in the repeated dose study conducted by Blanset (1996). Reproductive organs and tissuesHPV Robust Summaries and Test Plan

– C4

21

were examined as part of this study, including weight of ovaries and testes with epididymides as well as histopathology of epididymides, testes, ovaries, and uterus (body horns with c ervix). No effects on the reproductive organs or tissues of either sex were observed at doses up to and including the highest dose, which was approximately equal to 239 mg/kg bw/day.

A two

- generation study was conducted with dimethenamid following OECD g uideline 416 and under GLP (Sutter et al. , 1989). Dimethenamid was administered in the diet to groups of 25 male and 25 female sexually immature rats (F0 generation) at 0, 100, 500, and 2 , 000 ppm (0, 10, 50, and 150 mg/kg bw, as reported by the authors) . A fter 70 days of treatment, the F0 animals were mated and their pups (F1 generation, 25 of each sex) were dosed at the same concentrations for 101 days after weaning. This breeding program was repeated to produce the F2 generation, and the study terminated with sacrifice of the F2 weanlings and F1 adults. Although clear signs of systemic toxicity occurred in both parental generations at 2 ,000 ppm, there were no adverse effects on reproductive parameters of the parental animals at any dose level. The resultin g NOAEL for reproductive function is 2 , 000 ppm (ca. 150 mg/kg bw/day) and the NOAEL for systemic toxicity is 500 ppm (ca. 50 mg/kg bw/day). Data from both the 90

- day study and the
two

- generation study with dimethenamid support the lack of reproductive effe cts at the highest dose, a conc entration of approximately 58

– 66 mg/kg bw/day for C4.



### 5.4.6 Developmental Toxicity
No specific data are available on the developmental toxicity of C4. However, a number of reliable studies are available with data on the devel opmental endpoint for dimethenamid. As discussed above, the two

- generation study by Sutter et al. (1989) exposed rats to dietary doses of 0, 100, 500 , and 2 , 000 ppm. No effects upon survival of pups were seen in either generation. The only treatment

- relate d effect on the offspring was a decreased weight gain during lactation at the highest dose, resulting in a NOAEL for developmental toxicity of 500 ppm (ca. 50 mg/kg bw/day).

The developmental toxicity of dimethenamid was investigated in rats in a study c onducted under GLP and according to EPA guidelines (York, 1996). Dimethenamid was administered at 0, 25, 150 and 300 mg/kg bw to pregnant female rats (25 per group) by g astric intubation during daysHPV Robust Summaries and Test Plan

– C4

22

6

– 15 of gestation, with sacrifice at day 20. No mortaliti es, abortions or premature deliveries occurred, and there were no treatment

- related findings relative to pre

- or post

- implantation losses, number of resorptions, number of viable fetuses, sex ratio of offspring, or external, soft tissue , and skeletal malfo rmations in the offspring. Distinct signs of maternal toxicity resulted at the high dose (body weight reductions, clinical observations, increased liver weight) and reduced maternal body weight gain was also evident at 150 mg/kg bw. The NOAEL for maternal toxicity was therefore 25 mg/kg bw/day. The NOAEL for developmental toxicity was also 25 mg/kg bw/day based on an increased incidence of incomplete ossification of the second sterna centra and/or pelvic pubis at 150 and 300 mg/kg bw/day. These variations w ere considered to possibly relate to a delay in fetal maturity as a result of maternal effects (slightly smaller fetuses and decreases in maternal body weights/gains) at those doses.

A teratogenicity study was conducted for dimethenamid in rabb its accordi ng to OECD guideline 414 and under GLP (Hoberman, 1988)

. Dimethenamid was administered by gastric intubation at 0, 37.5, 75 , and 150 mg/kg bw to pregnant r abbits (25 per group) on days 6

– 18 after insemination. Animals were sacrificed at 29 days post insemi nation. No treatment

- related effects were seen on implantation, live litter size, fetal sex ratio, or fetal body weight, and no external, soft tissue , or skeletal abnormalities were found. Two animals aborted at the highest dose, which was considered treat ment

- related. Signs of maternal toxicity occurred at 75 mg/kg bw/day and 150 mg/kg bw/day, including reduced body weight gain and clinical signs. The NOAEL for maternal toxicity was 37.5 mg/kg bw/day and the NOAEL fo r developmental toxicity was 75 mg/kg bw /day.

Because of the close correspondence between the data for dimethenamid and C4 on the results of acute toxicity, repeated dose toxicity , and reproductive toxicity, developmental toxicity data for dimethenamid can be used to estimate a developmental N OAEL for C4 at a dose of approximately 50 mg/kg bw/day. The two

- generation rat study of dimethenamid (Sutter et al. , 1989) resulted in a developmental NOAEL of 50 mg/kg bw/day, while the developmental NOAEL in rabbits was 75 mg/kg bw/day (Hoberman, 1988). The developmental NOAEL for dimethenamid determined in rats by York (1996) was 25 mg/kg bw/day; however, this was basedHPV Robust Summaries and Test Plan

– C4

23

upon effects that may have been related to a delay in fetal maturity attributable to maternal toxicity.



### 5.4.7 Summary of health effects data

The SIDS endpoints relative to health effects for C4 and dimet henamid are summarized in Table 6 and Section 7 (SIDS Data Matrix), with more detailed information provided in the Robust Summaries submitted with this Test Plan.
Recommendation : No additi onal testing is necessary on health effects endpoints. Reliable data are available from recent, generally GLP

- compliant studies for C4 for the following health effects endpoints: acute oral toxicity, acute dermal toxicity, repeated dose toxicity, mutagenic ity, and reproductive toxicity. There are no data to assess acute inhalation toxicity, clastogenic effects, or developmental toxicity of C4. Reliable data exist for the analog, dimethenamid , for all health effects endpoints . Because of the high degree of s tructural similarity and close agreement between existing endpoints for C4 and dimethenamid, data for dimethenamid are considered sufficient for use in read

- across for C4 where data gaps exist. Therefore, no additional testing is proposed for health effect s data for C4.HPV Robust Summaries and Test Plan

– C4

24 Table 6. Health effects information for C4 and dimethenamid
Toxicity Endpoint C4 ( 170373

- 17

- 8 ) * Dimethenamid (163515

- 14

- 8) Acute oral LD50 (mg/kg) 1038 (rat) 1 (Guideline study, valid with restriction) 466 (rat) 5 (Guideline study, vali d without restriction)

Acute dermal LD50 (mg/kg) > 4153 (rat) 2 (Guideline study, valid without restriction) > 2000 (rabbit) 6 (Guideline study, valid without restriction)

Acute inhalation LC50 (mg/m 3 ) No data > 2.2 mg/L (rat) 7 (Guideline study, valid wi thout restriction)

Repeated dose, NOAEL (mg/kg bw/day) No effects at highest dose tested: 18.2 (males); 20.7 (females) (rat) 3 (Guideline study, valid without restriction) 39 (rat) 8 (Guideline study, valid without restriction)

Genetic Toxicity

– in vitr o In bacterial reverse mutation test, positive in TA1535 strain without metabolic activation, negative with activation in TA1535 and with and without activation in 4 additional strains 4 (Guideline study, valid without restriction) Not mutagenic in bacteri al reverse mutation assay 9 Not mutagenic in CHO/HGRPT assay 10

(Guideline studies, valid without restriction) Genetic Toxicity

– in vivo No data Not clastogenic in mouse micronucleus assay 11 (Guideline study, valid without restriction)
Reproductive toxic ity , NOAEL (mg/kg bw/day) Rat, 90

- day study: no effects on reproductive organs at doses up to and including the highest dose tested, 58

- 66 3 (Guideline study, valid without restriction) Rat, 90

- day study: no effects on reproductive organs at doses up to a nd including the highest dose tested, 239 8 Rat, 2

- generation study: NOAEL for reproductive function = 150 12 ; (Guideline studies, valid without restriction) Developmental toxicity, NOAEL (mg/kg bw/day)
No data Rat: NOAEL for developmental toxicity = 5 0 12 Rat: NOAEL for maternal and developmental toxicity = 25 13 Rabbit: NOAEL for maternal toxicity = 37.5; NOAEL for developmental toxicity = 75 14 (Guideline studies, valid without restriction) * Studies conducted on racemic C4
1 Hamburger, 1988a 9 Engl ehardt and Hoffman, 1997
2 Hamburger, 1988b 10 San and Clark, 1996
3 Schaefer, 1994 11 Putman et al. , 1996
4 Suter, 1988 a ; 1988 b ; 1988 c 12 Sutter, 1989
5 Blasczak, 1996a 13 York, 1996
6 Blasczak, 1996b 14 Hoberman, 1988
7 Hoffman, 1996
8 Blanset, 199 6HPV Robust Summaries and Test Plan

– C4

25



## 6.0 Conclusions and Recommendations

The SIDS Level I endpoints for C4 are filled by a combination of measured and estimated data for the chemical. The adequacy of this information is further supported by comparable data for a closely related chemical, dimethenamid. Where certain data are not available for C4, but reliable data exist for dimethenamid (e.g., toxicity to invertebrates, toxicity to fish, clastogenicity, and developmental toxicity) , information on dimethenamid is used in a read

- across manne r to fill these data gaps.HPV Robust Summaries and Test Plan

– C4

26 26 

## 7.0 SIDS Data Matrix

SIDS Endpoint C4 ( 170373

- 17

- 8 ) Supporting chemical: dimethenamid (163515

- 14

- 8)

Value Reference and

Reliability 1 Value Reference and Reliability Physicochemical Melting point 72.7°C EPIWIN (K2) ≤

- 50°C Kroehl, 1999 (K1) Boiling point 277.8°C EPIWIN (K2) ≥ 280oC Kroehl, 1999 (K1) Vapor pressure 0.002 96 hPa EPIWIN (K2) 0.0000251 hPa Chen and Laster, 1996 (K1) Partition coefficient (Log Kow) 2.68 EPIWIN (K2) 1.89 Lam, 1988 (K1) Water Solubil ity 472.5 mg/L at 2 2 oC Rachmalla, 2009 (K1) 1449 mg/L Laster, 1996 (K1) Environmental fate Photodegradation (t 1/2 ) 1.1 hr (12

- hr day) EPIWIN (K2) 2.5 hr (12

- hr day)

24

- 26 days (in water) EPIWIN (K2)
Guirguis, 1997a; Sabat, 1992 (K1) Hydrolysis S table Stable at pH 5, 7 and 9 for 31 days Guirguis, 1997b (K1) Fugacity <0.1% air, 2 1.1 % water, 7 8.6 % soil, 0.2% sediment EQC Level III (K2) 0. 1 % air, 18.9 % water, 80.8 % soil, 0. 2 % sediment EQC Level III (K2)
Biodegradability Not readily biodegradable (1.8% in 28 days) (OECD 310) Schwarz, 2009 (K1) Primary biodegradation in days

- weeks, ultimate biodegradation in months EPIWIN (K2) Ecotoxicity Acute Fish 96

- h LC50 12.0 mg/L (estimated) ECOSAR (K2) 6.3 mg/L ( O. mykiss ); 10 mg/L ( L. macrochirus ) Gr aves and Swigert, 1996a (K1) Graves and Swigert, 1996b (K1) Acute Invertebrate 48

- h EC50 8 .7 mg/L (estimated) ECOSAR (K2) 12 mg/L ( D. magna ) Graves and Smith, 1996 (K1) Algal Inhibition 72

- h EC50 58.9 mg/L based on yield ( P. subcapitata ) Salinas, 2011 (K1) 0.017 mg/L based on cell density at 5

- days ( S. capricornutum ) Hoberg, 1997 a (K1) Toxicity Acute Oral LD50 1038 mg/kg (rat) Hamburger, 1988a (K2) 2 466 mg/kg (rat) Blaszcak, 1996a (K1) Acute Dermal LD50 > 4153 mg/kg (rat) Hamburger, 1988b (K1 ) 2 > 2000 mg/kg (rabbit) Blaszcak, 1996b (K1) Acute Inhalation LC50 > 2.2 mg/L (rat) Hoffman, 1996 (K1) Repeated Dose, NOAEL 18.2 (males); 20.7 (females) mg/kg bw (rat) [highest dose tested] Schaefer, 1994 (K1) 2 39 mg/kg bw/day (rat) Blanset, 1996 (K 1)HPV Robust Summaries and Test Plan

– C4

27 27 SIDS Endpoint C4 ( 170373

- 17

- 8 ) Supporting chemical: dimethenamid (163515

- 14

- 8)

Value Reference and

Reliability 1 Value Reference and Reliability Genetic Tox

– In vitro Positive without S9 in TA1535; negative with S9 in TA1535 and negative with and without activation in four other strains Suter, 1988a (K1) 2 ; Suter 1988b (K1) 2 ; Suter, 1988c (K1) 2 Not mutagenic in bacterial reverse mutation
assa y Not mutagenic in the CHO/HGPRT assay Englehardt and Hoffman, 1997 (K1)
San and Clark, 1996 (K1) Genetic Tox

– In vivo Not clastogenic based upon read

- across from dimethenamid data Not clastogenic in mouse micronucleus assay Putman, 1996 (K1)
Reprod uctive , NOAEL Rat, 90

- day study: no effects on reproductive organs or tissues at highest doses tested, 58

- 66 mg/kg bw/day Schaefer, 1994 (K2) 2 Rat, 90

- day study: no effects on reproductive organs at doses up to and including the highest tested, 239 mg/kg bw/day

In a 2

- generation study, NOAEL for reproductive function = 150 mg/kg bw/day (rat) Blanset, 1996 (K1)

Sutter et al. , 1989 (K1)

Developmenta l, NOAEL Estimated at 50 mg/kg bw/day based upon a weighted data read

- across from dimethenamid NOAEL for developmental toxicity = 50 mg/kg bw/day (rat)
NOAEL for maternal and developmental toxicity = 25 mg/kg bw/day (rat)
NOAEL for maternal toxicity = 37.5 mg/kg bw/day and for developmental toxicity = 75 mg/kg bw/day (rabbit) Sutter et al. , 1989 (K1)

York, 1996 (K1)

Hoberman, 1988 (K1)

1 Reliability refers to the Klimisch score: K1 = Reliable without restriction K2 = Reliable with restriction K3 = Not reliable K4 = Not assignable 2 Studies conducted on racemic C4HPV Robust Summaries and Test Plan

– C4

28



## 8 .0 References

This li st of references is for studies as cited in Sections 1 through 7 , while a complete list of all data sources reviewed in the development of the Test Plan and Robust Summaries for C4 can be found in the Robust Summaries.

Blanset, D. 1996. A subchronic (3

- mon th) toxicity study of SAN 1289 H in the rat via dietary administration. Huntingdon Life Sciences, East Millstone, New Jersey, USA, unpublished. BASF RegDoc #96/5420. Blaszcak, D. 1996a. Acute oral toxicity with SAN 1289H Technical in rats. Huntingdon Life Sciences, East Millstone, New Jersey, USA, unpublished BASF RegDoc #96/11087. Blaszcak, D. 1996b. Acute dermal toxicity with SAN 1289 H technical in rabbits. Huntington Life Sciences, East Millstone, New Jersey, USA, unpublished. BASF RegDoc #96/5395.
Ch en, H. 1997. Boiling Point of SAN 1289 H, Technical. SANDOZ Agro, Inc., Des Plaines, Illinois, unpublished. BASF RegDoc #97/5194. Chen, H., Laster, W. 1996. Vapor pressure of SAN 1289 H. SANDOZ Agro, Inc., Des Plaines, Illinois, unpublished. BASF RegDoc #9 6/5418. Engelhardt, G., and Hoffman, H. 1997. Salmonella typhimurium / Escherichia coli reverse mutation assay (standard plate test and preincubation test) with s

- dimethenamid. BASF Aktiengesellschaft, Ludwigshafen, Germany, unpublished. BASF RegDoc #97/1062 1.
EPISuite v 4.00 , US Environmental Protection Agency, 2000

- 2008. Graves, W., and Smith, G. 1996. SAN 1289 H Technical: A 48

- hour flow

- through acute toxicity test with the cladoceran ( Daphnia magna ). Wildlife International, Ltd., Easton, Maryland, USA, unp ublished BASF RegDoc #96/5415/ Graves, W., Swigert, J. 1996a. SAN 1289 H Technical: A 96

- hour flow

- through acute toxicity test with rainbow trout ( Oncorchynchus mykiss ). Wildlife International, Ltd., Easton, Maryland, USA, unpublished. BASF RegDoc #96/5417

. Graves, W., Swigert, J. 1996b. SAN 1289 H Technical: A 96

- hour flow

- through acute toxicity test with the bluegill ( Lepomis macrochirus ). Wildlife International, Ltd., Easton, Maryland, USA, unpublished. BASF RegDoc #96/5414. Guirguis, A.S. 1997a. S

- dimet henamid: Photodegradation study in an aqueous solution. SANDOZ Agro, Inc., Des Plaines, Illinois, unpublished. BASF RegDoc #97/5195.HPV Robust Summaries and Test Plan

– C4

29

Guirguis, A.S. 1997b. Hydrolysis of s

- dimethenamid. SANDOZ Agro, Inc., Des Plaines, Illinois, unpublished. BASF RegDoc #97/ 5184. Hamburger, F. 1988a. T01184 (SAN 582

- Stufe C

- 4 "Via Keto

- Enol") Acute oral LD50 toxicity study in male rats . Sandoz, Ltd. Agro Division Department of Toxicology, Basel, Switzerland. Study No.: 6949/88. 17 Nov 1988. Hamburger, F. 1988b. T01184 (SAN 58 2

- Stufe C

- 4 "Via Keto

- Enol") Acute dermal toxicity study in male and female rats. Sandoz, Ltd. Agro Division Department of Toxicology, Basel, Switzerland. Study No.: 6963/88. 15 Dec 1988. Hoberg, J. 1997a. SAN 1289 H Technical: Toxicity to the freshwater g reen alga, Selenastrum capricornutum . Springborn Laboratoties, Inc., Wareham, Massachusetts, USA, unpublished. BASF RegDoc #97/5170. Hoberg, J. 1997b. SAN 1289 H Technical: Toxicity to duckweed, Lemna gibba . Springborn Laboratories, Inc., Wareham, Massachu setts, USA, unpublished. BASF RegDoc #97/10742. Hoberman, A. 1988. Developmental toxicity (embryo/fetal toxicity and teratogenic potential) study of SAN 582 H administered orally (stomach tube) to New Zealand white rabbits. ARGUS Research Laboratories, Hor sham, Pennsylvania, USA, unpublished. BASF RegDoc #88/11376. Hoffman, G. 1996. An acute (4

- hour) inhalation toxicity of SAN 1289 H technical in the rat via
nose

- only exposure. Huntington Life Sciences, East Millstone, New Jersey, USA, unpublished. BASF Re gDoc #96/5397. Klimisch, H.J., Andreae, M., and Tillmann, U. 1997. A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regulatory Toxicol. and Pharmacol. 25:1

- 5. Kroehl, T. 1999. Physical Properties of Dimethenamid

- P (PAI). BASF Aktiengesellschaft, Ecology and Environmental Analytics, BASF RegDoc #99/10167. Kruger, J.P., Bade, T.R. 1990. Aerobic soil metabolism of SAN 582H, SANDOZ Agro Inc., Des Plaines, IL, unpublished, BASF RegDoc.#90/11105
Lam, W.W. 1 988. Determination of the n

- Octanol/Water Partition Coefficient for Dimethenamid

- p. BASF Corporation Agricultural Products Group, Research Triangle Park, NC, unpublished. BASF RegDoc #98/5071. Laster, W. 1996. Solubility of SAN 1289 H in Water. SANDOZ Agr o, Inc., Des Plaines, Illinois, unpublished. BASF RegDoc #96/5411. Mackay, D., DiGuardo, A., Paterson, S., and Cowan, C. et al. 1996. Evaluating the environmental fate of a variety of types of chemicals using the EQC Model. Envir. Toxicol. Chem. 15:1627

- 37

.HPV Robust Summaries and Test Plan

– C4

30

Putman, D., et al. 1996. Micronucleus cytogenetic assay in mice: SAN 1289 H technical M icrobiological Associates, Rockville, Maryland, USA, unpublished. BASF RegDoc #96/5401. Rachmalla, L.R. 2009. Determination of the water solubility of 2,4

- dimethyl

- N

- ( 1

- methyl

2methoxy) ethyl

- 3

- aminothiophene (C4) by OECD Guideline for the Testing of Chemicals #105 Flask Method. BASF DocID 2008/7019372. BASF Corporation, 14385 West Port Arthur Road, Beaumont, TX 77705. Sabat, M. 1992. SAN 582 H: Photodegradation Study in Aqueous Solution. SANDOZ Agro, Inc., Des Plaines, Illinois, unpublished. BASF RegDoc #92/12388. Salinas, E. 2011. Report: Reg No. 364802 (Process

- intermediate of BAS 656

- PH, DMTA

- P), Growth inhibition study in unicellular green algae Pseudokirchneriella subcapitata Korshikov. BASF DocID 2010/1079321. Experimental Toxicology and Ecology, BASF SE 67056 Ludwigshafen, Germany, Project No. 60E0934/083697. San, R., Clark, J. 1996. CHO/HGPRT mutation assay: SAN 1289 H technical. M icrobiological Associates, Rock ville, Maryland, USA, unpublished. BASF RegDoc #96/5404. Schaefer, G.J. 1994. 13 week combined Subchronic oral toxicity and neurotoxicity study in rats. International Research and Development Corporation, Mattawan, MI. Study no. 658

- 005. Submitted to: Sand oz Agro, Inc., May 6, 1994. BASF RegDoc #94/11896. Schwarz, H. 2009. Report Reg. No. 364802 (Process

- intermediate of BAS 656

- PH, DMTA

- P), Determination of the biodegradability in the CO 2 - headspace test. BASF DocID 2009/1050251. Experimental Toxicology and Ecology, BASF SE 67056 Ludwigshafen, Germany, Project No. 27G0934/083656. Suter, W. 1988a. T01184 San 582H C

- 4 Intermediate (Via Keto

- Enol) Mutagenicity Evaluation Using Salmonella typhimurium . Sandoz, Ltd. Pharma Division Research and Development. Study N o.: Mut. Bact. 30/88_1. 11 Nov 1988. Suter, W. 1988b. T01184 San 582H C

- 4 Intermediate (Via Keto

- Enol) Mutagenicity Evaluation Using Salmonella typhimurium . Sandoz, Ltd. Pharma Division Research and Development. Study No.: Mut. Bact. 30/88_2. 11 Nov 1988. Suter, W. 1988c. T01184 San 582H C

- 4 Intermediate (Via Keto

- Enol) Mutagenicity Evaluation Using Salmonella typhimurium . Sandoz, Ltd. Pharma Division Research and Development. Study No.: Mut. Bact. 30/88_3. 11 Nov 1988. Sutter, P., et al. 1989. SAN 582 H: T wo

- generation reproduction study in the rat. RCC, Research & Consulting Company AG, Switzerland, unpublished. BASF RegDoc #90/11140.
U.S. EPA. 1999a. The use of structure

- activity relationships (SAR) in the High Production Volume Chemicals Challenge Progra m. Available at http://www.epa.gov/chemrtk/sarfinl1.htm

. U.S. EPA. 1999b. Determining the adequacy of existing data. Available at: http://www.epa.gov/chemrtk/pubs/general/datadfin.htm

.HPV Robust Summaries and Test Plan

– C4

31

U.S. EPA. 2011. Interpretive assistance document for assessment of discrete organic chemicals: sustainable futures summary assessment. Updated August 2011. Available at http://www.epa.gov/opptintr/sf/pubs/iad_discretes_092011.pdf

. Vollmin, S. 1992. Absorption, distribution, metabolism and excretion of (14C) SAN 582 in rat after single and multiple doses (adden dum to: SAN 582 H metabolism in rat; BASF RegDoc# 89/11026). SANDOZ Agro, Ltd., Basle, CH. BASF RegDoc# 92/12428. Wendt, D.R. 1997. Comparative aerobic soil metabolism of SAN 1289 H and SAN 582 H. Sandoz Agro, Inc., Des Plaines, Illinois 60018, unpublished . BASF RegDoc #97/5257. Wilson, L.C. 1989. Letter report of vapor pressure measurements for C

- 4 and C

- 5, letter to Cal Spencer, The M.W. Kellogg Company, from Loren C. Wilson, W il tec Research Company, Inc., dated March 8, 1989. Wyss

- Benz, M., Vokel, W. 199 4. [3

- 14C

- thienyl] dimethenamid degradation and metabolism in aerobic aquatic systems, RCC, Research and Consulting Company AG, Switzerland, unpublished, BASF RegDoc.#94/10641. York, R. 1996. Oral (gavage) developmental toxicity study of SAN 1289 H in rats . A rgus Research Laboratories, Horsham, Pennsylvania, USA, unpublished. BASF RegDoc #97/5274.