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 Road, Suite 500

Alexandria, VA 22314

On behalf of:

BASF Corporation

3150 Highway JJ

Palmyra, MO 63641

Date of submission:

February 16, 2012
HPV Robust Summaries and Test Plan – C4

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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 Ecotoxicity 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 28
HPV 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 24
HPV 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 known 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 C4 is an 

intermediate in the production of dimethenamid, the compounds are very similar in structure, the 

primary difference being the addition of chloroacetamide to 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 the 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 events 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 released to the environment, C4 is expected to 

partition primarily to soil (78.6%) and water (21.1%). 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 predicted 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 bioaccumulate. C4 was not biodegradable in 28 days in a ready biodegradability 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, according 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 C4 
HPV Robust Summaries and Test Plan – C4

2

to fish or invertebrates. Based upon structure-activity relationships, C4 is expected to be slightly 

to moderately 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 fish 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 

available 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 LD50 in rats was greater than 

4,153 mg/kg. Supporting data for dimethenamid consist of an acute oral 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/kg 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 next 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 decreased 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 for 
HPV Robust Summaries and Test Plan – C4

3

maternal toxicity and 75 mg/kg bw/day for developmental toxicity. Although there are no 

developmental toxicity 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 activation, 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, nor 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 solubility, 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 Fate

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 N
HPV Robust Summaries and Test Plan – C4

5

2.0 Introduction

2.1 Overview

Exponent, 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 Environmental 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 Screening 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 scientific 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 number 

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 physicochemical 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 approach. 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 similar 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 structural analogs is consistent with EPA guidance for use of structure-activity 

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

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 transport estimates were developed 

using the Level III Equilibrium Criteria Model (EQC) in EPIWIN v4.00 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 

available 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 of 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. Samples are handled in 

laboratory 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 prevented 
HPV Robust Summaries and Test Plan – C4

8

through worker training regarding proper health and safety procedures, the use 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 small 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 environmental 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 environmental release. In summary, C4 poses a minimal exposure threat to workers or 

the environment. 

4.0 Analogs 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 analogs for an HPV chemical are those that resemble the candidate chemical in terms 

of the following:

1. Molecular structure/size; 

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

3. Some molecular property (e.g., lipophilicity, electronic and steric parameters); 

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 metabolism.

4.2 Structural Similarity and Comparison of Data for C4 and 

Dimethenamid

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, the 

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 is 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-dimethenamid 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 exceptions: 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 dimethenamid-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 

presented in Figure 2. 

C4

 

Dimethenamid

Figure 2. Comparison of structures of C4 and Dimethenamid
HPV 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 these 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, metabolism, 

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 dimethenamid

Substance 

Information and 

Properties

C4

(170373-17-8)

Dimethenamid

(163515-14-8)

Synonym 3-thiophenamine, N[(1S)-2-methoxy-1-

methylethyl]-2,4-dimethylS-2-chloro-N-(2,4-dimethyl-3-thienyl)-N-(2-methoxy-1-methylethyl)-acetamide

Molecular Formula C10H17NOS C12H18ClNO2S

Molecular weight 199.3 275.79

Water solubility 472.5 mg/L 1449 mg/L

Algal toxicity EC50 58.9 mg/L10.017 mg/L2

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

Reproductive 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 density
HPV 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 Properties

Data on the physico-chemical properties of C4 and dimethenamid are presented in Table 3. The 

source of the information is classified as “estimated” 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 Robust 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 flask 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 temperature 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 provide 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 from 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 data on physico-chemical properties for C4. 
HPV Robust Summaries and Test Plan – C4

13

Table 3. Physico-chemical properties of C4 and dimethenamid

Substance 

Information and 

Properties

C4

(170373-17-8)

Dimethenamid

(163515-14-8)

Synonym 3-thiophenamine, N[(1S)-2-methoxy-1-

methylethyl]-2,4-dimethylS-2-chloro-N-(2,4-dimethyl-3-thienyl)-N-(2-methoxy-1-methylethyl)-acetamide

Molecular Formula C10H17NOS C12H18ClNO2S

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 0.00296 hPa (estimated)

0.0000251 hPa (measured)3

(Guideline study, valid 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 study, 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 

available data fill the HPV required data elements with sufficient precision to define the potential 

hazards of C4.

5.2 Environmental Fate and Pathways

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 C4 using AOPWIN v1.92. The resulting halflife 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 solution, the photodegradation half-life was 24–26 days (Guirguis, 

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

3

/mole; 

HENRYWIN v3.20) is very low and indicates a lack of volatility. A guideline study 

demonstrated that dimethenamid 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 lacks functional groups that 

hydrolyze under environmental conditions. 

5.2.2 Bioaccumulation, Fugacity, and Biodegradation

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 (78.6%) and water (21.1%), 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 sealed 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%) indicated 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 half-life of dimethenamid was 
HPV 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 (estimated)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: 21.1%; Soil: 78.6%; 

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 daysweeks, 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 Guirguis, 1997a; Sabat, 1992

5 Guirguis, 1997b

6

Schwarz, 2009

5.3 Ecotoxicity

Acute aquatic toxicity data are summarized in Table 5 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. 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 to 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 of C4 (10 to 220 mg/L nominal) in algal medium. Test 
HPV 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 basis 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 slightly toxic to algae,1and 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), the 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 

an 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 performed 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 daphnids (estimated EC50 value 8.7 mg/L). Predictions 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 ecotoxicity 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.htm
HPV 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-hour

(mg/L) 12.0 (estimated)1

6.3 for Oncorhynchus mykiss, 10 for Lepomis 

macrochirus (measured)2

(Guideline studies, valid without restriction)

Acute invertebrate EC50, 48-

hour (mg/L) 8.7 (estimated)1

12 for Daphnia magna (measured)3

(Guideline study, valid without restriction)

Algal growth inhibition EC50, 

72-hour (mg/L)

58.9 based upon yield for 

Pseudokirchneriella subcapitata

(measured)4

(Guideline study, valid without 

restriction)

0.017 based upon cell density for 

Pseudokirchneriella subcapitata (120-hour 

exposure) (measured)5

(Guideline study, 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 Effects

5.4.1 Absorption, Distribution, Metabolism and Excretion

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 

gavage 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 eliminated 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 through 
HPV Robust Summaries and Test Plan – C4

18

glutathione conjugation pathways, but reductive dechlorination, oxidation, hydroxylation, Odemethylation, and cyclization were additional metabolic pathways. 

5.4.2 Acute Toxicity

The oral LD50 of racemic C4 was determined in a study using 6 male rats dosed by oral 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-compliant study in 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 GLPcompliant 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 than 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) were 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/kg 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 gamma-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, slight increase in relative liver weight in males, and 

slight hepatocellular hypertrophy in females) were not considered adverse.

5.4.4 Genetic Toxicity

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 

concentrations 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), using 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 the 

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 OECD guidelines (Englehardt and Hoffman, 1997). Four strains of 

S. typhimurium (TA98, TA100, TA1535, TA1537) and one strain of E. coli (WP2 uvrA) were 
HPV 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 female 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 highdose groups, no increase in the number of polychromatic erythrocytes containing micronuclei 

was observed at any dose group at any exposure period.

5.4.5 Reproductive Toxicity

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 racemic 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 

effects 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 tissues 
HPV 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 cervix). 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 guideline 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). After 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 resulting 

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 effects at the highest 

dose, a concentration 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 developmental 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-related 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 conducted 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 gastric intubation during days 
HPV Robust Summaries and Test Plan – C4

22

6–15 of gestation, with sacrifice at day 20. No mortalities, 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 malformations 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 were 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 rabbits according 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 rabbits (25 per group) on days 6–18 after 

insemination. Animals were sacrificed at 29 days post insemination. 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 treatment-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 for 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 NOAEL 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 based 
HPV 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 dimethenamid 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 additional 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, mutagenicity, 

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 structural 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 effects 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, valid 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/m3)

No data > 2.2 mg/L (rat)7

(Guideline study, valid without 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 vitro 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 strains4

(Guideline study, valid without restriction) 

Not mutagenic in bacterial reverse mutation assay9

Not mutagenic in CHO/HGRPT assay10

(Guideline studies, valid without restriction)

Genetic Toxicity – in vivo No data Not clastogenic in mouse micronucleus assay11

(Guideline study, valid without restriction)

Reproductive toxicity, 

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 and including the highest dose tested, 

239 8

Rat, 2-generation study: NOAEL for reproductive 

function = 15012; 

(Guideline studies, valid without restriction)

Developmental toxicity, 

NOAEL

(mg/kg bw/day)

No data

Rat: NOAEL for developmental toxicity = 50 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

1Hamburger, 1988a 9 Englehardt and Hoffman, 1997

2Hamburger, 1988b 10 San and Clark, 1996

3

Schaefer, 1994 11 Putman et al., 1996

4 Suter, 1988a; 1988b; 1988c12 Sutter, 1989

5 Blasczak, 1996a 13 York, 1996

6 Blasczak, 1996b 14 Hoberman, 1988

7 Hoffman, 1996

8 Blanset, 1996
HPV 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 manner 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 

Reliability1 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 0.00296 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 Solubility 472.5 mg/L at 22oC Rachmalla, 2009 (K1) 1449 mg/L Laster, 1996 (K1)

Environmental fate

Photodegradation (t1/2) 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 Stable Stable at pH 5, 7 and 9 for 31 days Guirguis, 1997b (K1)

Fugacity <0.1% air, 21.1% water, 78.6% 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)

Graves 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, 1997a (K1)

Toxicity

Acute Oral LD50 1038 mg/kg (rat) Hamburger, 1988a (K2)2466 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)239 mg/kg bw/day (rat) Blanset, 1996 (K1)
HPV Robust Summaries and Test Plan – C4

27

27

SIDS Endpoint

C4

(170373-17-8)

Supporting chemical: dimethenamid

(163515-14-8)

Value

Reference and 

Reliability1 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 

assay

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)

Reproductive, 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)

Developmental, 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)

1Reliability refers to the Klimisch score:

K1 = Reliable without restriction

K2 = Reliable with restriction

K3 = Not reliable

K4 = Not assignable

2

Studies conducted on racemic C4
HPV Robust Summaries and Test Plan – C4

28

8.0 References

This list 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-month) 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.

Chen, 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 #96/5418.

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 #97/10621.

EPISuite v4.00, 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, 

unpublished 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 

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study in male rats. Sandoz, Ltd. Agro Division Department of Toxicology, Basel, Switzerland. 

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Hamburger, F. 1988b. T01184 (SAN 582-Stufe C-4 "Via Keto-Enol") Acute dermal toxicity 

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Putman, D., et al. 1996. Micronucleus cytogenetic assay in mice: SAN 1289 H technical 

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aerobic aquatic systems, RCC, Research and Consulting Company AG, Switzerland, 

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