## U.S. EPA

High Production Volume Chemical Challenge Program

Robust Summaries and Test Plan for Trichlorinated Ketone (CAS No. 145556

- 04

- 3 )

Revised Submission



## Submitted by:

Exponent, Inc.
1800 

## Diagonal Road, Suite 500 Alexandria, VA 22314

On behal f of:

BASF Corporation 3150 Highway JJ Palmyra, MO 63641

Date of submission: December 21 , 2011- This page intentionally left blank

-HPV Robust Summaries and Test Plan

– Trichlorinated ketone

ii Table of Contents

1.0 Executive Summary 1

2.0 Introduction 4
2.1 Overview 4
2.2 Methods for Data Review 4

3.0 Substance Information for Trichlorinated Ketone 6
3.1 Substance Description 6
3.2 Use and Exposure Information 6

4.0 Analogs for Trichlorinated Ketone 7
4.1 EPA Guidance for Use of Analogs 7
4.2 Structural Similarity and Comparison of Data for TCK and DCP 8

5.0 Data Analysis 9
5.1 Physicochemical Properties 10
5.2 Environmental Fate and Pathways 10 5.2.1 Photodegradation, V olatilization, and Hydrolysis 10 5.2.2 Bioaccumulation, Fugacity, and Biodegradation 11
5.3 Ecotoxicity 12
5.4 Health Effects 14 5.4.1 Absorption, Distribution, Metabolism and Excretion 14 5.4.2 Acute Toxicity 14 5.4.3 Repeated Dose Toxicity 15 5.4.4 Genetic Toxicity 15 5.4.5 Reproductive Toxic ity 16 5.4.6 Developmental Toxicity 16 5.4.7 Summary of Health Effects Data 17

6.0 Conclusions and Recommendations 19

7.0 SIDS Data Matrix 20

8.0 References 22HPV Robust Summaries and Test Plan

– Trichlorinated ketone

iii List of Figures

Figure 1. Structure of trichlorinated ketone 6 Figure 2. Comparison of structures of TCK and DCP 8

List of Tables

Table 1. Testing plan and ra tionale 3 Table 2. Comparison of physicochemical properties of TCK and DCP 9 Table 3. Environmental fate and pathways informatio n for TCK and DCP 12 Table 4. Ecotoxicity information for TCK and DCP 13
Table 5. Health effects information for TCK and DCP 18HPV Robust Summaries and Test Plan

– Trichlorinated ketone

1 

## 1.0 Executive Summary

Trichlorinated ketone (CAS No. 145556

- 04

- 3), also known as TCK or 3

- pentanone, 1,2,4

- trichloro

- 2

- methyl, is a colorless to slightly yellow liquid with a pungent odor and a molecular weight of 203. 5 g/mole. The available data for TCK (measured, estimated, and from references) were supplemented with data on a related chemical, dichloropinacolin (CAS No. 22591

- 21

- 5), also known as DCP, which was used as an analog.

Trichlorinated ketone is a closed

- sy stem intermediate in the manufacturing process for the
herbicide dimethenamid . Potential exposures are thought to be extremely limited, because of the moderately low volatility of TCK
, which limits inhalation exposures, and because personal protective equi pment 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 fugacit y modeling predicts that, if released to the environment, TCK is expected to partition primarily to soil (7 1.7 %) and water (2 6.6 %). Vapor

- phase TCK , which is expected
to be limited as a result of its moderate volatility, will be degraded in the atmosphere by reaction with hydroxyl radicals, with a half

- life of 6.8 days. TCK is not expected to undergo hydrolysis
in the environment because of the lack of functional groups that hydrolyze under environmental
conditions. Because of its relatively low octanol

- water partition coefficient, TCK is not expected
to bioaccumulate to any great extent

. TCK was not biodegradable in 28 days in a ready biodegradability test conducted according to OECD Guideline 3 10

.

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

- h our EC50 for TCK, based upon yield, was 6.32 mg/L

. There are no studies available on the toxicity
of TCK to fish or invertebrates

. However, b ased upon structure

- activity relationships
, TCK is estimated to be highly toxic to fish ( LC50 of 0.11 mg/L) and Daphnia ( EC50 of 0.66 mg/L).HPV Robust Summaries and Test Plan

– Trichlorinated ketone

2 Reliable data from guideline studies conducted under Good Laboratory Practices ( GLP ) are available for T CK to fulfill the SIDS Level 1 endpoints for health effects. The acute oral LD50
for TCK in rats was 500

– 2 , 500 mg/kg , while the acute dermal LD50 in rats was greater than
2 , 000 mg/kg. Supporting data for DCP consist of an acute oral LD50 for rats of 1
, 820 mg/kg for
males and 1
, 300 mg/kg for females, an acute dermal LD50 for rabbits of > 5,000 mg/kg for males and approximately 5
, 000 mg/kg for females, and acute inhalation LC50 values of > 1
, 179 mg/m 3 for rats and mice and > 1
, 234 mg/m 3 for hamsters and rabbi ts. In a 13

- week repeated dose oral study with rats, the NOAEL for TCK was 200 ppm (21.1−23.1 mg/kg bw/day)

. This study also found no evidence of gross or histopathological effects in the reproductive organs of male or female rats up to and including a dose of 2
, 000 ppm (211

– 231 mg/kg bw/day).

In the bacterial reverse mutation assay, TCK was positive in only one of five strains , in which a
4.7

- fold increase in revertants per plate was observed. In an in vitro mammalian chromosomal aberration test conducted according to OECD 473, clastogenic effects were observed both in the

presence a nd absence of metabolic activation. Effects on reproductive organs were not observed
in a 90

- day repeated dose study with rats at doses up to and including 211 mg/kg bw/day for males and 231 mg/kg b w/day for females. In developmental toxicity testing with rats and rabbits, effects on the offspring occurred only at maternally toxic doses. For rats, the maternal NOAEL was 125 mg/kg bw/day and the developmental NOAEL was 250 mg/kg bw/day. For rabbits, the maternal NOAEL was 50 mg/kg bw/day and the dev elopmental NOAEL was 100 mg/kg bw/day.

The original test plan submitted by BASF to EPA for TCK in May 2008 identified several data gaps for HPV elements. This revised test plan incorporates the results of testing conducted on TCK by the sponsor since that date
, to determine the boiling point, water solubility, biodegradability, acute toxicity to algae, and clastogenicity. Including these new data, the overall conclusions and recommendations are that adequate information exists for all HPV elements for
tric hlorinated ketone. T his information is summarized in Table 1

.HPV Robust Summaries and Test Plan

– Trichlorinated ketone

3 Table 1

. Testing plan and rationale

CAS # 145556

- 04

- 3 T richlorinated Ketone (T CK ) Information Available?

OECD Study?

GLP Study?

Supporting Information?

Estimation Method?

Acceptable?

Testing Rec ommended?

HPV Endpoint
Physicochemical Properties
Melting Point Y N N Y Y Y N
Boiling Point Y Y 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 Y 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 Y 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 Y N

Hea lth Effects

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

– Trichlorinated ketone

4 

## 2.0 Introduction

2.1 Overview

Exp onent, on behalf of BASF Corporation, has prepared the revised robust summaries and revised test plan for trichlorinated ketone, also referred to as TCK or 3

- pentanone, 1,2,4

- trichloro

- 2

- methyl (CAS No. 145556

- 04

- 3 ), under the United States Environmental P rotection Agency’s (U.S. EPA) Extended High Production Volume (eHPV) Chemical Challenge Program.

The purpose of this plan is to develop physicochemical data, environmental fate and effects data,
and mammalian health effects data for TCK consistent with th e Screening Information Data Set (SIDS). Therefore, this plan summarizes the existing SIDS data for TCK and an analog, dichloropinacolin, 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 trichlorinated ketone and the analog, dichloropinacolin

. Searches were conducted on CAS numbers and chemical names 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.) we re consulted for physicochemical properties.

This document addresses a single e HPV sponsored chemical; however, data for a closely related compound, dichloropinacolin (CAS No. 22591

- 21

- 5 ) have been used to support the data set for the sponsored chemical t hrough a read

- across approach. Data read

- across means thatHPV Robust Summaries and Test Plan

– Trichlorinated ketone

5 physicochemical property and toxicological data from one chemical are used to estimate those same characteristics for another chemical, and is appropriate only when the two chemicals are
deemed su fficiently 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 (EPA, 1999a).

In accordance with U.S. EPA guidance, in those instances where measured physicochemical

para meters and environmental fate data were not available, these properties were developed using EPIWIN (EPISuite version4.0) modeling. EPIWIN is an acronym for the Estimation Programs Interface for Microsoft Windows, and is a package of computer programs dev eloped by the U.S. EPA Office of Pollution Prevention and Toxics (OPPTS)
, which uses computational
methods and SAR s in estimating chemical properties, environmental fate, and aquatic toxicity of organic chemicals. Because of the inherent limitations of SA R approaches, EPIWIN modeling may produce non

- realistic estimates; therefore, EPIWIN data are evaluated for reasonableness prior to use as surrogate data

. In accordance with EPA guidance, environmental transport and fate estimates were developed using the Level III Equilibrium Criteria Model (EQC) in EPIWIN v4.0 as described by Mackay et al. (1996).

Robust summaries were prepared for trichlorinated ketone and dichloropinacolin in EPA’s High Production Volume Information System (HPVIS) for key studies to p rovide a detailed summary
of the test methods and results. Though several studies may have been evaluated for a particular SIDS endpoint, robust summaries were generally prepared only for the critical study that represented the best available data. Selec tion 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. EPA’s (1999b) methods for determining the adequacy of existing data.
Reliable studie s that provided supporting data were also included.HPV Robust Summaries and Test Plan

– Trichlorinated ketone

6 

## 3.0 Substance I nformation for Trichlorinated Ketone

3.1 S ubstance D escription

Trichlorinated ketone (CAS No. 145556

- 04

- 3 ) , also known as 3

- pentanone, 1,2,4

- trichloro

- 2

- methyl, or TCK, is used in the m anufacture of the herbicide dimethenamid. It is a colorless to slightly yellow liquid with a pungent odor and has a molecular weight of 203.5 g/mole. The structure of TCK is shown in Figure 1.

Figure 1. Structure of trichlorinated ketone



### 3.2 Use and Exp osure Information

Trichlorinated ketone is a closed

- system intermediate used in the manufacture of the herbicide
dimethenamid. P roduction volume is between 5 and 15 million pounds per year; hence TCK 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. Trichlorinated ketone 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 through worker trainingHPV Robust Summaries and Test Plan

– Trichlorinated ketone

7 regarding proper health and safety proced u res , the use of proper personal protective equipment ( PPE ) , and engineering controls.

The vast majority of TCK is converted to the desired product and the inventory onsite at any one time is small, i.e., less than 250,000 pounds of TCK in a single storage tank. No TCK is present in the final product. The aqueous waste streams are sent to an onsite deep well. There is no organic waste stream for TCK. Potential environmental exposures are limited to spills onsite,
which are h andled in accordance with recognized emergency response and safety procedures to minimize potential exposures. The use of secondary containment at the manufacturing site further limits environmental release. In summary, TCK poses a minimal exposure threat to workers or the environment.



## 4.0 Analog s for Trichlorinated Ketone

4.1 EPA Guidance for Use of Analo gs

In its SAR guidance for the HPV Chemical Challenge Program, EPA states that the most likely analogs for an HPV chemical are those that resemble the ca ndidate chemical in terms of the following:

1. M olecul ar structure/size;

2. S ome substructure that may play a critical functional role;

3. S ome molecular property (e.g., lipophilicity, electronic and steric parameters);
and/or

4. S ome precursor, metabolite, or break down product.HPV Robust Summaries and Test Plan

– Trichlorinated ketone

8 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:

 Ph ysicochemical properties (e.g., physical state, molecular weight, log K ow , water solubility);

 Absorption potential;

 Mechanism of action of biological activity; and

 Metabolic pathways/kinetics of metabolism.



### 4.2 Structural S imilarity and C omparison of D ata for TCK and D CP

The selected analog is dichloropinacolin or DCP. Also known as 1,1

- dichloro

- 3,3

- methyl

- 2

- butanone, or dic hloromethyl tert

- butyl ketone, this compound differs from the HPV chemical by having one less chlorine atom and a n additional methyl g roup. It is believed to possess most of the desired properties for an a nalog as described in U.S. EPA guidance. The structures of the two chemicals are shown in Figure 2.

Trichlorinated ketone Dichloropinacolin

Figure 2. Comparison of structures of TCK and DCPHPV Robust Summaries and Test Plan

– Trichlorinated ketone

9 Table 2 compares the properties of TCK and DCP . The source of the information is classified as “measured” or “estimated.” Measured data were obtained through experimental procedures,
while estimated data we re obtained through structure

- activity correlations (EPIWIN). Complete details on the sources of information for each data element are provided in the Robust
Summaries submitted with this Test Plan.

Table 2. Comparison of physicochemical properties of TCK and DCP

Substance Information and Properties Trichlorinated ketone (145556

- 04

- 3) Dichloropinacolin (22591

- 21

- 5)

Synonym 3

- pentanone, 1,2,4

- trichloro

- 2

- methyl; TCK 1,1

- dichloro

- 3,3

- dimethyl

- 2

- butanone; dichloromethyl tert

- butyl ketone; DCP Molecular For mula C 6 H 9 Cl 3 O C 6 H 10 Cl 2 O Molecular weight 203.50 169.05

Melting point 13 ° C (estimated)

- 14 ° C (estimated)

Boiling point 190

- 195 ° C (measured) 1 17 8 ° C (estimated)

Vapor pressure 0. 681 hPa (estimated) 1.44 h Pa ( estimated ) Water solubility 136.8 mg/L (measured) 2 2882 mg/L (estimated) Partition coefficient (log Kow) 1.8 2 (estimated) 1.56 ( estimated)

Note: estimated values are from EPIWIN 1 Ji, 2009 2 Rachmalla, 2009 These compounds have reasonably similar physicochemical properties and would be exp ected to have similar environmental fate patterns. The absorption, distribution, metabolism, elimination and toxicity of these compounds are also expected to be similar. Therefore, data read

- across from
DCP is used in a suppor ting manner for the data for T CK

.


## 5.0 Data Analysis

A summary of the available data for TCK and DCP 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.HPV Robust Summaries and Test Plan

– Trichlorinated ketone

10 

### 5.1 Physicochemical P roperties

BASF conducted testing to determine the boiling point and water solubility of TCK

. Boiling point is a key property that is used in estimation of other properti es, while water solubility is a key property because of its potential relevance for human and environmental risk assessment. These studies were conducted following OECD guidelines although they were not performed under GLP. The boiling point of TCK was det ermined to be 190

– 195 °C according to the distillation method in OECD Guideline 103 (Ji, 2009). The water solubility of TCK was determined following the flask method in OECD Guideline 10 5 , with a result of 136.8 mg/L at 22 °C (Rachmalla, 2009). The remaini ng data values for physicochemical properties for TCK
and DCP were estimated using EPIWIN. These data are presented in Table 2 (in the previous section) and in the Robust Summaries.

Recommendation: No additional physicochemical properties studies are nec essary. The
available d ata fill the HPV required data elements with sufficient precision to define the potential
hazards of TCK

.



### 5.2 Environmental F ate and P athways

The environmental fate data for trichlorinated ketone and dichloropinacolin are summarized in Table 3 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.



### 5.2.1 Photodegradation, V olatilization, and H ydrolysis

Indirect p hotodegradation in air was calculated for TCK using AOPWIN v1.92 . The resulting
half

- life was 6.8 days. A similar estimation was made for DCP, resulting in an atmospheric half

life of 5.9 days. The predicted Henry’s Law Constant for TCK is 1.00 x 10 − 3 atm

- m 3 / moleHPV Robust Summaries and Test Plan

– Trichlorinated ketone

11 (HENRYWIN v3.20), which indicates moderate volatility. Neither TCK nor DCP is expected to undergo hydrolysis in the environment because of the lack of functional groups that hydrolyze
under environmental conditions.



### 5.2.2 Bioaccumulation, F ugaci ty, and B iodegradation

TCK is not expected to bioaccumulate to any extent, as its estimated log Kow value (1.82) and log BCF (0.865) are relatively low ( U.S. EPA, 2011 ). If released to the environment, TCK is expected to partition primarily to soil ( 71.1 % ) and water (2 6.6% ), as predicted by EQC Level III fugacity modeling. The behavior of DCP is predicted to be similar ( 63.5 % soil, 33.3 % water).

A study to determine the biodegradability of TCK in the carbon dioxide headspace test (OECD
Guideline 3 10 ) was performed, under GLP , by Schwarz (2009). The test substance, mixed with
mineral salts and a non

- adapted inoculum of municipal sludge, was incubated in sealed vessels with a headspace of air for 28 days. The extent of biodegradation was expressed as a per centage of the total inorganic carbon formed based on the amount of the total organic carbon initially added. The results (biodegradation of 1%) indicated that TCK was not readily biodegradable under the conditions of the test. Ready biodegradability studi es have not been performed with DCP, but it is not predicted to be readily biodegradable according to BIOWIN v4.10.

Recommendation: No additional studies on environmental fate and pathways are necessary. The HPV required endpoints are fulfilled by a comb ination of test results and estimation using acceptable methods.HPV Robust Summaries and Test Plan

– Trichlorinated ketone

12 Table 3

. Environmental f ate and p athways i nformation for TCK and DCP

Environmental Fate Endpoint Trichlorinated ketone (TCK) (145556

- 04

- 3) Dichloropinacolin (DCP) (22591

- 21

- 5) Photodegra dation half

- life 6.8 days (estimated) 1 5.9 days (estimated) 1 Hydrolysis Expected to be stable to hydrolysis Expected to be stable to hydrolysis Fugacity (percent distribution over time assuming equal emissions to air, water and soil) Air: 2.2%; Water: 26 .6%; Soil: 71.1%; Sediment: <1% (estimated) 2 Air: 3.1%; Water: 33.3%; Soil: 63.5%; Sediment: <1% (estimated) 2

Biodegradation Not readily biodegradable (1% in 28 days) per OECD 310 3 (Guideline study, valid without restriction) Primary biodegradation in we eks, ultimate biodegradation in months 4

1 estimated by AOPWIN v1.92 2 estimated by EQC Level III 3 Schwarz, 2009 4 estimated by BIOWIN v4.10



### 5 .3 Ecotoxicity

The acute toxicity data are summarized in Table 4 along with identification of the sources of
inf ormation (measured or estimated). Additional information is tabulated in Section 7 and more fully described in the Robust Summaries. Because TCK is an intermediate in the production of an herbicide ( dimethenamid ), it might be expected that algae would be the most sensitive aquatic organis ms relative to fish and inverte brates. Therefore, an algal toxicity test was conducted according to OECD Guideline 201 and under GLP ( Salinas , 20 11 ). In this study, the green alga Pseudokirchneriella subcapitata was expo sed for 72 hours to five concentrations of TCK (1

. 0 to 100 mg/L in algal medium) . Test concentrations were analytically verified to be within 83 % to
98% of nominal at test initiation and 84% to 98% of nominal a t test termination for the three highest test treatments; the two lowest test treatments were below the calibration curve and reported as below the limit of quantitation

. The results of the study were calculated on the basis
of the nominal concentrations. The EC50 for yield (final cell density minus initial cell density)HPV Robust Summaries and Test Plan

– Trichlorinated ketone

13 was calculated to be 6.32 mg/L while the EC50 for growth rate (increase in cell density per day)

was calculated to be 19.2 mg/L, indicating that TCK is moderately to slightly toxic to algae

. 1

There are no data on the acute toxicity of TCK to fish or invertebrates. These endpoints were fulfilled using estimates from ECOSAR v1.00 in EPI Suite. Estimates for DCP are also presented
in Table 4. The ECOSAR class that forms the basis for the estimation of toxicity for TCK is the
Halo Ketones (2 Free H) class, while the Halo Ketones (0

- 1 Free H) class is used for DCP, resulting in estimates that are dissimilar. The additional chlorine atom in TCK is likely affecting the aquatic toxicity estimate, as aqueous solutions of chlorine are quite toxi c to aquatic animals. Based upon the ECOSAR prediction, TCK is conservatively estimated to be highly toxic to fish (96

- h our LC50 of 0.11 mg/L) and invertebrates (48

- h our LC50 of 0.66 mg/L)

.

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

.

Table 4

. Ecotoxicity i nformation for TCK and DCP

Ecotoxicity Endpoint Trichlorinated ketone (TCK) (145556

- 04

- 3) Dichloropinacolin (DCP) (22591

- 21

- 5)

Acute fish LC50 , 96

- h our (mg/L) 0.11 mg/L (estimated) 1 317 mg/L (estimated) 1

Acute invertebrate EC50, 48

- h our (mg/L) 0.6 6 mg/L (estimated) 1 167 mg/L (estimated) 1

Algal growth inhibition EC50, 7 2

- h (mg/L) 6.32 mg/L based upon yield for Pseudokirchneriella subcapitata ( measured) 2 (Guideline study, valid without restriction) 6 6 mg/L (96

- h EC50, estimated) 1

1 estimated by ECOSAR v1.00 2 Salinas, 2011

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

– Trichlorinated ketone

14 

### 5.4 Health E ffects

5.4.1 Absorption, Distribution, Metabolis m and E xcretion

No information is available on the absorption, distribution, metabolism
, and excretion of trichlorinated ketone or dichloropinacolin.



### 5.4.2 Acute T oxicity

The oral LD50 of trichlorinated ketone was determined in a GLP

- compliant study using 12 rats (6 per sex) exposed to 500 and 2
, 500 mg/kg bw. All animals in the high dose group died while all animals in the low dose group survived, resulting in an LD50 between 500 and 2
, 500 mg/kg bw (Reagen, 1989a). The dermal LD50 of TCK was determined in a GLP

- compliant study in which TCK was administered topicall y to 6 rats (3 per sex) at 500 and 2
, 000 mg/kg bw. One female rat in the high dose group died during the study, while all other animals survived until study termination. The acute dermal LD50 of TCK was thus greater than 2
, 000 mg/kg bw (Reagen, 1989b).

Th e oral LD50 of dichloropinacolin was determined to be 1820 mg/kg bw for male rats and
1 ,300 mg/kg bw for female rats, in a study using eight doses with 15 rats per sex per dose (Flucke and Kimmerle, 1978). Flucke and Kimmerle (1978) also reported the resul ts of an acute inhalation study on dichloropinacolin conducted with male rats, male mice, male hamsters and female rabbits. Animals were exposed for 1 or 4 hours to three measured concentrations and observed for 14 days after exposure. Based upon 4

- hour ex posures, the LC50 values were

> 1 , 179 mg/m 3 for rats and mice and > 1
, 234 mg/m 3 for hamsters and rabbits. In a dermal exposure of rats to 2500 and 5000 mg/kg bw dichloropina colin, the LC50 for males was > 5 , 000 mg/kg bw and the LD50 for females was approxi mately 5
, 000 mg/kg bw (Flucke and Kimmerle, 1978).HPV Robust Summaries and Test Plan

– Trichlorinated ketone

15 

### 5.4.3 Repeated Dose Toxicity

In a GLP

- compliant study conducted according to EPA guidelines (Pannock, 1994), rats (15 per sex per dose) were exposed via the diet for 13 weeks to 0, 200, 630, and 2
, 000 ppm trichlorinated ketone. (These values were converted to mg/kg bw/day using the default values given in U.S. EPA, 1988 as described in the robust summary). The NOAEL was 200 ppm (21.1 mg/kg bw/day for males and 23.1 mg/kg bw/day for females) based upon redu ctions in body weight gain in the 630 ppm group. Reductions in body weight gain and in motor activity, increases in kidney weights, and microscopic changes in kidneys and nasal turbinates were noted in the 2
, 000 ppm

group.



### 5.4.4 Genetic T oxicity

For trich lorinated ketone, bacterial reverse mutation tests were conducted under GLP using five
strains of S. typhimurium (TA98, TA100, TA1535, TA1537, TA1538), both with and without metabolic activation. TCK caused a positive increase (4.7 fold) in the number of T A100 revertants per plate in the presence of S9 mix. Positive results were not seen with this strain in the absence of S9, nor with any of the other four strains tested either with or without metabolic
activation (Lawlor, 1989). An in vitro mammalian chrom osome aberration test was performed according to OECD Guideline 473 and under GLP for trichlorinated ketone (Schulz and Landsiedel, 2009) . Chinese hamster lung fibroblast cells (V79) were exposed to TCK with and without metabolic activation (S9 mix), inclu ding appropriate positive controls and vehicle
controls. Seven doses from 0.31 to 20 μg/mL were used without metabolic activation and seven doses from 0.63 to 40 μg/mL were used with metabolic activation. A statistically significant and biologically relevant increase in the number of chromosomal aberrations was seen both with and without activation, indicating that TCK was clastogenic in this assay. Changes in the number of chromosomes (aneugenic activity) were not observed, either with or without activation. No genetic toxicity data were available for dichlorop inacolin.HPV Robust Summaries and Test Plan

– Trichlorinated ketone

16 

### 5.4.5 Reproductive Tox icity

The 90

- day repeated dose study of TCK with rats (Pannock, 1994) described in Section 5.4.3 included gross and histopathological examinations of reproductive organs for both the males and
females. No effects upon absolute or relative organ weights, or macroscopic or microscopic pathology, were found for the reproductive organs and tissues up to and including a dose level of
2 , 000 ppm (211 mg/kg bw/day for males and 231 mg/kg bw/day for females). Addit ional information on the toxicity of TCK for reproductive parameters in rats and rabbits is discussed
below

.



### 5.4.6 Developmental Toxicity

The developmental toxicity of TCK was determined in both rats and rabbits in studies conducted

acco rding to EPA guideline 798.4900 and under GLP. Groups of 25 pregnant rats received doses of 0, 125, 250 and 500 mg/kg bw/day of TCK via gavage daily on days 6 though 15 of gestation (Martin, 1993a) . Observations were made through day 20 of gestation
, at wh ich time the animals were sacrificed. The maternal NOAEL was 125 mg/kg bw/day, based upon reductions in body weight gain or weight losses and reduced absolute and relative feed consumption values in the higher dose groups. Significantly reduced live litter sizes were observed at 500 mg/kg bw/day, but reproductive parameters were not affected at 125 and 250 mg/kg bw/day. The developmental NOAEL was 250 mg/kg bw/day, based on an increase in early resorptions, reduced fetal body weights, and delayed fetal ossi fication in the 500 mg/kg bw/day group. Effects on development occurred only at the higher of two maternally toxic doses
, so TCK was not considered a developmental toxicant to the offspring of rats.

Pregnant rabbits (20 per group) were dosed via gavage on days 6 through 18 of gestation at 0, 25, 50 and 100 mg/kg bw/day of TCK (Martin, 1993b) . Animals were observed through sacrifice at day 29 of gestation. The maternal NOAEL was 50 mg/kg bw/day based on the following effects observed at 100 mg/kg bw/day: we ight loss and reduced feed consumption, and in one doe, absent or dried feces, gastric erosions, abortion and death. No reproductive parameters were affected at doses up to and including 100 mg/kg bw/day. The developmental NOAEL wasHPV Robust Summaries and Test Plan

– Trichlorinated ketone

17 100 mg/kg bw/day, as th e observed abortion was a maternal effect, and no other adverse effects of this dose were seen on embryo

- fetal viability, body weights, or morphology. Thus, TCK was not considered a developmental toxicant to the offspring of rabbits.



### 5.4. 7 Summary of Heal th Effects Data

The SIDS endpoints relative to health effects for TCK are su mmarized in Table 5 and Section 7 (SIDS Data Matrix), with more detailed information provided in the Robust Summaries
submitted with this Test Plan.

Recommendation : No additional t esting is necessary on health effects endpoints. Reliable data are available from recent, GLP

- compliant studies for TCK for the follo wing health effects endpoints: acute oral toxicity, acute dermal toxicity, repeated dose toxicity, mutagenicity, clastogeni city, reproductive toxicity and developmental toxicity. Data for DCP are available for acute oral toxicity that indicate the similarity in toxicity between TCK and DCP. Therefore, the additional data on acute toxicity for DCP (inhalation toxicity) are suff icient for use in read

- across for TCK.HPV Robust Summaries and Test Plan

– Trichlorinated ketone

18 Table 5

. Health effects inf ormation for TCK and DCP

Toxicity Endpoint Trichlorinated ketone (TCK) (145556

- 04

- 3) Dichloropinacolin (DCP) (22591

- 21

- 5)

Acute oral LD50 (mg/kg) Between 500

- 2500 (rat) 1 (Similar to guideline study, valid without restriction) 1820 (male rat); 1300 (female rat) 7 ( Valid with restriction)

Acute dermal LD50 (mg/kg) > 2000 (rat) 2 (Similar to guideline study, valid without restriction) > 5000 for males; approx. 5000 for females 7 ( Valid w ith restriction)

Acute inhalation LC50 (mg/m 3 ) No data Rat and Mouse: >1179 7
Hamster and Rabbit: >1234 7 ( Valid with restriction)
Repeated dose, NOAEL (mg/kg bw/day) 21.1

– 23.1 (rat) 3 (Guideline study, valid without restriction) No data

Genetic Toxicit y

– in vitro In bacterial reverse mutation test, positive in TA100 strain with metabolic activation, negative without activation in TA100 and with and without activation in 4 additional strains 4 (Guideline study, valid without restriction) In chromosomal aberration test, clastogenic both with and without activation. Not aneugenic. 8 (Guideline study, valid without restriction) No data

Genetic Toxicity

– in vivo No data No data

Reproductive toxicity , NOAEL (mg/kg bw/day) Rat: no effects on reproductive org ans at doses up to and including 211

– 213 3 (Guideline study, valid without restriction)

Developmental toxicity , NOAEL (mg/kg bw/day) Rat : NOAEL for maternal toxicity = 125; NOAEL for developmental toxicity = 250 5 (Guideline study, valid without restriction) Rabbit : NOAEL for mater nal toxicity = 50; NOAEL for developmental toxicity = 100 6 (Guideline study, valid without restriction) No data

1 Reagen, 1989a 5 Martin, 1993a 2 Reagen, 1989b 6 Martin, 1993b 3 Pannock, 1994 7 Flucke and Kimmerle, 1978 4 Lawlor, 1989 8 Schulz and Land siedel, 2009HPV Robust Summaries and Test Plan

– Trichlorinated ketone

19 

## 6.0 Conclusions and R ecommendations

The SIDS Level I endpoints for trichlorinated ketone (TCK) are filled by a combination of
measured and estimated data for the chemical. The adequacy of this information is further supported by comparabl e data for a closely related chemical, dichloropinacolin (DCP)

. Where
certain data are not available for TCK , but reliable data exist for DCP (e.g., acute inhalation toxicity ) , information on DCP is used in a read

- across manner to fill these data gaps. N o additional testing is proposed for TCK

.HPV Robust Summaries and Test Plan

– Trichlorinated ketone

20 

## 7.0 SIDS Data Matrix

SIDS Endpoint trichlorinated ketone (145556

- 04

- 3) Supporting chemical: dichloropinacolin (22591

- 21

- 5)

Value Reference and Reliability 1 Value Reference and Reliability Physicochemical Melting point 13 ° C EPIWIN (K2)

- 14 ° C EPIWIN (K2) Boiling point 190

– 195 °C Ji, 2009 (K1) 178 ° C EPIWIN (K2) Vapor pressure 0. 681 hPa EPIWIN (K2) 1.44 hPa EPIWIN (K2) Partition coefficient (Log Kow) 1.8 2 EPIWIN (K2) 1.56 EPIWIN (K2)
Water Solubil ity 136.8 mg/L Rachmalla, 2009 (K1) 2882 mg/L EPIWIN (K2) Environmental fate Photodegradation (t 1/2 ) 6.8 days (12

- hr day) EPIWIN (K2) 5.9 days (12

- hr day) EPIWIN (K2) Hydrolysis Stable Stable Fugacity 2. 2 % air, 26.6 % water, 71.1 % soil, < 1% se diment EQC Level III (K2) 3. 1 % air, 33.3 % water, 63. 5% soil, < 1% sediment EQC Level III (K2)

Biodegradability Not readily biodegradable (1% in 28 days) per OECD 310 Schwarz, 2009 (K1) Primary biodegradation in weeks, ultimate biodegradation in mon ths EPIWIN (K2)
Ecotoxicity

Acute Fish 96

- h LC50 0.11 mg/L (estimated) ECOSAR (K2) 317 mg/L (estimated) ECOSAR (K2)
Acute Invertebrate 48

- h EC50 0.6 6 mg/L (estimated) ECOSAR (K2) 167 mg/L (estimated) ECOSAR (K2) Algal Inhibition 72

- h EC50 6.32 m g/L based upon yield ( P. subcapitata ) Salinas, 2011 (K1) 6 6 mg/L (estimated) ECOSAR (K2) Toxicity

Acute Oral LD50 Between 500

– 2500 mg/kg (rat) Reagen, 1989a (K1) 1820 mg/kg (male rat); 1300 mg/kg (female rat) Flucke and Kimmerle, 1978 (K2)
Acute Dermal LD50 > 2000 mg/kg (rat) Reagan, 1989b (K1) > 5000 mg/kg (male rabbit); approx. 5000 mg/kg (female rabbit) Flucke and Kimmerle, 1978 (K2)
Acute Inhalation LC50 > 1179 mg/m 3 (rat and mouse); > 1234 mg/m 3 (hamster and rabbit) Flucke and Kimmerle, 1978 (K2) Repeated Dose NOAEL 211

– 231 mg/kg/day (rat) Pannock, 1994 (K1)HPV Robust Summaries and Test Plan

– Trichlorinated ketone

21 SIDS Endpoint trichlorinated ketone (145556

- 04

- 3) Supporting chemical: dichloropinacolin (22591

- 21

- 5)

Genetic Tox

– In vitro In bacterial reverse mutation test, p ositive with S9 in TA100; negative without S9 in TA100 and negative with and without activation in four other strain s

.

In chromosomal aberration test, clastogenic both with and without activation. Not aneugenic. Lawlor, 1989 (K1)

Schulz and Landsiedel, 2009 (K1)

Gene tic Tox

– In vivo Reproductive NOAEL Rat : no effects on reproductive organs at 211

– 231 mg/k g bw /day Pannock, 1994 (K1)

Developmental NOAEL Rat : Maternal NOAEL = 125 mg/kg bw/day ; Developmental NOAEL = 25 0 mg/kg bw/day
Rabbit : Maternal NOAEL = 50 mg/kg bw/day; Developmental NOAEL = 100 mg/kg bw/day Martin, 1993a (K1)

Martin, 1993b (K1)

1 Reliability refers to the Klimisch score : K1 = reliable without restriction K2 = r eliable with restriction K3 = n ot reliable K4 = not assignableHPV Robust S ummaries and Test Plan

– Trichlorinated ketone

22 

## 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
trichlorinated ketone can be found in the Robust Summaries.

EPISuite v4.00 , U.S. Environmental Protection Agency, 2000

- 200 8

. Flucke, W., and Kimmerle, G., 1978. Dichloropinacolin

- Study of Acute Toxicity. Bayer AG Institüt für Toxikologie, Report No. 7305. March 8, 1978.
Ji, J ., 2009. Determination of boiling point/boiling range of 1,2,4

- trichloro

- 2

- methyl

- 3

- pentanone (TCK), CAS # 145556

- 04

- 3) by OECD guideline for the testing of chemicals #103. BASF DocID 2008/7019374, BASF Beaumont Plant, 14385 West Port Arthur Road, Beaumont , Texas 77705. 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. Lawlor, T.E., 1989. Mutagenicity Test O n Trichlorinated Ketone 96.8% In the Ames Salmonella /Microsome Reverse Mutation Assay. Revised Final Report. May 31, 1989. Hazelton Laboratories America, Inc. 5516 Nicholson Lane, Kensington, MD 20895. HLA Study No.: 10716

- 0

- 401. Submitted To: Sandoz Crop Protection Corp. 1300 East Touhy Ave., Des Plaines, IL 60018. 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.

Ma rtin, T

. , 1993a

. Developmental Toxicity (Embryo

- Fetal Toxicity and Teratogenic Potential) Study of Trichlorinated Ketone (TCK) Administered Orally Via Gavage to Crl:CDBR VAF/Plus Presumed Pregnant Rats. December 14, 1993. Argus Research Laboratories, Inc., 905 Sheehy Drive, Bldg A, Horsham, PA 19044

- 1297. Laboratory Project ID: Protocol Number: 1819

- 007.
Martin, T

. , 1993b. Developmental Toxicity (Embryo

- Fetal Toxicity and Teratogenic Potential) Study of Trichlorinated Ketone (TCK) Administered Orally Via St omach Tube to New Zealand White Rabbits. December 14, 1993. Argus Research Laboratories, Inc., 905 Sheehy Drive, Bldg. A, Horsham, PA 19044

- 1297. Laboratory Project ID: Protocol Number: 1819

- 006.
Pannock, K.S., 1994. A subchronic (3

- Month) Oral Toxicity/N eurotoxicity Study of Trichloro Ketone (TCK) in the Rat Via Dietary Administration. Final Report. Pharmaco LSR, Inc., Toxicology Services North America. Study No.93

- 4057. May 11, 1994.HPV Robust S ummaries and Test Plan

– Trichlorinated ketone

23 Rachmalla, L.R., 2009. Determination of water solubility of 1,2,4

- tri chloro

- 2

- methyl

- 3

- pentanone (TCK) by OECD guideline for the testing of chemicals #105 flask method. BASF DocID 2008/7019370. BASF Beaumont Plant, 1485 West Port Arthur Road, Beaumont, TX 77705.
Reagen, E.L., 1989a. Acute Oral Toxicity Study of Trichlorinat ed Ketone (TCK) In Sprague

Dawley Rats. Food & Drug Research Laboratories, Division of Enviro/Analysis Corporation. FDRL Study No. 89.2385.019. April 28, 1989.
Reagen, E.L., 1989b. Acute Dermal Toxicity Study of Trichlorinated Ketone (TCK) In Sprague

Daw ley Rats. Food & Drug Research Laboratories, Division of Enviro/Analysis Corporation. FDRL Study No. 89.2385.020. April 28, 1989.
Salinas, E., 2011. Report: Reg No. 3 95233 (Process

- intermediate of BAS 656

- PH, DMTA

- P), Growth inhibition study in unicellul ar green algae Pseudokirchneriella subcapitata Korshikov. BASF DocID 2010/ 1154437 . Experimental Toxicology and Ecology, BASF SE 67056 Ludwigshafen, Germany, Project No. 60E0 716 /083 698

. Schulz, M. and Landsiedel, R. , 2009. Report : Reg. No. 395233 (Process

- i ntermediate of BAS 656

- PH, DMTA

- P), In vitro chromosome aberration assay in V79 cells. BASF DocID 2009/ 1103581. Experimental Toxicology and Ecology, BASF SE 67056 Ludwigshafen, Germany, Project No. 32M0716/084315

. Schwarz, H.
, 2009. Report : Reg. No. 395233 (Process

- intermediate of BAS 656

- PH, DMTA

- P), Determination of the biodegradability in the CO2

- headspace test. BASF DocID 2009/ 1046772. Experimental Toxicology and Ecology, BASF SE 67056 Ludwigshafen, Germany, Project No. 27G0 716/083671

. U.S. EPA, 19 8 8. R ecommendations for and Documentation of Biological Values for Use in Risk Assessment. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/6

- 87/008 (NTIS PB88179874).

U.S. EPA

. 1999a. The use of structure

- activity relationships (SAR) in the High Production Volume Chemicals Challenge Program. A vailable 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

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

.