201-14677A
TEST PLAN FOR DIMETHYLOCTANAMIDE AND DIMETHYLDECANAMIDE
CATEGORY
OVERVIEW
The C.P. Hall Company agrees to sponsor N,N-dimethyloctanamide (CAS No. 1118-92-9) and
N,N-dimethyldecanamide (CAS No. 14433-76-2) as a two substance category in the
Environmental Protection Agency's (EPA) High Production Volume (HPV) Chemical Challenge
Program. The company hereby submits a category justification/test plan for these two substances.
It is the intent of the sponsoring company to use existing data combined with new studies
specified in the test plan to fulfill the Screening Information Set (SIDS) endpoints for
environmental fate, ecotoxicity and human health effects.
RECEIVED
OPPT CBIC
2003 AUG 18 PM 1:32
N,N-Dimethylalkanamides Test Plan 1
08-11-2003
Table 1. Test Plan Matrix for N,N- dimethyl octaneacidamide (CAS No. 1118-92-9) and N,N-
dimethyl decaneacidamide (CAS No. 14433-76-2)
CAS Nos. 1118-92-9 and
New Testing
Information
Acceptable
14433-76-2
Estimation
Required
OECD
Study
Other
GLP
Y/N Y/N Y/N Y/N Y/N Y/N Y/N
ENDPOINT
PHYS/CHEM PROPERTIES
Melting Point Y(C8,C10) N Y N N Y N
Boiling Point Y(M) N Y N N Y N
E(B) N Y Y N Y N
Density Y(C10) Y N N Y Y N
Y(M) N Y N N Y N
Vapor Pressure E(C8) N Y Y N Y N
Y(C10) Y N N Y Y N
Partition Coefficient Y(B) Y N N Y Y N
Water Solubility Y(B) Y N N Y Y N
ENVIRONMENTAL FATE
Photodegradation Y(C10) N Y N Y Y N
Stability in Water Y(C10) N Y N Y Y N
Biodegradation Y(C10) N Y N Y Y N
Transport between Environmental E(B) N N Y N Y N
Compartments (Fugacity)
ECOTOXICITY
Acute Toxicity to Fish Y(M) Y N N Y Y N
Acute Toxicity to Aquatic Y(M) N Y N Y Y N
Invertebrates
Toxicity to Aquatic Plants Y(M) Y N N Y Y N
Toxicity to Terrestrial (NR) Y(M) N Y N Y Y N
TOXICOLOGICAL DATA
Acute Toxicity Y(M) Y N N Y Y N
Repeated Dose Toxicity Y(M) Y N N Y Y N
Genetic Toxicity-Mutation Y(M) Y N N Y Y N
Genetic Toxicity-Chromosomal Y(M) Y N N Y Y N
Aberrations
Y(M)1
Toxicity to Reproduction Y N N Y Y N
Developmental Toxicity Y(M) Y N N Y Y N
OTHER TOXICITY DATA
Skin Irritation (NR) Y(M) N Y N Y/N Y N
Eye Irritation (NR) Y(M) N Y N Y Y N
Sensitization (NR) Y(M) N Y N Y Y N
Y = yes; N = no; E = estimated
(C8) = N,N-dimethyl octaneacidamide only; (C10) = N,N-dimethyl decaneacidamide only; (B) = both;
(M) = mixture containing C8 and C10
1
Reproductive organ toxicity data from 91-day study
N,N-Dimethylalkanamides Test Plan 2
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TABLE OF CONTENTS
1. Introduction............................................................................................................................. 4
2. Designation of Test Substance................................................................................................ 4
3. Criteria for Determining Adequacy of Data ........................................................................... 4
4. Discussion of Available Test Information .............................................................................. 5
4.1 Chemical and Physical Properties................................................................................... 5
4.1.1 Melting Point .......................................................................................................... 5
4.1.2 Boiling Point ........................................................................................................... 6
4.1.3 Vapor Pressure ........................................................................................................ 6
4.1.4 Octanol/Water Partition Coefficient ....................................................................... 6
4.1.5 Water Solubility ...................................................................................................... 6
4.1.6 Summary/Test Plan for Physical Properties ........................................................... 6
4.2 Environmental Fate/Pathways ........................................................................................ 7
4.2.1 Photodegradation .................................................................................................... 7
4.2.2 Stability in Water .................................................................................................... 8
4.2.3 Fugacity................................................................................................................... 8
4.2.4 Biodegradation ........................................................................................................ 8
4.2.5 Summary/Test Plan for Environmental Fate Parameters........................................ 9
4.3 Ecotoxicity .................................................................................................................... 10
4.3.1 Acute Toxicity to Fish .......................................................................................... 10
4.3.2 Acute Toxicity to Aquatic Invertebrates............................................................... 10
4.3.3 Acute Toxicity to Aquatic Plants.......................................................................... 10
4.3.4 Toxicity to other Non-Mammalian Terrestrial Species ........................................ 10
4.3.5 Summary/Test Plan for Ecotoxicity...................................................................... 11
4.4 Human Health Data....................................................................................................... 11
4.4.1 Acute Mammalian Toxicity .................................................................................. 11
4.4.2 Repeated Dose Mammalian Toxicity.................................................................... 12
4.4.3 Genetic Toxicity.................................................................................................... 13
4.4.4 Reproductive Toxicity .......................................................................................... 14
4.4.5 Developmental Toxicity........................................................................................ 14
4.4.6 Additional Data..................................................................................................... 15
4.4.7 Summary/Test plan for mammalian toxicity ........................................................ 15
5. Summary ............................................................................................................................... 16
6. References............................................................................................................................. 16
7. Appendix I ?Robust Summaries..................................................................... 20
N,N-Dimethylalkanamides Test Plan 3
08-11-2003
1. Introduction
The C.P. Hall Company submits this test plan for N,N-dimethyloctanamide (CAS No. 1118-92-
9) and N,N-dimethyldecanamide (CAS No. 14433-76-2) for hazard review under the
Environmental Protection Agency High Production Volume Chemical Program. The technical
contact at this company is:
Gary Wentworth
The C.P. Hall Company
5851 West 73rd Street
P. O. Box 910
Bedford Park Illinois 60499-0910
Phone (708) 594-5062
2. Designation of Test Substance
The category addressed in this test plan is comprised of the following two substances:
CH3CH2CH2CH2CH2CH2CH2(C=O)N(CH3)2
N,N-Dimethyloctanamide (CAS No. 1118-92-9)
and
CH3CH2CH2CH2CH2CH2CH2CH2CH2(C=O)N(CH3)2
N,N-Dimethyldecanamide (CAS No. 14433-76-2)
These substances are homologs with the same functionality, and differ only in that N,N-
dimethyldecanamide has two more carbons in its alkyl chain than N,N-dimethyloctanamide.
Dimethyldecanamide is available commercially as Hallcomid M-10? Dimethyloctanamide is
not manufactured in pure form, but is commercially available as the major component in
Hallcomid M-8-10? Hallcomid M-8-10 contains (in weight %) 50-65% N,N-
dimethyloctaneacidamide and 37-50% N,N- dimethyldecaneacidamide, with minor impurities
N,N- dimethylhexaneacidamide (0-5%) and N,N- dimethyldodecaneacidamide (0-2%). This
product will be referred to by its commercial name (Hallcomid M-8-10) for the remainder of this
document. Both Hallcomid products are used principally as pesticide inert ingredients.
3. Criteria for Determining Adequacy of Data
All available studies were reviewed and assessed for adequacy according to the standards of
Klimisch et al. (1997). Studies receiving a Klimisch rating of 1 or 2 were considered to be
adequate.
N,N-Dimethylalkanamides Test Plan 4
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4. Discussion of Available Test Information
The N,N- dimethyl octaneacidamide and N,N- dimethyl decaneacidamide test plan matrix (as
shown in Table 1 on page 2) was constructed after a careful evaluation of all existing data (see
below). This matrix is arranged by study type (columns) and screening data endpoints (rows),
and indicates if data are provided for each end point in the sets of robust summaries.
4.1 Chemical and Physical Properties
The results of chemical/physical property testing are shown in Table 2.
Table 2. Chemical/physical properties of N,N-dimethyloctanamide and N,N-
dimethyldecanamide
Value*
Endpoint N,N-Dimethyloctanamide N,N-Dimethyldecanamide
(CAS No. 1118-92-9) (CAS No. 14433-76-2)
Molecular Weight grams/mol 171.28 199.34
-27 to -22癈a -11 to -7癈a
Melting point (?C)
240 - 265.5 at 1015 hPa**,b 240 - 265.5 at 1015 hPa**,b
Boiling point (?C)
257.2 at 1016 hPa 289.7 at 1016 hPa
0.8835**,b 0.88 at 20癈c
Relative Density
0.00114 d
Vapor pressure (hPa at 25?C) 0 .026
0 .01
2.59 at 23?Cc 3.92 at 24癈c
Partition coefficient
(Log Pow or Kow) 2.46 3.44
Water solubility (mg/l at 25 ?C) 4300 at 20癈f 344 at 20癈f
372.3 19.8
* Values shown in italics were estimated using the EPIWIN model program.
** Value is for Hallcomid M-8-10, a mixture containing 50-60% N,N-dimethyloctanamide and 35-45% N,N-
dimethyldecanamide
a
Internal communication from The C. P. Hall Company; b C. P. Hall Company MSDS ; cKrohn, 1995; dKrohn,
1994a; eKrohn, 1993; fKrohn, 1994b
4.1.1 Melting Point
Measured melting points were determined by the C. P. Hall Company using differential scanning
calorimetry. The test materials were typical commercial Hallcomid M-10 (of =>98% purity) and
Hallcomid M-8-10, which is a mixture containing 50-60% N,N-dimethyloctanamide and 35-45%
N,N-dimethyldecanamide. Melting points were also estimated using EPIWIN MPBPWIN, but
the values were much greater than room temperature. Both products are known to be liquids at
room temperature.
N,N-Dimethylalkanamides Test Plan 5
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4.1.2 Boiling Point
A measured boiling point range of 240-265.5?C is available for Hallcomid M-8-10, a mixture
containing 50-60% N,N-dimethyloctanamide and 35-45% N,N-dimethyldecanamide N,N-
dimethyloctanamide (The C. P. Hall Company, 2002). Boiling points for the individual
chemicals have been estimated by EPIWIN. These boiling points (257.2?C and 289.7?C for
N,N-dimethyloctanamide and N,N-dimethyldecanamide, respectively) are in agreement with the
measured boiling point for Hallcomid M-8-10, with an expected somewhat higher boiling point
for N,N-dimethyldecanamide, which has a longer alkyl chain and higher molecular weight.
These data are adequate for addressing this endpoint.
4.1.3 Vapor Pressure
The vapor pressure of 0.00114 hPa measured for N,N-dimethyldecanamide (Krohn, 1994a) is in
close agreement with the EPIWIN estimate of 0.01 hPa. The EPIWIN estimate of 0.026 hPa for
N,N-dimethyloctanamide is reasonable in comparison with the determinations for N,N-
dimethyldecanamide, based on the expected somewhat higher volatility for the shorter chain, and
lower molecular weight of N,N-dimethyloctanamide. These data are adequate for characterizing
the vapor pressure for these substances
4.1.4 Octanol/Water Partition Coefficient
Log Pows of 2.59 and 3.92 have been determined for N,N-dimethyloctanamide and N,N-
dimethyldecanamide (respectively), using 14C-labeled test substance and following OECD
Guideline No. 107 (Krohn, 1993). Values of ca. 2.46 and 3.44 (respectively) estimated by
EPIWIN KOWWIN, are in the same ranges. These data are adequate for characterizing
octanol/water partitioning for these substances.
4.1.5 Water Solubility
Water solubilities of 4.3 g/l and 344 mg/l have been determined for N,N-dimethyloctanamide
and N,N-dimethyldecanamide (respectively), using 14C-labeled test substance and following
OECD Guideline No. 105 (Krohn, 1994b). EPIWIN WSKOW (v1.40) estimates somewhat
lower respective values of 372.3 and 19.8 mg/l based on the estimated Log Kow values given
above. It is likely that the measured values are more accurate than the estimated values. The
data are adequate for characterizing water solubility of these substances.
4.1.6 Summary/Test Plan for Physical Properties
Both of the test substances are liquids with fairly high boiling points, low vapor pressures,
limited water solubility, and positive partition coefficients. Measured data are available for both
substances with respect to melting point, water solubility and partition coefficients. The
measured density value for N,N-dimethyldecanamide is similar to the value measured for
Hallcomid M-8-10, a mixture containing 50-60% N,N-dimethyloctanamide and 35-45% N,N-
dimethyldecanamide. EPIWIN appears to be a valid model for estimating the vapor pressure for
N,N-dimethyloctanamide, since the EPIWIN-estimated and measured values for
N,N-Dimethylalkanamides Test Plan 6
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dimethyldecanamide are in good agreement. Most measured values for the individual
components and Hallcomid M-8-10 are similar to EPIWIN-estimated values, indicating that
EPIWIN is a good model to predict physical properties of these materials. As the EPIWIN
model cannot accurately predict the melting point, testing is planned to address this endpoint.
4.2 Environmental Fate/Pathways
Results of environmental fate modeling and studies are summarized in Table 3.
Table 3. Environmental fate parameters for N,N-dimethyloctanamide and N,N-
dimethyldecanamide
Endpoint Value*
N,N-dimethyloctanamide N,N-dimethyldecanamide
(CAS No. 1118-92-9) (CAS No. 14433-76-2)
Photolysis (Atmospheric T1/2, days)
Direct Photolysis in aira No data >30
Direct Photolysis in soilb No data 33
Indirect Photolysis (OH sensitizer)
2.7 x 10-11 2.98 x 10-11
Hydroxyl Radical Rate Constant
cm3/(molecule * sec)
Atmospheric T1/2 (days) 0.4 0 .4
Stability in Water** Half-life >1 year Half-life >1 year
Insignificant hydrolysis after
30 days at 25癈 at pH 5,7,9c
50 % after 0.5 - 6.5 hrsd,e
Biodegradation No data
90% after 0.65 - 7.5 daysd,e
Henry's Law Constant (atm-m3/mol) 2.95 x 10-7 5.2 x 10-7
Koc 118 1,130
Environmental transport Air 1.6% Air 1.19%
(Fugacity Level III mass percentages) Water39% Water 37.8%
Soil 59.5% Soil 58.9%
Sediment 0.23% Sediment 2.09%
*Values given in italics are estimated by EPIWIN.
**The test substances do not possess functional groups generally recognized to be readily hydrolyzable in water
under neutral ambient conditions.
a
Burri, 1995a; bBurri, 1996; cBurri, 1995b; d Flueckiger,1995; e Wyss-Benz and Tschech, 1995
4.2.1 Photodegradation
Direct photolysis of N,N-dimethyldecanamide has been determined in water (Burri, 1995a) and
in soil (Burri, 1996), following EPA Guide-line subdivision N 161-2 and EPA Guide-line
subdivision N 161-3, respectively. The results of these studies indicate that this substance is not
rapidly photolyzed in either medium. Atmospheric hydroxyl radical-induced photodegradation
rate constants of ca. 2.7 x 10-11cm3/(molecule*sec) and 2.98 x 10-11cm3/(molecule*sec) have
been estimated for N,N-dimethyloctanamide and N,N-dimethyldecanamide using EPIWIN AOP
N,N-Dimethylalkanamides Test Plan 7
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(v1.90). The same program estimates half-lives of 0.4 days for both substances for atmospheric
photodegradation with hydroxyl radical as a sensitizer. These results are consistent for both
members of the category and indicate that hydroxyl radical-induced atmospheric
photodegradation proceeds readily, whereas direct photolysis in water or soil proceeds very
slowly. No additional testing is necessary.
4.2.2 Stability in Water
The hydrolysis rate of N,N-dimethyldecanamide has been determined (Burri, 1995b) following
EPA Pesticide Assessment Guidelines, Subdivision N. The results of this study indicate
insignificant hydrolysis after 30 days at 25癈 at pH 5, 7, and 9. EPIWIN modeling of both
substances suggests that the amide group is the functionality in the molecule that is most
susceptible to hydrolysis, and that hydrolysis at this position is extremely slow (half-life greater
than one year). This result is consistent with the measured result and with generally recognized
knowledge that amide functions are resistant to hydrolysis under neutral, ambient conditions.
Because both test substances contain identical functional groups that are recognized to be
resistant to hydrolysis, no testing of this endpoint is recommended.
4.2.3 Fugacity
Level III fugacity modeling has been conducted on the test materials using EPIWIN. The results
are nearly identical for both members of the category, and indicate that the test substances will
partition preferentially to water and soil. The model predicts that the lower homolog, N,N-
dimethyloctanamide has a very slightly greater affinity for water. The calculated Henry's Law
Constants of 2.95 x 10-7 and 5.2 x 10-7 atm-m3/mol suggest that neither category member will
rapidly volatilize from water, which is due to their low vapor pressures. Volatilization from soil
or sediment is also strictly limited. A soil adsorption/desorption study with N,N-
dimethyldecanamide indicates that this material has low or low to medium mobility in soil
(Morgenroth, 1995). Water soil partition constants (Koc) of 118 and 1,130 have been estimated
using EPIWIN PCKOC for N,N-dimethyloctanamide and N,N-dimethyldecanamide,
respectively. These values suggest (as would be expected) that the lower homolog would have
somewhat higher soil mobility than N,N-dimethyldecanamide. Additional fugacity testing is not
recommended.
4.2.4 Biodegradation
Two well-conducted studies performed with C14 labeled N,N-dimethyldecanamide indicate that
this material rapidly biodegrades in soil (Flueckiger,1995; Wyss-Benz and Tschech, 1995). The
rates of degradation of 50% and 90% of the material in different types of soil ranged from 0.5 to
6.5 hours, and 0.65 to 7.5 days, respectively. Since N,N-dimethyloctanamide is closely related
in structure and chemical physical properties to N,N-dimethyldecanamide, this material is also
expected to rapidly degrade in soil.
Measured data are not available for biodegradation in water. However, the EPIWIN BIOWIN (v
4.00) program predicts that both substances are readily biodegradable. In addition, aliphatic
amides are generally known to readily undergo biodegradation; first to carboxylic acids,
followed by further microcosm-induced breakdown. To further illustrate the general ability of
N,N-Dimethylalkanamides Test Plan 8
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aliphatic amides to biodegrade, biodegradation data for two similar aliphatic amides are
presented. These other amides are:
Caprolactam (CAS No. 105-60-2). This amide is the cyclic amide of 6-aminohexanoic acid,
with the molecular structure shown below:
H
O
N
Caprolactam is a reasonably good surrogate for N,N-dimethyloctanamide and N,N-
dimethyldecanamide, because its alkyl chain length is in a similar range (C6) and because its
amide function is alkylated. The ring structure and alkylated amide function would tend to make
this substance somewhat more hindered to biodegradative attack as compared to an open chain,
non-alkylated carboxylic acid amide, and therefore would be a conservative predictor of
biodegradability of N,N-dimethyloctanamide and N,N-dimethyldecanamide. Even so, results of
a 5-day COD test performed on over 100 materials showed that caprolactam was readily
degraded (94.3%, 16.0 mg COD/g/h)(Pittier, 1976).
N,N-dimethylacetamide (CAS No. 127-19-5):
CH3(C=O)N(CH3)2
N,N-dimethylacetamide (DMAC) is a good supporting surrogate because it has a tertiary,
dimethylated amide function as is the case for N,N-dimethyloctanamide and N,N-
dimethyldecanamide. The only difference between DMAC and the sponsored chemicals is the
length of the alkyl chains (2-carbon for DMAC and 8- or 10-carbon for N,N-dimethyloctanamide
and N,N-dimethyldecanamide). In one study, DMAC biodegradation was 96% after 5 days
(BASF AG, 1977). In a MITI (BOD of ThOD) test, biodegradation was 77-83% after 14 days
(CITI, 1992). Since the original studies themselves were not available for review, they were
given reliability ratings of 4. However, the MITI study is a standard test, and both studies lend
support to a weight of evidence approach that suggests that dimethylated amides are
biodegradable.
In conclusion, results of two well-conducted biodegradation tests in soil, together with estimates
from the EPIWIN/BIOWIN program and measured data from other aliphatic amides
(caprolactam and dimethylacetamide) are adequate to characterize this endpoint for N,N-
dimethyloctanamide and N,N-dimethyldecanamide, demonstrating that these substances
biodegrade readily.
4.2.5 Summary/Test Plan for Environmental Fate Parameters
Level III fugacity modeling indicates that N,N-dimethyloctanamide and N,N-
dimethyldecanamide will tend to partition to water and soil when released to the environment.
Although both substances have low vapor pressures and moderately low Henry's Law Constants,
EPIWIN modeling predicts that molecules entering the atmosphere will readily undergo
N,N-Dimethylalkanamides Test Plan 9
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hydroxyl radical-induced photodegradation. Well-conducted photodegradation studies are
available for N,N-dimethyldecanamide in both soil and water. These studies indicate that the test
substance is highly resistant to direct sunlight-induced photolysis in both media. The identical
functionality of N,N-dimethyloctanamide suggests that this category member is also resistant to
photolysis in these media. The abiotic hydrolysis of N,N-dimethyldecanamide has been studied
at pH 3,5, and 7, indicating that this substance is resistant to hydrolysis at ambient temperatures,
as is generally recognized for simple aliphatic amides. This study would predict similar behavior
for the shorter chain analog, N,N-dimethyloctanamide .
Water-soil partition constants measured for dimethyldecanamide and estimated for N,N-
dimethyloctanamide by EPIWIN predict some (albeit limited) soil mobility. Biodegradation
studies and modeling indicate that N,N-dimethyldecanamide is readily degraded in soil and
water, and that molecules with a similar structure readily biodegrade in water. Modeling results,
together with measured determinations of photolysis, hydrolysis and biodegradation are
sufficient to characterize environmental fate end points for N,N-dimethyloctanamide and N,N-
dimethyldecanamide at the screening level; therefore no further testing for these endpoints is
planned.
4.3 Ecotoxicity
4.3.1 Acute Toxicity to Fish
A static OECD guideline study in rainbow trout was performed with Hallcomid M-8-10
(Dogerloh, 1993). The no observable effect concentration (NOEC) and lethal concentration in
50% of the organisms (LC50) in this 96-hour study were 5 and 21.1 mg/l, respectively. None of
the fish exposed to 15.8 mg/l died by 96 hours.
4.3.2 Acute Toxicity to Aquatic Invertebrates
A static EPA guideline study in Daphnia magna was performed with Hallcomid M-8-10 (Forbis,
1990). The NOEC and LC50 values in this 48-hour study were 4 and 7.7 mg/l, respectively.
4.3.3 Acute Toxicity to Aquatic Plants
The toxicity of Hallcomid M-8-10 to Selenastrum capricornutum was tested according to OECD
Guideline 201 (Anderson, 1993). For inhibition of growth rate, the NOEC, and effective
concentration in 50% of the organisms (EC50) were 1.80 and 16.06 mg/l for 72 hours,
respectively. For inhibition of biomass, the NOEC and the EC50 were < 1.80 and 5.47 mg/l,
respectively. Although the pH of the control flasks was slightly higher (0.10 units) at the end of
the study than the recommended value, this did not appear to adversely affect the outcome of the
test.
4.3.4 Toxicity to other Non-Mammalian Terrestrial Species
Although not required, an EPA guideline test with Hallcomid M-8-10 was performed in
bobwhite quail (Grau, 1994). Five groups of 10 birds (five per sex) were given a single oral dose
N,N-Dimethylalkanamides Test Plan 10
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of 0, 200, 400, 800 or 1600 mg/kg Hallcomid M-8-10 by gelatin capsule and observed for 14
days. None of the birds exposed to 800 mg/kg or less Hallcomid M-8-10 died. Transient signs
of toxicity (ptosis, loss of equilibrium and/or apathy) were observed in 5 animals treated with
800 mg/kg. Five animals exposed to 1600 mg/kg died and all exhibited convulsions, ptosis, loss
of equilibrium and/or apathy on the day of treatment. The no observable effect level (NOEL),
lowest observable effect level (LOEL) and lethal dose in 50% of the animals (LD50) values were
therefore 400, 800 and 1600 mg/kg, respectively.
4.3.5 Summary/Test Plan for Ecotoxicity
Results of guideline studies in rainbow trout, Daphnia magna and Selenastrum capricornutum
show that Hallcomid M-8-10 is of moderate toxicity to these species. An additional study
indicates that Hallcomid M-8-10 is of low toxicity to bobwhite quail. The studies that have been
performed adequately assess the toxicity of Hallcomid M-8-10 to fish, aquatic invertebrates,
algae and birds. Since this material predominantly contains N,N- dimethyl octaneacidamide and
N,N- dimethyl decaneacidamide (in approximately equal amounts), and the two materials are
closely related in chemical structure and physical properties, the potential for ecotoxicity of the
two category members is not expected to differ substantially from that of Hallcomid M-8-10.
Therefore, additional testing with the individual materials is not necessary.
4.4 Human Health Data
4.4.1 Acute Mammalian Toxicity
This endpoint is filled by sufficient oral, inhalation and dermal toxicity studies in rats performed
with Hallcomid M-8-10 (Kreuzmann, 1990a, Pauluhn, 1991, Bomann, 1995). The LD50 and
LD100 (lethal dose in 10% of animals) values for the oral study were 1,250 mg/kg and 2,500
mg/kg, respectively. The NOEC and LC50 value for inhalation were 118.5 mg/m3 and greater
than 3551 mg/m3, respectively. The dermal LD50 values were 2000 mg/kg for males and
between 400 and 2000 mg/kg for females. The NOEL for systemic effects in the dermal study
was 200 mg/kg.
Symptoms observed in rats orally treated with 1,250 to 5,000 mg/kg Hallcomid M-8-10 included
ataxia, depression, and labored breathing prior to death. Piloerection, red stains around nostrils,
brownish urine stains and/or hunched posture were noted up to study day 4 in surviving rats
treated with 1.25 or 2.5 g/kg (3/4 and 1/4, respectively). Rats treated orally with 0.025 g/kg
exhibited signs of toxicity only on the day of dosing. Survivors appeared normal after
approximately day 5, and had normal necropsies at study termination.
In rats exposed to 586.4 mg/m3 Hallcomid M-8-10 for 4 hours by inhalation, signs of toxicity
such as reddening of the nose, reduced motility and piloerection occurred on the day of exposure
only. Most of the rats exposed to higher concentrations also exhibited additional signs and
symptoms of respiratory irritation. Symptoms in rats exposed to 2007.6 or 3550.7 mg/m3
persisted for up to 7 and 14 days, respectively. The necropsy of the one animal that died after
exposure to 3550.7 mg/m3 revealed distended, liver-like and edematous lungs, hydrothorax, and
reddened and swollen rhinarium. Surviving rats exposed to 3550.7 mg/m3 also had a higher
N,N-Dimethylalkanamides Test Plan 11
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incidence of distended lung. Animals exposed to lower concentrations did not exhibit any gross
pathological changes with respect to controls.
In the dermal study, four out of 5 females exposed to 400 mg/kg and all rats exposed to higher
concentrations exhibited clinical signs of toxicity. These signs generally occurred within 30
minutes of treatment and reversed within 6 days treatment. Skin irritation was noted at the site
of administration of most animals exposed to 200 mg/kg, all animals exposed to 400 mg/kg, and
all males exposed to 2000 mg/kg. The skin effects lasted from day 2 until the end of the study.
One female treated with 50 mg/kg had some squamation at the treatment area. Since none of the
others treated with 50 mg/kg had skin reactions, this dose was chosen as the threshold level for
local effects.
Since Hallcomid M-8-10 predominantly contains N,N- dimethyl octaneacidamide and N,N-
dimethyl decaneacidamide (in approximately equal amounts), and the two materials are closely
related in chemical structure and physical properties, the potential for acute mammalian toxicity
of the two category members is not expected to differ substantially from that of Hallcomid M-8-
10. Therefore, additional acute toxicity testing with the individual materials is not necessary.
4.4.2 Repeated Dose Mammalian Toxicity
Four repeated dose toxicity studies have been performed with Hallcomid M-8-10. The critical
study for the endpoint was a 91-day oral dietary study performed according to OECD guideline
408 (Wirnitzer and Ruhl-Fehlert, 1993). The no observable adverse effect level (NOAEL) for
Hallcomid M-8-10 in this study was 2,000 ppm (136.8 mg/kg/day for males and 178.5
mg/kg/day for females), and the lowest observable adverse effect level (LOAEL) was 10,000
ppm (787.6 mg/kg/day for males and 894.6 mg/kg/day for females). Effects noted at 10,000
ppm included emaciation (5/10 males), decreased body weight gain (which normalized during a
28 day recovery period), increased serum cholesterol, increased liver weight, and pathological
changes in the kidneys (males only). Similar findings were observed in rats ingesting 10,000
ppm Hallcomid M-8-10 in a 28-day range finding study (Wirnitzer, 1993).
In dogs treated orally by gavage with 20, 100, or 500/1000 mg/kg Hallcomid M-8-10 for 6
weeks, no effects were noted at 20 mg/kg/day (Vliegen, 1996). The study personnel set the
NOAEL at 100 mg/kg/day; however, the data suggested that there were some treatment-related
effects at this dose (i.e. increased vomiting, salivation, and liver, kidney and pancreas weights).
Dogs dosed with 500 mg/kg/day for two weeks and 1000 mg/kg/day for the remainder of the
study exhibited vomiting, salivation, increases in some liver enzymes, and increased liver,
kidney and pancreas weights.
A five day inhalation study of Hallcomid M-8-10 in rats was conducted according to OECD
guidelines (Pauluhn, 1992). In this study, rats were exposed (head and nose only) to an aerosol
containing 24.6, 111.2 and 521.2 mg/m3 material with an average MMAD (and GSD) of 1.4
(1.5) microns. The NOAEL and LOAEL in this study were 111.2 and 521.2 mg/m3,
respectively. Effects noted at 521.2 mg/m3 included difficulties in breathing, reduced motility,
hypothermia and weight loss during treatment, and pathological changes in the nasal and
paranasal cavities (females only) after a 15-day recovery period. Lesions in other organs were
not observed at necropsy.
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Since Hallcomid M-8-10 predominantly contains N,N- dimethyl octaneacidamide and N,N-
dimethyl decaneacidamide (in approximately equal amounts), and the two materials are closely
related in chemical structure and physical properties, the potential for repeated dose mammalian
toxicity of the two category members is not expected to differ substantially from that of
Hallcomid M-8-10. Therefore, additional repeat dose toxicity testing with the individual
materials is not necessary.
4.4.3 Genetic Toxicity
4.4.3.1 Mutagenicity
Hallcomid M-8-10 tested negative for mutagenicity in an Ames test (OECD 471) involving S.
typhimurium strains TA98, TA100, TA1535, and TA1537 in the absence and presence of a
metabolic activation system (Herbold, 1992) and a HGPRT assay (OECD 476) conducted with
V79 Chinese hamster lung cells in the absence and presence of a metabolic activation system
(Brendler-Schwaab, 1994).
The potential for mutagenicity of N,N- dimethyloctanamide and N,N-dimethyldecanamide is not
expected to differ substantially from that of Hallcomid M-8-10, since they are the predominant
ingredients. Therefore, mutagenicity testing with the individual materials is not necessary.
4.4.3.2 Chromosomal aberration
An OECD Guideline 473 study has been conducted with Hallcomid M-8-10 in Chinese Hamster
Ovary Cells in the absence and presence of a metabolic activation system (Gahlmann, 1995). In
this study, incubation with up to 160 micrograms/ml (without activation) and 180 micrograms/ml
(with activation) did not lead to an increase in the number of aberrants with respect to historical
controls. The finding of an increased number of aberrants at 8 hours for cells treated with 180
micrograms/ml in the presence of a metabolic activation system with respect to the solvent
control was considered by study personnel to be due to the unusually low number of solvent
control cells with aberrations (0.5%).
Based on the fact that N,N-dimethyloctanamide and N,N-dimethyldecanamide are the
predominant ingredients of Hallcomid M-8-10 and have similar structures and physical
properties, the results of the study with Hallcomid M-8-10 are likely to be predictive of those
with the individual category members. Therefore, additional chromosomal aberration testing
with the individual materials is not necessary.
4.4.3.3 Additional Studies
The ability of Hallcomid M-8-10 to cause unscheduled DNA synthesis in rat primary
hepatocytes in the absence of metabolic activation was tested according to OECD Guideline 402
(Brendler-Schwab, 1994). At concentrations up to 98.8 micrograms/ml (the highest
concentration that did not cause excessive toxicity), there was no increase in nuclear labeling or
the percentage of cells in repair.
N,N-Dimethylalkanamides Test Plan 13
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4.4.4 Reproductive Toxicity
No mating studies with the individual category members or Hallcomid M-8-10 have been
performed. However, the 91-day rat dietary study that was conducted with Hallcomid M-8-10
included examination of reproductive organs (Wirnitzer and Ruhl-Fehlert, 1993). In this study,
the NOAEL for reproductive effects was 10000 ppm, which was higher than the NOAEL for
systemic effects. Changes in the testes, prostate and/or epididymis that were noted in 1-2 males
from the control, low and high dose groups were not considered to be related to treatment since
the incidences and degrees of severity of the lesions in were low (with the exception of one low
dose animal that had a high degree of tubular atrophy in the testes) and not dose-dependent.
Results of the developmental toxicity studies (see Section 4.4.5 below) indicate that treatment
with up to 450 mg/kg/day Hallcomid M-8-10 in rats or 1000 mg/kg/day of Hallcomid M-8-10 in
rabbits during organogenesis has no effect on the number of resorptions, implantations, corpora
lutea or viable or nonviable fetuses. At the clearly maternally toxic dose of 450 mg/kg/day, rats
had a small increase in post-implantation (embryonic) loss (9.4% vs. 5.6% in controls).
Altogether, the results of the repeated dose and developmental studies suggest that the potential
for reproductive toxicity of Hallcomid M-8-10 is low. Therefore, reproductive toxicity testing
with N,N- dimethyloctanamide and N,N-dimethyldecanamide is not necessary.
4.4.5 Developmental Toxicity
Results of two OECD guideline studies show that Hallcomid M-8-10 is not a developmental
toxicant at non-maternally toxic doses. In a study in rats treated with 50, 150 or 450 mg/kg/day
Hallcomid M-8-10 from Days 5 though 15 of gestation (Becker and Biedermann, 1991a), 50
mg/kg/day was the NOAEL for maternal toxicity. Reduced food consumption was observed in
dams treated with 150 mg/kg/day (the LOAEL), and more severe signs of toxicity (ventral
recumbancy, dyspnea, apathy, coma, and weight loss) were noted in dams treated with 450
mg/kg. Treatment with 50 or 150 mg/kg/day had no effect on any reproductive or fetal
parameter. Treatment with 450 mg/kg/day was associated with increased post-implantation
(embryonic) loss, reduced fetal weight, and an increased incidence of fetuses (and litters) with
skeletal abnormalities (eg. wavy ribs and dumbbell-shaped thoracic bodies) and variations (e.g.
non-ossified or incompletely ossified vertebrae, sternebrae or metatarsala). Study personnel did
not consider the abnormal skeletal findings in fetuses from dams treated with the high dose to be
indicative of a specific teratogenic effect of the test article because they are commonly found in
Wistar rats and correlated with reduced fetal weight.
The results of the OECD study in rabbits (Becker and Biedermann, 1991b) show that Hallcomid
M-8-10 is not a developmental toxicant at doses up to 1000 mg/kg/day, which was a maternally
toxic dose. Although a number of skeletal variations were observed in this study, there appeared
to be no clear-cut, dose-dependent differences in the incidences of variants between treated and
control animals. Therefore, study personnel did not consider them to be related to administration
of test material.
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As the results of the developmental studies with Hallcomid M-8-10 are likely to be predictive of
results for N,N- dimethyl octaneacidamide and N,N- dimethyl decaneacidamide, no additional
testing is necessary.
4.4.6 Additional Data
4.4.6.1 Skin and Eye Irritation
The results of a DOT corrosivity potential study performed in 6 rabbits indicate that Hallcomid
M-8-10 causes moderate-severe skin irritation but is not corrosive (Harris, 1990). An additional
skin irritation study performed in one rabbit indicates that the material is corrosive (Kreuzmann,
1990b). Altogether, these results suggest that Hallcomid M-8-10 is severely irritating to the skin.
Due to the suspected irritation potential of Hallcomid M-8-10, the material was tested for eye
irritation in a single young adult male New Zealand White rabbit (Kreuzmann, 1990c). The total
irritation scores ranged from 26 (at 1 hr) to 66 (at Day 4), indicating that the material was highly
irritating.
Based on the fact that the two category members are the predominant ingredients of Hallcomid
M-8-10 and have similar structures and physical properties, the results of the study with
Hallcomid M-8-10 are likely to be predictive of those with the individual category members. No
additional testing is necessary.
4.4.6.2 Sensitization
The ability of Hallcomid M-8-10 to produce sensitization has been tested in a GLP study in
guinea pigs (Kreuzmann, 1990c). After initiation with the highest dose that did not cause
irritation (5% test material in 80% ethanol/20% distilled water), challenge with 2.5% test
material in acetone did not produce skin irritation. Therefore, Hallcomid M-8-10 did not cause
sensitization in the guinea pig. Based on the rational presented above, the results of this study are
likely to be predictive of results with N,N- dimethyloctanamide and N,N-dimethyldecanamide.
Therefore, testing of the category members is not necessary.
4.4.7 Summary/Test plan for mammalian toxicity
Adequate studies with Hallcomid M-8-10 have been conducted for all required endpoints. Acute
oral, inhalation and dermal toxicity studies show that exposure to fairly large amounts of
Hallcomid M-8-10 is required to produce acute toxicity. Inhalation of a very high concentration
(521 mg/m3) for 5 days causes toxicity to the respiratory system of rats (but not other organs).
Results of an OECD guideline, 91-day oral study show that repeated ingestion of doses up to
approximately 800 mg/kg/day for 91 days is well tolerated in rats. The material is irritating to
the skin and eyes, and is not a sensitizer. Repeated exposure to doses equal to or greater than
100 mg/kg/day also appears to be irritating to the GI tract of dogs, as evidenced by vomiting and
increased salivation after dosing. Adequate studies show that Hallcomid M-8-10 is not
mutagenic or clastogenic. Results of the 91-day test indicate that the material is not toxic to
reproductive organs, and developmental studies in rats and rabbits indicate that the material is
not a developmental or reproductive toxicant.
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Since Hallcomid M-8-10 predominantly contains N,N- dimethyloctaneacidamide and N,N-
dimethyldecaneacidamide (in approximately equal amounts), and the two materials are closely
related in chemical structure and physical properties, the potential for mammalian toxicity of the
two category members is not expected to differ substantially from that of Hallcomid M-8-10.
Therefore, additional mammalian toxicity testing with the individual materials is not necessary.
5. Summary
In summary, valid data are present to satisfy all physical/chemistry, environmental, aquatic and
mammalian toxicity endpoints. In general, measured physical chemistry values for dimethyl
octaneacidamide, dimethyl decaneacidamide and Hallcomid M-8-10 are similar to each other and
to EPIWIN-estimated values for the individual components, indicating that EPIWIN is a good
model to predict physical properties and environmental fate of these materials, that data for one
category member will be predictive of the other, and those data for Hallcomid M-8-10 can be
used to predict behavior of the individual components. No additional testing is necessary.
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Herbold BA. 1992. Hallcomid M-8-10 Salmonella/Microsome Test. Study Number T3039100,
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