Product Safety and Regulatory Affairs
August 27,2003
Marianne L, Horinko
Acting Administrator
U. S. Environmental Protection Agency
P.O. Box 1473
Merrifield, VA 22 116
Attn: Chemical Right-To-Know Program
Dear Administrator Horinko,
Crompton Corporation is submitting the enclosed Robust Summary and Test plan for the
following chemical:
Dimethyl 3,3 `-thiobispropionate (CAS # 413 l-74-2).
If you have any questions, please contact me at 203-573-3390 or e-mail to
mark-thomson@cromptoncorp.com
Sincfi
anager, Toxicology & International Product Registration
rompton Corporation
Middlebury, CT 06749
USA
Responsible
Care"
A PublicCommitment
Crompton Corporation 199 Benson Road, Middlebury, CT 06749
HIGH PRODUCTION VOLUME (HPV)
CHEMICAL CHALLENGE PROGRAM
TEST PLAN
For
Dimethyl 3,3'-thiobispropionate
CAS No. 4131-74-2
Submitted to the US EPA
BY
Crompton Corporation.
1 of7
1. General Information
CAS Number: 4 13l-74-2
1.1
Molecular Weight: 206.26
1.2
Structure and formula: C8H1404S
1.3
1.4 Introduction
Dimethyl 3,3'-thiobispropionate is used as an antioxidant in PVC systems.
2. Justification for Use of Read Across Data for Human Health Toxicity Endpoints
Studies have been reported in the literature concerning the metabolism of thiodipropionic acid (TDPA)
and its esters (seerobust summary section 5). These studies show that estersof TDPA are almost
completely absorbed and hydrolysed to TDPA, which itself is largely eliminated in the urine, either as
the free acid or as an acid labile conjugate. Absorption of the various estersof TDPA is not
significantly affected by the water solubility as demonstratedby the high degree of absorption of one
analog, didodecyl3,3'-thiodipropionate (insoluble in water), following oral administration in the rat.
Radiolabeled studies show estersof TDPA will undergo hydrolytic cleavage. This processcan occur
to a significant extent within the gastrointestinal tract. It is therefore likely that any toxicity, or lack of
toxicity, will be as a consequenceof exposure to hydrolytic degradants, particularly the parent acid. It
can be predicted that TDPA will be the most significant degradant following oral ingestion of
dimethyl 3,3'-thiodipropionate, therefore the toxicity of this product has been evaluated indirectly
from toxicity studieswith didodecyl3,3'-thiodipropionate.
3. Review of Existing Data and Development of Test Plan
Crompton Corporation has undertaken a comprehensive evaluation of all relevant data on the SIDS
endpoints of concern for dimethyl 3,3'-thiobispropionate and structural analogs.
The availability of the data on the specific SIDS endpoints is summarized in Table 1. Table 1 also
shows data gaps that will be filled by additional testing.
3 of 7
Available adequate data and proposed testing on Dimethyl 3,3'-thiobispropionate
Table 1:
CAS No. 10081-67-l
%6
.s 3
"3
E r=
&:
24
Y/N Y/N Y/N Y/N Y/N Y/N Y/N
* Data available on analogs
Evaluation of Existing Physicochemical Data and Proposed Testing
A.
1. Melting Point
The substance is a liquid at room temperature. The melting point is estimated to be -38.3"C
using MPBPWIN ~1.40.
2. Boiling Point
The boiling point is estimated to be 242癈 using MPBPWIN ~1.40.
3. Vapour Pressure
4 of 7
The vapour pressure is estimated to be 0.055 hPa at 25癈 using MPBPWIN ~1.40.
4. Water Solubility
The MSDS for dimethyl 3,3'-thiodipropionate states that it is practically insoluble in water.
5. Partition Coefficient
The partition coefficient is estimated as log Kow = 0.98 using KOWWIN ~1.66.
Summary of Physicochemical Properties Testing: Existing data for melting point, boiling point,
vapour pressure, water solubility and partition coefficient are considered to fdl these endpoints
adequately. No additional testing is recommended.
B. Evaluation of Existing Environmental Fate Data and Proposed Testing
1. Biodegradation
The biodegradability of the chemical has been estimated using Biowin ~4.00 and the results
indicate the chemical to be readily biodegradable.
2. Hydrolysis
The half life is estimated to be 1.02 years at pH7 using HYDROWIN ~1.67.
3. Photodegradation
The potential for photodegradation has been estimated using the AOPWIN VI .90, and
indicates atmospheric oxidation via OH radicals reaction with a half-life of 6.2 hours.
Transport and Distribution between Environmental Compartments
4.
An Epiwin Level III Fugacity Model calculation has been conducted for the chemical and
indicates distribution mainly to water and soil for emissions of 1000 kg/hr simultaneously to
air water and soil compartments.
Summary of Environmental Fate Testing: The endpoints for biodegradation, hydrolysis,
photodegradation and transport and distribution between environmental compartments are
filled adequately. No additional testing is recommended.
C. Evaluation of Existing Ecotoxicity Data and Proposed Testing
1. Acute Toxicity to Fish
The LC50 (96 h) is estimated to be 109.7 mg/L, calculated using ECOSAR vO.99g.
2. Acute Toxicity to Algae
5 of 7
The EC50 (96 h) is estimated to be 8.41 mg/L, calculated using ECOSAR vO.99g.
Acute Toxicity to Daphnia
3.
The EC50 (48 h) is estimated to be 1388.7 mg/L, calculated using ECOSAR vO.99g.
Summary of Ecotoxicity Testing: No further ecotoxicity testing is recommended due to the
extremely low water solubility and high estimated log &, value. The ecotoxicity endpoints are
considered to be adequate.
Evaluation of Existing Human Health Effects Data and Proposed Testing
D.
1. Acute Oral Toxicity
The LDso (rat) has been reported as between >2500 and ~5000 mg/kg b.w. and LD50 (mouse)
as >2000 in studies conducted using the analog didodecyl3,3'-thiodipropionate. In studies
using the parent thiodipropionic acid, LDsO (mouse) of 2000 mg/kg b.w. and LD50 (rat) of
3000 mg/kg b.w. were reported.
Repeat Dose Toxicity
2.
In a repeat dose toxicity study (oral, 13 weeks, rat) using the analog didodecyl3,3'-
thiodipropionate a NOAEL of 350 mg/kg b.w./day was reported.
3. Genotoxicity
An Ames test will be conducted using OECD 47 1.
An in vitro chromosome aberration study will be conducted using OECD Method 473.
Reproductive and Developmental Toxicity
4.
In a study using the analog didodecyl3,3'-thiodipropionate (oral, 13 week, rat) no adverse
effects were seen in the reproductive organs of the test animals up to and including the high
dose of 1000 mgikg b.w./day. This is suggestive of no adverse effects on reproduction.
Developmental toxicity studies have been conducted using the analog didodecyl3,3'-
thiodipropionate (oral, essentially following OECD 414, rat, mouse, rabbit, hamster). In all
these studies, no adverse effects were seen in the parents or the offspring at the highest dose
used.
Summary of Human Health Effects Testing: The potential to cause in vitro chromosomal
aberrations will be determined using OECD Method 473 and an Ames test will be performed
using OECD Method 471. Existing data for the analog substance and parent thiopropionic acid
are considered to fdl the remaining endpoints adequately.
6 of 7
Evaluation of Data for Quality and Acceptability
3.
The collected data were reviewed for quality and acceptability following the general US EPA
guidance [2] and the systematic approach described by Klimisch et al [3]. These methods include
consideration of the reliability, relevance and adequacy of the data in evaluating their usefulness for
hazard assessment purposes. This scoring system was only applied to ecotoxicology and human
health endpoint studies per EPA recommendation [4]. The codification described by Klimisch
specifies four categories of reliability for describing data adequacy. These are:
Reliable without restriction: Includes studies or data complying with Good Laboratory
(1)
Practice (GLP) procedures, or with valid and/or internationally accepted testing guidelines, or
in which the test parameters are documented and comparable to these guidelines.
Reliable with Restrictions: Includes studies or data in which test parameters are documented
(2)
but vary slightly from testing guidelines.
Not Reliable: Includes studies or data in which there are interferences, or that use non-relevant
(3)
organisms or exposure routes, or which were carried out using unacceptable methods, or
where documentation is insufficient.
Not Assignable: Includes studies or data in which insufficient detail is reported to assign a
(4)
rating, e.g. listed in abstracts or secondary literature.
4. References
PI US EPA, EPI Suite Software, 2000
USEPA (1998). Guidance for Meeting the SIDS Requirements (The SIDS Guide). Guidance
PI
for the HPV Challenge Program. Dated 1 l/2/98.
Klimisch, H.-J., et al (1997). A Systematic Approach for Evaluating the Quality of
[31
Experimental Toxicological and Ecotoxicological Data. Regul. Toxicol. Pharmacol. 25: l-5
USEPA (1999). Determining the Adequacy of Existing Data. Guidance for the HPV
[41
Challenge Program. Draft dated 2/l O/99.
7 of 7
ao/-/47//B
IUCLID
Data Set
Robust Summaries
: ID: 4131-74-2
Existing Chemical
: 4131-74-2
CAS No.
: dimethyl 3,3'-thiobispropionate
EINECS Name
: 223-948-9
EC No.
: C8H1404S
Molecular Formula
Status
: Mark 5152 US HPV Crompton Corporation
Memo
: 2506.2003
Printing date
.
Revision date
: 2506.2003
Date of last update
: 18
Number of pages
: Chapter: 2, 3,4, 9
Chapter (profile)
: Reliability: without reliability, 1, 2, 3, 4
Reliability (profile)
: Flags: without flag, confidential, non confidential, WGK (DE), TA-Luft (DE),
Flags (profile)
Material Safety Dataset, Risk Assessment, Directive 67/548/EEC, SIDS
1 I18
Id 4131-74-2
2. Physico-Chemical Data
Date 08.052003
2.1 MELTING POINT
Value : -38.3 "C
.
Sublimation
: other: Estimation using MPBPWIN VI .40
Method
Year : 2003
GLP
Test substance . Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
Remark : Subtance is a liquid at room temperature.
: (2) valid with restrictions
Reliability
27.03.2003 (9)
2.2 BOILING POINT
Value : 242 "C at
.
.
Decomposition
Method : other: Estimation using MPBPWIN VI .40
Year : 2003
.
GLP
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
Reliability : (2) valid with restrictions
27.03.2003 (9)
2.4 VAPOUR PRESSURE
Value : .055 hPa at25 "C
Decomposition
Method : other (calculated): MPBPWIN VI .40
Year : 2003
GLP
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
Reliability : (2) valid with restrictions
27.03.2003 (9)
2.5 PARTITION COEFFICIENT
Partition coefficient : octanol-water
- .98 at "C
.
Log pow
:
pH value
Method : other (calculated): KOWWIN VI .66
Year : 2003
GLP
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
Reliability : (2) valid with restrictions
27.03.2003
2.6.1 SOLUBILITY IN DIFFERENT MEDIA
Solubility in : Water
Description : not soluble
Method : other: unknown
: 2002
Year
GLP : no data
2118
Id 4131-74-z
2. Physico-Chemical Data
Date 08.052003
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
: (4) not assignable
Reliability
08.052003 (2)
3118
Id 4131-74-2
3. Environmental Fate and Pathways
Date 08.052003
3.1.1 PHOTODEGRADATION
: air
Type
.
Light source
.
. nm
Light spectrum
Relative intensity : based on intensity of sunlight
DIRECT PHOTOLYSIS
Halflife t112 : 6.2 hour(s)
Degradation % after
Quantum yield
Deg. product
Method : other (calculated): AOPWIN VI .90'
Year : 2003
GLP
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
: Concentration of hydroxyl radicals in air = 1.5E6 OH/cm3
Remark
12-hour day
27.03.2003 (9)
3.1.2 STABILITY IN WATER
: abiotic
Type
t112 pH4 at "C
t112 pH7 at "C
:
t112 pH9 at "C
Deg. product
Method : other (calculated): Estimated using HYDROWIN VI .67
Year : 2003
GLP
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
: Half life at pH 8: 37.14 days
Result
Half life at pH 7: 1.02 years
Reliability : (2) valid with restrictions
27.03.2003 (9)
3.3.1 TRANSPORT BETWEEN ENVIRONMENTAL COMPARTMENTS
: fugacity model level III
Type
Media
Air : % (Fugacity Model Level I)
Water : % (Fugacity Model Level I)
Soil : % (Fugacity Model Level I)
.
Biota . % (Fugacity Model Level ll/lll)
Soil : % (Fugacity Model Level II/Ill)
Method : other: Calculation using EPIWIN Level III Fugacity Model
Year : 2003
Test condition : Henry's Law Constant: 3.15E-10 atm-mYmole (Henrywin program)
Vapor pressure: 0.0417 mmHg (Mpbpwin program)
Log Kow: 0.98 (experimental value)
Soil Koc: 3.92 (talc by model)
1000 kg/hr emissions to air, water and soil compartments.
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
4118
Id 4131-74-2
3. Environmental Fate and Pathways
Date 08.052003
MassAmount Half-life Emissions
(percent) (W (kg/hr)
Air 0.01 12.4 1000
Water 42 360 1000
Soil 57.9 360 1000
Sediment 0.0757 1.44E+3 0
Fugacity Reaction Advection Reaction Advection
(percent) (percent)
(W h'W Ow'W
Air 1.51E-13 7.17 1.28 0.239 0.0426
Water 4.09E-15 l.O3E+3 536 34.4 17.9
Soil 1.59E-13 1.42E+3 0 47.4 0
3.37E-15
Sediment 0.465 0.0193 0.0155 0.000645
Persistencetime: 425 hr
Reactiontime: 518hr
Advection time: 2.38E+3hr
Percentreacted:82.1
Percentadvected: 17.9
Half-lives (hr), (basedupon Biowin (ultimate) andAopwin):
Air: 12.36
Water: 360
Soil: 360
Sediment:1440
Biowin estimate:3.024(weeks)
Advection times(hr):
Air: 100
Water: 1000
Sediment:5E+4
: (1) valid without restriction
Reliability
27.03.2003 (9)
BIODEGRADATION
3.5
- aerobic
.
Type
lnoculum
Deg. product
Method : other: estimation using BIOWIN ~4.00
: 2003
Year
.
GLP
Test substance : Dimethyl 3,3'-thiobisprop'ionate(CAS No. 4131-74-2)
Result : MIT1 Linear Biodegradation Probability = 0.9845
MIT1 Non-linear Biodegradation Probability = 0.9616
The substance is predicted to be readily biodegradable
: (2) valid with restrictions
Reliability
27.03.2003 (9)
5118
Id 4131-74-2
4. Ecotoxicity
Date 08.052003
4.1 ACUTE/PROLONGED TOXICITY TO FISH
Type
Species
Exposure period : 96 hour(s)
Unit : mg/l
LC50 : 109.7
Method : other: Estimated using ECOSAR vO.999
Year : 2003
GLP
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
Test condition : Log Kow: 0.98 (KOWWIN estimate)
Water solubility: 1 E+4 mg/l
Ecosar Class: Esters
Reliability : (2) valid with restrictions
27.03.2003 (9)
4.2 ACUTE TOXICITY TO AQUATIC INVERTEBRATES
:
Type
Species : Daphnia sp. (Crustacea)
Exposure period : 48 hour(s)
Unit : mg/l
EC50 : 1388.7
Method : other: Estimated using ECOSAR vO.99g
Year : 2003
GLP
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
Test condition : Log Kow: 0.98 (KOWWIN estimate)
Water solubility: 1 E+4 mg/l
Ecosar Class: Esters
Reliability : (2) valid with restrictions
27.03.2003 (9)
4.3 TOXICITY TO AQUATIC PLANTS E.G. ALGAE
Species
Endpoint
: 96 hour(s)
Exposure period
Unit : mg/l
EC50 : 8.41
Method : other: Estimated using ECOSAR vO.99g
Year : 2003
GLP
Test substance : Dimethyl 3,3'-thiobispropionate (CAS No. 4131-74-2)
Test condition : Log Kow: 0.98 (KOWWIN estimate)
Water solubility: 1 E+4 mg/l
Ecosar Class: Esters
Reliability : (2) valid with restrictions
27.03.2003 (9)
6118
Id 4131-74-2
5. Toxicity
Date 08.05.2003
TOXICOKINETICS, METABOLISM AND DISTRIBUTION
5.0
In Vitro/in vivo : In vivo
Type
: rat
Species
Number of animals
Males :
Females :
Doses
Males :
Females :
Vehicle
.
Method .
Year : 1973
GLP
Test substance . Eiodipropionic acid (CAS No. 11 l-l 7-l)
Didodecyl thiodipropionate (CAS No. 123-28-4)
POLY-TDPS-2000
[l-14C]Thiopropionic acid ([`4C]TDPA] of specific activiy 1.71 mCi/mmol
was used to prepare'4C-labeled POLY-TDPS-2000 ([I CITDPS) of specific
activity 5pCi/mg (equivalent to 58% TDPA).
Carboxy 14C-labeled didocyl thiodipropionate ([`4C]DDTDP), specific
activity 60 pCi/mmol. was purified (99.2%) by recrystallization from
aqueous acetone.
: Animals: Male Sprague-Dawley rats weighing 215-325 g were housed in
Method
glass metabolism chambers fitted for the collection of urine, feces and
respiratory C02.
Dosages: In some experiments the dose was incorporated into feed.
Starved rats were given the food and COn collection was started. After 4-8
hr any unconsumed dose was removed and rats were returned to the
regular diet.
In other experiments the dissolved dose was intubated in to the stomach.
[14C]TDPA was dissolved in ethanol-water (1 :I ) and f4C]DDTDP in corn
oil.
Urines and feces in the f4C]TDPS study were collected at the end of
dosing and then at 24 hr intervals. f4C]TDPA and f4C]DDTDP experiment
urines and COP absorbers were processed daily. Liver, kidneys, brain,
heart, lungs, whole gastrointestinal tracts and fat samples were removed at
sacrifice and frozen with carcasses until assayed.
Result : Elimination of radioactivity:
f4C]TDPA and [14C]TDPS were almost entirely absorbed from the
gastrointestinal tract when fed at levels of 3-6 mg/kg, and f4C]TDPA and
[14C]DDTDP were almost entirely absorbed at levels up to 650 and 210
mg/kg, respectively (Table 1). Urinary excretion represented the major
pathway of disposal for all 3 materials, generally accounting for 90% of the
total eliminate in all experiments. Elimination of radioactivity as 14C02 was
significant in all experiments, amounting to about 5% of the dose.
was very rapid. Over 90% of the total radioactivity eliminated
Elimination
was eliminated in less than 24 hour by all rats (Table 2). The excretion
patterns and rates did not appear to be dose-related (Table 1).
7118
Id 4131-74-2
5. Toxicity
Date 08.052003
Distribution of radioactivity in organs at sacrifice:
Levels of radioactivity of organs from rats fed [14C]TDPS were slightly
elevated at 4 days but had decreased to normal by 34 days. The value in
fat was somewhat higher than the other tissue values at 4 days but had
decreased to the same levels as the other tissues by 34 days. Rats fed
p4C]TDPA and f4C]DDTDP had tissue radioactivity values throughout
which were close to normal values except that the value of radioactivity in
the fat of rats fed f4C]DDTDP were elevated at 4 days after dosing and
remained so at 8 and 34 days.
Nature of the radioactive urinary metabolites of f4C]TDPA, [14C]TDPS and
[14C]DDTDP:
Thin-layer and paper chromatography of urine for metabolite detection was
unsuccessful because of the tendency of TDPA to migrate as more than
one spot with most solvent systems. In consequence, reverse isotope
dilution studies were carried out with untreated and hydrolyzed urines to
assay elimination of free and combined [14C]TDPA (Table 2). Acid
hydrolyses were performed without added TDPA in the [`4C]TDPS studies,
but after addiion of TDPA in the [14C]TDPA and f4C]DDTDP experiments.
Assays of untreated urines from rats fed f4C]TDPA and [`4C]TDPS at low
dose levels (3.1 and 5.6 mg/kg) showed only a small portion of the
radioactivity was eliminated as free TDPA. At high dose levels (627
mg/kg), most of the excreted radioactivity was free TDPA. Acid hydrolysis
of urine samples afforded high recovery of radioactivity as TDPA,
approaching 10% of the urinary radioactivity after feeding f4C]TDPA and
[`4~]~~~~~ and 70% after [`~C]TDPS.
To determine whether the combined radioactivity was present as an ester
glucuronide, a urine sample from a rat fed [14C]TDPS at the low level was
hydrolyzed with Gglucuronidase. f4C]TDPA amounted to 14.4% of the
urinary radioactivity compared to 7.0% without treatment. Mild alkaline
hydrolysis was unsuccessful and led to decomposition of TDPA.
The results show that oral doses of f4C]TDPA in the range of 3-650 mg/kg
are almost entirely and rapidly absorbed from the gastrointestinal tract of
the rat, and that the absorbed f4C]TDPA is very rapidly eliminated in the
urine with only a small amount entering an oxidative metabolic pathway.
Reverse isotope dilution studies indicate that f4C]TDPA is excreted in the
urine either largely unchanged (627 mg/kg dose) or as an acid labile
conjugate (3.1 mglkg dose) which is apparently not a glucuronide.
The disposition of f4C]TDPA combined as part of the TDPS or DDTDP
molecules was very similar to the disposition of orally intubated free
p4C]TDPA. The rapidity of elimination, the relative importance of the
various pathways, and the tissue retentions for each substance were not
apparently different. At least 65% of ingested [14C]TDPS appeared as free
or combined [14C]TDPA in the urine, the metabolites apparently being
identical with those found after feeding f4C]TDPA. Similarly, [ 4C]DDTDP
was also excreted as free [14C]TDPA or an acid labile conjygate. The
identification of only 65% of the urinary radioactivity in the [ C]TDPS study
as free or combined f4CJTDPA could be due to degradation by the acid of
the small quantities of [1 C]TDPA present.
Tissue radioactivity levels indicate that large oral doses of f4C]TDPA lead
neither to preferential incorporation of the label into tissues nor to a
significant increase in the general tissue radioactivity.
Rats fed t4C]TDPS showed a slight initial increase in the level of
radioactivity in most tissues and slightly larger incorporation into the fat.
8118
Id 4131-74-2
5. Toxicity
Date 08.052003
These levels declined to background values by day 34. This radioactivity
could arise from TDPS partially absorbed as fat-soluble esters which may
be widely disseminated but are fairly rapidly eliminated.
Feeding of large doses of DDTDP led to some retention of radioactivity by
fat. This radioactivity stil remained after 34 days.
The intake levels encountered in use at the maximum allowable daily
intake would be markedly lower than the doses used in this study and it is
expected that there would be rapid elimination of all these substances,
probably as thiodipropionic acid and the constituent moieties, with
negligible retention by the organism.
Table 1: Eliminationof rats fed [14C]TDPA,[14C]DDTDPand [14C]TDPS
Rat Dose Time Elimination("Y of dose)
Compound
No. Method a mg mgikg pCi (days) Urine COZ Feces Totals
3.1 9.3 4 90.1 3.1 0.5 93.6
[14C]TDPA 1 Gavage 1.0
8.2 0.5 86.8
Gavage 152 650
2 9.0 4 78.1
Gavage 160 572
3 9.3 4 84.5 2.8 0.9 88.4
152 551 8.9 8 88.5 7.2 0.2 95.9
Gavage
4
3.3 a 0.1 b 90.7
Feed 55 241 8.2 34
5 87.4
2.9 3.5 90.9
[14C]DDTDP 1 Gavage 32 107 3.3 4 84.6
Gavage 64
2 208 6.6 8 88.5 3.9 1.8 94.2
166 4.0 34 86.1 3.2a 0.1 b 89.4
Feed 36
3
5.6 6.9 4 94.7 5.9 0.7 101.2
[14C]TDPS 1 Feed 1.4
5.3 0.6 101.3
Feed 1.3 4.8 6.2 8
2 95.4
7.4 = 0.7 b
4.7 5.3 34 97.6 105.6
Feed 1.1
3
aBy direct scintillationassay;othersby BaC03procedure
b By hydrolysis anddirect assay;othersby extraction andcombustion.
Table 2: Recoveryof [14C]TDPAfrom rat urine by isotopedilution a
% of urine
Material fed Dose Treatmentb
@g/W radioactivity '
pH to 10andthen to <2 7.0 (2)
[14C]TDPA 3.1
Acid hydrolysis (3N) with addedTDPA 104.6(2)
80.9(2)
pH to 10andthen to ~2
627
Acid hydrolysis (3N) with addedTDPA 107.3(2)
[14C]DDTDP 107 Acid hydrolysis (3N) with addedTDPA 93.3 (3)
100.0(3)
Acid hydrolysis (3N) with addedTDPA
208
100.0(3)
166 Acid hydrolysis (3N) with addedTDPA
3.5 (5)
[14C]TDPS 5.6 None
Acid hydrolysis (6N), no addedTDPA 66.7 (3)
aTDPA and TDPSby Geiger counter,DDTPD by scintillationspectrometer.
Eachvalue is a singleexperiment
bNone indicatesadditionof TDPA andrecrystallization at pH 2
' Numberin parentheses indicatednumberof recrystallizations
: The results show that esters of TDPA are almost completely absorbed and
Conclusion
hydrolyzed to TDPA, which is itself largely eliminated in the urine, either as
the free acid or conjugated.
: (1) valid without restriction
Reliability
10.04.2003 (7)
5.1 .I ACUTE ORAL TOXICITY
: LD50
Type
mglkg bw
: :, 2500
Value
9118
Id 4131-74-2
5. Toxicity
Date 08.052003
Species : rat
Strain : nodata
Sex : no data
:
Number of animals
Vehicle : other: olive oil
Doses : 2000,250O mglkg bw
Method
: 1947
Year
GLP
: gemical name: 3,3'-thiodipropionic acid, didodecyl ester (CAS No. 123-
Test substance
28-4)
Purity: >97% w/w
Method : Groups of 5 or IO rats were dosed orally with 2000 or 2500 mg/kg,
respectively. Test material was dissolved in olive oil. Dosed animals were
observed for 7 days after dosing.
Result : There were no deaths observed at either dose level.
: (2) valid with restrictions
Reliability
10.04.2003 03)
: LD50
We
Value : > 5000
: rat
Species
Strain : no data
.
Sex . male
:
Number of animals
Vehicle : physiol. saline
Doses : 50,500, 5000 mg/kg bw
Method
: 1973
Year
GLP
Test substance : zemical name: 3,3'-thiodipropionic acid, didodecyl ester (CAS No. 123-
28-4)
Purity: >97% wlw
Method .
* A group of 12 male rats was dosed with 5000 mg/kg while groups of IO
male rats were dosed with 50 or 500 mg/kg. Animals were necropsied on
day 6.
Result : All animals survived to the scheduled necropsy and appeared normal
during the 5 day observation period. No gross morphological changes
were observed.
Reliability : (2) valid with restrictions
07.04.2003 (6)
: LD50
Type
: > 2000 mglkg bw
Value
Species : mouse
Strain : no data
: no data
Sex
Number of animals :
Vehicle : other: olive oil
Doses : 300,500,1000,2000 mg/kg
,
.
Method
Year : 1947
.
GLP .
Test substance : Eemical name: 3,3'-thiodipropionic acid, didodecyl ester (CAS No. 123-
28-4)
Purity: >97% w/w
Method : Groups of 19, IO, 20 or 20 mice were dosed orally with 300, 500, 1000 or
2000 mg/kg, respectively. Test material was dissolved in olive oil. Animals
were observed for one week after dosing with the test material.
IO/ 18
Id 4131-74-2
5. Toxicity
Date 08.052003
: There were 4,0,0, 1 deaths observed at 300,5000, 1000 and 2000 mg/kg,
Result
respectively.
No further information was provided.
: (2) valid with restrictions
Reliability
07.04.2003 (8)
Type : LD50
: 2000 mglkg bw
Value
.
. mouse
Species
:
Strain
Sex
:
Number of animals
Vehicle
Doses
Method
: 1951
Year
.
GLP
Test substance : Thiodipropionic acid (CAS No. 11 l-l 7-l)
Purity: No data
: No Experimental details available
Method
Reliability : (4) not assignable
11.04.2003 (5)
: LD50
Type
: 3000 mglkg bw
Value
Species : rat
Strain
Sex :
:
Number of animals
:
Vehicle
Doses
Method .
: 1951
Year
.
.
GLP
: Thiodipropionic acid (CAS No. 111-17-1)
Test substance
Purity: No data
Method : No Experimental details available
Reliability : (4) not assignable
11.04.2003 (5)
5.4 REPEATED DOSE TOXICITY
Type
Species : rat
: male/female
Sex
Strain : Sprague-Dawley
: gavage
Route of admin.
Exposure period : 13 weeks
Frequency of treatm. : daily
: 4 weeks
Post exposure period
. 125, 350, 1000 mg/kg/day
Doses
: yes
Control group
: 350 mg/kg bw
NOAEL
NOEL : 125 mg/kg bw
Method
Year : 1993
: yes
GLP
11 I18
4131-74-2
Id
5. Toxicity
Date 08.052003
: Chemical name: 3,3'-thiodipropionic acid, didodecyl ester (CAS No. 123-
Test substance
28-4)
Purity: >97% w/w
: Test subjects:
Method
Age at study initiation: 6 weeks, males 162-l 939, females 142-l 809.
No. of animals/sex/dose: 10 rats/sex/group
Study Design:
Vehicle: 1% carboxymethyl cellulose in water.
Clinical observations:
All animals were observed twice daily for morbidity and mortality. Clinical
observations were done daily, with full clinical evaluations done weekly.
Body weights and food consumption were recorded weekly.
Ophthalmoscopy was performed on all animals pretest and at week 13 in
the control and high dose animals. Clinical pathology was performed on 10
animals/sex in control and high dose groups after week 4, 10 animals/sex
in all groups after week 13, and in all recovery animals after week 17.
Parameters included hematology (except on treatment-free period
animals), blood clinical chemistry and urinalysis.
Organs examined at necropsy: All animals were submitted to full necropsy.
Organ weights were taken at necropsy. Histopathology was performed on
all selected organs/tissues for all animals in the control and high dose
groups, the liver, kidneys and lungs for all animals in all groups, and the
heart from animals in groups 2 and 3 and in all recovery group animals.
The hearts from all animals was examined after PTAH staining. Organs
examined histologically also included the epidymides, mammary glands,
ovaries, prostate, seminal vesicles, testes, uterus (horn + cervix).
: Body weight: No treatment related differences in body weight gain.
Result
Food/water consumption: Unaffected by treatment.
Mortality: No unscheduled deaths.
Clinical signs: No treatment related clinical signs
Ophthalmology: No treatment related eye lesions.
Hematology: None of the hematologic parameters were considered to
represent an adverse effect of treatment.
Urine: Urine parameters were unaffected other than being slightly more
acidic in the high dose animals as compared to the controls. This was
reversible after the 4 week treatment-free period.
Clinical chemistry: None of the clinical chemistry parameters other than a
reversible elevation in serum cholesterol in the high dose females and a
reversible elevation of alanine and aspartate aminotransferase activities in
all high dose animals were related to an effect of treatment.
Gross pathology: Macroscopic changes were considered to either be
agonal or incidental in origin or unrelated to treatment. Treatment related
microscopic lesionswere seen in the heart of high dose animals. The
lesion was described as small foci of degenerated or necrotic fibers
associated with minimal to moderate mononuclear cell infiltration. This
association suggested early or ongoing myocarditis. These lesions were
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Id 4131-74-2
5. Toxicity
Date 08.052003
not present in animals previously treated at the high dose level but allowed
a 4 week period without treatment. There were no other treatment related
microscopic lesions.
Organ weight changes: Minor differences in the weight of the major organs
were considered of no toxicological significance in the absence of
microscopic lesions.
: The oral (gavage) administration of the test material to the rat for 13 weeks
Conclusion
at a dose level of 1000 mg/kg/day was associated with a minor increase in
serum cholesterol concentrations in females, increased serum ALAT and
ASAT activities and decreased urinary pH in both sexes.
Microscopic findings in the heart of these animals suggested as ongoing
myocarditis. The heart was therefore identified as the target organ. All
these changes were reversible after 4 weeks without treatment. At a dose
level of 350 mg/kg/day there was no evidence for any treatment related
microscopic effect in the heart. Females at this dose exhibited a very
small, but not significantly significant, increase in Hb concentrations.
These individual values fell in the normal background range and are
Clinical
considered unlikely to be a direct toxic effect of the test material.
chemistry results indicated calcium concentrations of the males were
slightly elevated compared with controls. However, the differences were
small, not statistically significant and generally well within the normal
background range. No other differences to indicate an adverse effect of
the test material were noted. This dose level is therefore considered to be
the no observed adverse effect level for the test material in the rat. There
were no changes considered to represent an effect of the test material at
125 mg/kg/day and therefore this dose level is considered to be the no
observed effect level for the test material in the rat.
: (2) valid with restrictions
Reliability
07.052003 (1)
5.5 GENETIC TOXICITY `IN VITRO`
GENETIC TOXICITY `IN VIVO'
5.6
5.8.1 TOXICITY TO FERTILITY
: other
Type
Species : rat
: male/female
Sex
Strain : Sprague-Dawley
Route of admin. : gavage
: 13 weeks + 4 weeks post exposure
Exposure period
: daily
Frequency of treatm.
Premating exposure period
Male :
Female :
Duration of test
No. of generation
studies
Doses : 125, 350, 1000 mg/kg/day
:
Control group
Method
: 1993
Year
: yes
GLP
13118
Id 4131-74-2
5. Toxicity
Date 08.052003
: Chemical name: 3,3'-thiodipropionic acid, didodecyl ester (CAS No. 123-
Test substance
28-4)
Purity: >97% w/w
Method : Test subjects:
Age at study initiation: 6 weeks, males 162-l 939, females 142-l 809.
No. of animals/sex/dose: IO rats/sex/group
Study Design:
Vehicle: 1% carboxymethyl cellulose in water.
Clinical observations:
All animals were observed twice daily for morbidity and mortality. Clinical
observations were done daily, with full clinical evaluations done weekly.
Body weights and food consumption were recorded weekly.
Ophthalmoscopy was performed on all animals pretest and at week 13 in
the control and high dose animals. Clinical pathology was performed on IO
animals/sex in control and high dose groups after week 4, IO animals/sex
in all groups after week 13, and in all recovery animals after week 17.
Parameters included hematology (except on treatment-free period
animals), blood clinical chemistry and urinalysis.
Organs examined at necropsy: All animals were submitted to full necropsy.
Organ weights were taken at necropsy. Histopathology was performed on
all selected organs/tissues for all animals in the control and high dose
groups, the liver, kidneys and lungs for all animals in all groups, and the
heart from animals in groups 2 and 3 and in all recovery group animals.
The hearts from all animals were examined after PTAH staining. Organs
examined histologically also included the epidymides, mammary glands,
ovaries, prostate, seminal vesicles, testes, uterus (horn + cervix).
Result : NOAEL = 350 mg/kg/day
NOEL = 125 mg/kg/day
Body weight: No treatment related differences in body weight gain.
Food/water consumption: Unaffected by treatment.
Mortality: No unscheduled deaths.
Clinical signs: No treatment related clinical signs
Ophthalmology: No treatment related eye lesions.
Hematology: None of the hematologic parameters were considered to
represent an adverse effect of treatment.
Urine: Urine parameters were unaffected other than being slightly more
acidic in the high dose animals as compared to the controls. This was
reversible after the 4 week treatment-free period.
Clinical chemistry: None of the clinical chemistry parameters other than a
reversible elevation in serum cholesterol in the high dose females and a
reversible elevation of alanine and aspartate aminotransferase activities in
all high dose animals were related to an effect of treatment.
Gross pathology: Macroscopic changes were considered to either be
agonal or incidental in origin or unrelated to treatment. Treatment related
microscopic lesions were seen in the heart of high dose animals. The
14/18
Id 4131-74-2
5. Toxicity
Date 08.052003
lesion was described as small foci of degenerated or necrotic fibers
associated with minimal to moderate mononuclear cell infiltration. This
association suggested early or ongoing myocarditis. These lesions were
not present in animals previously treated at the high dose level but allowed
a 4 week period without treatment. There were no other treatment related
microscopic lesions.
Organ weight changes: Minor differences in the weight of the major organs
were considered of no toxicological significance in the absence of
microscopic lesion.
Conclusion : This study included specific evaluation of the reproductive organs of the
test animals. No adverse effects on these organs were seen at the dose
levels used in this study. This is suggestive of no adverse effects on
reproduction.
Reliability : (2) valid with restrictions
07.052003 (1)
5.8.2 DEVELOPMENTAL TOXlClTY/lERATOGENlClTY
Species : rat
Sex : female
: Wistar
Strain
: gavage
Route of admin.
Exposure period : days 6-l 5 of gestation
Frequency of treatm. :
Duration of test
Doses : 16, 74, 350 or 1600 mg/kg in corn oil
Control group : yes
NOAEL maternal tox. : 1600 mg/kg bw
: 1600 mglkg bw
NOAEL teratogen.
Method : other: essentially follows OECD 414
Year : 1972
GLP .
Test substance : zemical name: 3,3'-thiodipropionic acid, didodecyl ester (CAS No. 123-
28-4)
Purity: not stated
: A positive control group received 250 mg/kg aspirin. Frequency of
Method
The number of pregnant
treatment for positive control group not stated.
rats at the end of the study ranged from 19-21/dose level. Feed and water
were available ad libitum. The rats were observed daily for general
appearance and behaviour, with emphasis on feed consumption and
weight. Weights were obtained on days 0, 6, 11, 15 and 20 of gestation.
On day 20 of gestation caesarian sections were performed and the
numbers of implantation and resorption sites as well as the numbers of live
and dead fetuses were recorded. The urogenital tract of each dam was
examined for any abnormality, all fetuses were examined for any gross
external abnormalities, and all live pups were weighed. Visceral
examinations were performed on one-third of the fetuses of each litter, and
the remaining two-thirds were examined for skeletal defects.
Result : No adverse effects with respect to number of implantations and maternal or
fetal death were noted after oral administration to rats of up to 1600 mg/kg
dilauryl thiodipropioinc acid on days 6-l 5 of gestation. There were no
significant differences in numbers of abnormalities of the soft or skeletal
tissues between the treated and sham control fetuses.
Reliability : (2) valid with restrictions
07.05.2003 (4)
Species : mouse
Sex : female
15118
Id 4131-74-2
5. Toxicity
Date 08.052003
Strain : CD-l
Route of admin. : gavage
Exposure period : days 6-l 5 of gestation
Frequency of treatm. : daily
Duration of test
Doses : 16, 74, 350 and 1600 mg/kg in corn oil
Control group : yes
NOAEL maternal tox. : 1600 mglkg bw
NOAEL teratogen. : 1600 mg/kg bw
Method : other: essentially follows OECD 414
Year : 1972
GLP
Test substance : %emical name: 3,3'-thiodipropionic acid, didodecyl ester (CAS No. 123-
28-4)
Purity: not stated
Method : A positive control group received 150 mg/kg aspirin. Frequency of
treatment for the positive control not stated. The number of pregnant mice
at the end of the study ranged from 20-22/dose level. Feed and water
were available ad libitum. The mice were observed daily for general
appearance and behaviour, with emphasis on feed consumption and
weight. Weights were obtained on days 0, 6, 11, 15 and 17 of gestation.
On day 17 of gestation, caesarian sections were performed and the
numbers of implantation and resorption sites, as well as the numbers of
live and dead fetuses, were recorded. The urogenital tract of each dam
was examined for any abnormality, all fetuses were examined for any gross
external abnormalities, and all live pups were weighed. Visceral
examinations were performed on one-third of the fetuses of each litter, and
the remaining two-thirds were examined for skeletal defects.
Result : No adverse effects were found with respect to implantations and maternal
and fetal survival after oral administration to mice of up to 1600 mg/kg test
material on days 6-15 of gestation. The number of abnormalities seen in
the soft or skeletal tissues of the treated fetuses was comparable to that
seen in the sham control fetuses.
Reliability : (2) valid with restrictions
07.05.2003 (4)
Species : rabbit
Sex : female
Strain : Dutch
Route of admin. : gavage
Exposure period : days 6-18 of gestation
Frequency of treatm. : daily
Duration of test
: 2.5, IO, 45, 216, 1000 mg/kg in corn oil
Doses
Control group : yes
NOAEL maternal tox. : 1000 mglkg bw
NOAEL teratogen. : 1000 mg/kg bw
Method : other: essentially follows OECD 414
Year : 1973
GLP
Test substance : zemical name: 3,3'-thiodipropionic acid, didodecyl ester (CAS No. 123-
28-4)
Purity: not stated
Method : Groups of 15-29 artificially inseminated females/dose level resulted in 8-13
pregnant rabbits/dose level. On day 29, all does were subjected to
caesarian section. The numbers of corpora lutea, implantation sites,
resorption sites, and live and dead fetuses were recorded. The body
weights of the live pups were also recorded. The urogenital tract of each
animal was examined in detail for normality. All fetuses underwent a
detailed gross examination for the presence of external congenital
16118
Id 4131-74-2
5. Toxicity
Date 08.052003
abnormalities. The live fetuses of each litter were then placed in an
incubator for 24 hours for the evaluation of neonatal survival. All surviving
pups were sacrificed, and all pups examined for visceral abnormalities by
dissection. All fetuses were then cleared in potassium hydroxide, stained
with alizarin red S dye and examined for skeletal defects.
: Eight to thirteen pregnant dams survived to term. There was no clearly
Result
discernible effect on nidation or on maternal or fetal survival at doses as
high as 1000 mg/kg. The number of abnormalities seen in either soft or
skeletal tissues of the test groups did not differ from the number occurring
spontaneously in the control.
Reliability : (2) valid with restrictions
07.052003 (3)
Species : hamster
: female
Sex
Strain : other: Golden
Route of admin. : gavage
Exposure period : days 6-10 of gestation
Frequency of treatm. : daily
Duration of test
Doses : 16, 74, 350 or1 600 mg/kg in corn oil
Control group : yes
NOAEL maternal tox. : 1600 mg/kg bw
NOAEL teratogen. : 1600 mglkg bw
Method : other: essentially follows OECD 414
: 1972
Year
.
GLP
: gemical name: 3,3'-thiodipropionic acid, didodecyl ester (CAS No. 123-
Test substance
28-4)
Purity: not stated
: The number of hamsters at the end of the study ranged from 20-23/dose
Method
level. Feed and water were available ad libitum. The hamsters were
observed daily for general appearance and behaviour, with emphasis on
feed consumption and weight. Weights were obtained on days 0, 8, 10 and
14 of gestation. On day 14 of gestation caesarian sections were performed
and the numbers of implantation and resorption sites as well as the
numbers of live and dead fetuses were recorded. The urogenital tract of
each dam was examined for any abnormality, all fetuses were examined
for any gross external abnormalities, and all live pups were weighed.
Visceral examinations were performed on one-third of the fetuses of each
litter, and the remaining two-thirds were examined for skeletal defects.
: The numbers of implantations and maternal and fetal survival were not
Result
adversely affected by oral administration to hamsters of up to 1600 mg/kg
No significant differences in the
test material on days 6-l 0 of gestation.
number of soft or skeletal tissue abnormalities were found between treated
and sham control fetuses.
: (2) valid with restrictions
Reliability
07.052003 (4)
17118
-*
Id 4131-74-2
9. References
Date 08.05.2003
13 Week Oral (gavage) Toxicity Study in the Rat followed by a 4 Week Treatment-free
(1)
Period. Ciba-Geigy Ltd., Basel, Switzerland, December 14, 1993: Reported in, Thioesters
Association, Thiodipropionates Category Robust Summaries, EPA HPV Chemical
Challenge Program, December 2001
Crompton Corporation, Mark 5152 Safety Data Sheet VI, April 24, 2002; Chevron Phillips
(2)
Chemical Co., Dimethyl Thiodipropionate Material Safety Data Sheet, MSDS #644740, rev.
#I, February 21,2002
FDA (1973). Teratologic evaluation of FDA 71-40 (dilauryl thiodipropioinc acid) NTIS PB-
(3)
223 824: Reported in, Thioesters Association, Thiodipropionates Category Robust
Summaries, EPA HPV Chemical Challenge Program, December 2001
Food and Drug Research Labs, Inc. (FDRL). (Dec.29, 1972). Teratologic evaluation of
(4)
FDA 71-40 (Dilauryl thiodipropionic acid) in mice, rats and hamsters. Springfield, VA: US
Department of Commerce, National Technical Information Service (NTIS). NTIS
publication #PB22177: Reported in, Thioesters Association, Thiodipropionates Category
Robust Summaries, EPA HPV Chemical Challenge Program, December 2001
Lehman, A.J., et al, Advanc. Food Res., 3, 197, 1951; Reported in Eighth Report of th
(5)
eJoint FAO/WHO Expert Committee on Additives, Wld Hlth Org. techn. Rep. Ser., 1965,
309; FAO Nutrition Meetings Report seriess 1965, 38
Litton Bionetics, Inc. (1973). Mutagenic evaluation of compound FDA 71-40, dilauryl
(6)
thiodipropionic acid US Dept of Commerce. NTIS PB245452: Reported in, Thioesters
Association, Thiodipropionates Category Robust Summaries, EPA HPV Chemical
Challenge Program, December 2001
Reynolds, R.C., Astill, B.D., & Fassett, D.W., The Fate of [14C]Thiodipropionates in Rats,
(7)
Toxicol. & Appl. Pharmacol., 28, 133-141 (1974)
Tullar, P.E. (1947) The pharmacology and toxicology of thiodipropionic acid and its dilauryl
(8)
and distearyl esters. Final Report. The Kalusowski Memorial Research Laboratories,
School of Pharmacy, The George Washington University, Washington D.C. Unpublished
data: Reported in, Thioesters Association, Thiodipropionates Category Robust Summaries,
EPA HPV Chemical Challenge Program, December 2001
US EPA, EPI Suite Software, 2000
(9)
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