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Submission Information

Submission ID : 25349326 Submission Name : 2,5-Furandione, 3-dodecenyldihydroAR Number : 

Chemical Information

CAS Number : 25377-73-5 Ninth Collective Index Name : 2,5-Furandione, 3-(dodecenyl)dihydroSubmitter Information

Submitter's Name : EPA

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State : DC

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Technical Point of Contact Information

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 Acute Toxicity to Aquatic Vertebrates

CAS Number : 25377-73-5

Sponsored

Chemical Name :

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Acute Toxicity To Aquatic Vertebrates

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test

Substance

Comments:

Purity not specified

Sponsored

Chemical Result

Type:

Measured

Test Substance

Result Type:

Measured

Method - Acute Toxicity To Aquatic Vertebrates

Year Study

Performed:

1979

Method/Guideline

Followed:

Other

Other

Method/Guideline:

Standard Methods for the Examination of Water and Wastewater (1971) American Public

Health Association, Static acute toxicity test, Method No. 231

Deviations from

Method/Guideline:

Yes

Species: Carassius auratus

GLP: No Data

Analytical

Monitoring:

Yes

Test Type: Static

Test Vessel: Closed

Water Media Type: Freshwater

Test

Concentrations:

Measured

Nominal and

Measured

Concentrations:

Not Specified
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Exposure Period: 96 Hours

Vehicle Used: No Data

Vehicle Name:

Vehicle Amount

and Units:

Alkalinity:

Dissolved Oxygen:

pH Value: Value/Lower Range: = 6 Upper Range: 7

Test Temperature

and Units:

Value/Lower Range: 19 Upper Range: 21 °C

Photo

(Light/Dark):

Salinity:

TOC:

Water Hardness:

Method/Guideline

Test Conditions

Remarks:

Ten fish per test concentration were exposed at 20 ± 1 °C in 25 L of solution

contained in all-glass tanks measuring 42 x 28 x 28 cm. The duration of the test was

24 or 96 hours and the solutions were aerated throughout the test period. The

concentration of the chemical in solution was determined before and after each test,

either with a total organic carbon analyzer or by extraction and subsequent GC

analysis. Based on the average fish weight of 3.3 g and the testing of 10 fish/25L,

the loading rate was 1.32 g fish/L. The latter value exceeds the OECD TG 203-

recommended maximum loading of 1g fish/L for static tests.

Solutions were made in local tap water. The analysis was:

Cl- = 65 mg/L

NO2- = 0 mg/L

NO3- = 4 mg/L

SO42- = 35 mg/L

PO43- = 0.15 mg/L

HCO3- = 25 mg/L

SiO2 = 25 mg/L

NH4+ = 0 mg/L

Fe = 0.05 mg/L

Mn = 0 mg/L

Ca2+ = 100 mg/L

Mg2+ = 8 mg/L 

Na+ = 30 mg/L

pH = 7.8

Limit Test: Unknown

Test Results - Acute Toxicity To Aquatic Vertebrates

NOEC Exposure

Duration:

NOEC:

LOEC Exposure

Duration:

LOEC:
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NOELR Exposure

Duration:

NOELR:

LOELR Exposure

Duration:

LOELR:

LC/EC Mean Value : Exposure

Duration

Exposure

Units

LC/EC % Value

Description

Mean

Value

or

Lower

Mean

Value

Upper

Mean

Value

Units Effect

Observed

Basis for

Concentration

24 Hours LC 50 % = 2 4 mg/L Mortality Calculated

96 Hours LC 50 % = 2 3 mg/L Mortality Calculated

Results Remarks: 24-hour LC50 (pH = 7.0) = 4 mg/L

96-hour LC50 (pH = 7.0) = 3 mg/L

24-hour LC50 (pH = 6.0) = 2 mg/L

96-hour LC50 (pH = 6.0) = 2 mg/L

The LC50 was obtained by interpolation from a graph of the logarithm of the

concentration versus the percentage mortality.

Reliability/Data Quality - Acute Toxicity To Aquatic Vertebrates

Reliability: 3 - Not Valid

Reliability

Remarks:

Non-preferred species and fish loading rate that exceeded guidline recommendations;

missing study details included water hardness, total organic carbon, test substance

purity, nominal and measured test concentrations, and mortality at each concentration

Key Study Sponsor

Indicator:

Reference - Acute Toxicity To Aquatic Vertebrates

Reference: Bridie et al. (1979) The acute toxicity of some petrochemicals to goldfish. Water

Research 13, 623 - 626.

Bridie et al. (1974) Determination of Acute Toxicity to Fish of Shell Chemicals,

II. AMGR.0071.74. 

TSCATS OTS0206206; Doc ID: 878210130. Shell Oil Company (12/10/82).

 Acute Toxicity to Aquatic Invertebrates

CAS Number : 25377-73-5

Sponsored

Chemical Name :

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Acute Toxicity To Aquatic Invertebrates

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydro-
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Test Substance

Purity/Composition

and Other Test

Substance

Comments:

Sponsored

Chemical Result

Type:

Test Substance

Result Type:

Method - Acute Toxicity To Aquatic Invertebrates

Year Study

Performed:

Method/Guideline

Followed:

Other

Method/Guideline:

Deviations from

Method/Guideline:

Species/In Vitro

System:

GLP:

Analytical

Monitoring:

Test Type:

Test Vessel:

Water Media Type:

Test

Concentrations:

Nominal and

Measured

Concentrations:

Exposure Period:

Vehicle Used:

Vehicle Name:

Vehicle Amount

and Units:

Alkalinity:

Dissolved Oxygen:

pH Value:

Test Temperature

and Units:

Photo

(Light/Dark):

Salinity:
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TOC:

Water Hardness:

Method/Guideline

Test Conditions

Remarks:

Limit Test:

Test Results - Acute Toxicity To Aquatic Invertebrates

NOEC Exposure

Duration:

NOEC:

LOEC Exposure

Duration:

LOEC:

NOELR Exposure

Duration:

NOELR:

LOELR Exposure

Duration:

LOELR:

LC/EC Mean Value : Exposure

Duration

Exposure

Units

LC/EC % Value

Description

Mean

Value

or

Lower

Mean

Value

Upper

Mean

Value

Units Effect

Observed

Basis for

Concentration

Results Remarks:

Reliability/Data Quality - Acute Toxicity To Aquatic Invertebrates

Reliability:

Reliability

Remarks:

As of February 2010, no data were available for this endpoint.

Key Study Sponsor

Indicator:

Reference - Acute Toxicity To Aquatic Invertebrates

Reference:
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 Acute Toxicity to Aquatic Plants

CAS Number : 25377-73-5

Sponsored

Chemical Name :

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Acute Toxicity To Aquatic Plants

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test

Substance

Comments:

Sponsored

Chemical Result

Type:

Test Substance

Result Type:

Method - Acute Toxicity To Aquatic Plants

Year Study

Performed:

Method/Guideline

Followed:

Other

Method/Guideline:

Deviations from

Method/Guideline:

Species:

GLP:

Analytical

Monitoring:

Test Type:

Test Vessel:

Water Media Type:

Test

Concentrations:

Nominal and

Measured

Concentrations:

Exposure Period:

Vehicle Used:

Vehicle Name:

Vehicle Amount

and Units:

Alkalinity:

Dissolved Oxygen:
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pH Value:

Test Temperature

and Units:

Photo

(Light/Dark):

Salinity:

TOC:

Water Hardness:

Method/Guideline

Test Conditions

Remarks:

Limit Test:

Test Results - Acute Toxicity To Aquatic Plants

NOEC Exposure

Duration:

NOEC:

LOEC Exposure

Duration:

LOEC:

NOELR Exposure

Duration:

NOELR:

LOELR Exposure

Duration:

LOELR:

Effect : Exposure

Duration

Exposure

Units

Type % Value

Description

Mean

Value

or

Lower

Mean

Value

Upper

Mean

Value

Units Basis

for

Effect

Basis for

Concentration

Results Remarks:

Reliability/Data Quality - Acute Toxicity To Aquatic Plants

Reliability:

Reliability

Remarks:

As of February 2010, no data were available for this endpoint.
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Key Study Sponsor

Indicator:

Reference - Acute Toxicity To Aquatic Plants

Reference:

 Acute Toxicity

CAS Number : 25377-73-5

Sponsored Chemical Name

:

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Acute Toxicity

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test Substance

Comments:

Purity not specified; Appearance: Amber liquid; Sponsor's

identification code: 127-2638, Dodecenyl Succinic Anhydride;

FDRL identification code: 80-1168 

Sponsored Chemical Result

Type:

Measured

Method - Acute Toxicity

Route of Administration: Inhalation

Type of Exposure: Aerosol

Species: Rat

Mammalian Strain: Sprague-Dawley

Gender: Both M/F

Number of Animals per

Dose:

10

Concentration: 5.3 mg/L (nominal); 1.22 mg/L (time-weighted gravimetric

concentration) 

Year Study Performed: 1981

Method/Guideline

Followed:

Other

GLP: Yes

Method/Guideline and

Test Condition Remarks:

Method/guideline followed: Similar to OECD limit test; FDA

guidelines for Good Laboratory Practice were followed.

Test species: Sprague-Dawley rats obtained from Blue Spruce

Farms, Altamont, NY. Group mean body weight (g) on day 1: 285

± 5 (males) and 247 ± 6 (females)

The purpose of the study was to evaluate the acute inhalation

toxicity of dodecenyl succinic anhydride (DDSAA) according to

the OECD Acute Toxicity Screening Program, Acute Inhalation

Studies Protocol, as modified and amplified by the

sponsor. The aerosol consisted of 90% DDSAA and 10% ethanol

(w/w) with a geometric mean particle size of 2.3 μm (S.D. =

2.2 μm). To serve as a control, additional animals were
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exposed to an atmosphere containing a liquid droplet aerosol

of ethanol and observed a required by the protocol. The

animals were exposed to an airborne aerosol of the test

article for 4 hours. During exposure, the animals were

individually housed in wire mesh cages and denied food and

water. Following exposure, the animals remained individually

housed and food and water were provided ad libitum. 

The animals were observed for pharmacotoxic signs during

exposure (day 1), subsequent to exposure on day one, and

daily for 14 additional days (days 2 - 15). Body weights

were also recorded from day 1 to 15 of the study. All

animals were subject to gross necropsy. During necropsy, all

major organs were examined for any signs of abnormalities and

the following tissues excised and preserved in 10% neutral

buffered formalin: whole head with nasal passages, trachea,

bronchi, lungs, liver, and kidneys. 

The actual exposure concentrations were determined by

gravimetric analysis; a known volume of chamber air was drawn

through a preweighed filter and the actual concentration was

calculated by dividing the filter weight gain by the sample

volume, and then correcting for dilution (by multiplying by

0.90).

Test Results - Acute Toxicity

Concentration (LC/LD) : LC/LD % Value

Description

Value/Lower

Concentration

Upper

Concentration

Units

LC 50 % > 1.2 mg/L

Number of Deaths ( Male

):

2

Number of Deaths ( Female

):

2

Number of Deaths ( Total

):

4

Results Remarks: The observed mortality was 2/5 for females by the second day

and 2/5 males by the fifth day of post-exposure

observation. No further deaths were observed by the 15th day

post-exposure. Thus, the LC50 for 4-hour inhalation exposure

is greater than 1.2 mg/L. 

Significant observations included labored breathing, nasal

discharge, urinary incontinence, and eye irritation. Labored

breathing was present in all animals and continued throughout

the study. 

Bloody nasal discharge was also observed in all animals

during exposure and generally persisted throughout the

observation period. Eye irritation, closing of the eyes (due

to swelling of 

periorbital tissues) and a cloud or film-covered appearance

of the eye was evident. Apparent blood around the eyes may

have been porphyrin-containing secretions of the Harderian

glands and is often seen in debilitated animals. Urinary

incontinence was noted in all males on days two through four,

and alopecia (hair loss) was evident in two males and one
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female subsequent to day seven. Following exposure to the

test article, body weight loss occurred in all animals. This

was due to dodecenyl succinic anhydride exposure, as ethanol

treatment caused no comparable effect. 

By day 15, the three surviving males and one female had

regained their original body weights. 

No findings attributable to test article exposure were

evident upon gross necropsy. Various color alterations of

the lung and other organs (dark, pale, spotting) are routine

post mortem observations in the laboratory rat and results

from post mortem congestion within the tissues. 

Conclusion: Four-hour exposure to liquid droplet aerosol of dodecenyl

succinic anhydride (90% w/w solution in ethanol) produced

mortality in two of five male and two of five female

rats. Labored breathing, transient urinary incontinence,

alopecia, eye irritation, and body weight loss were observed

following exposure to the test article.

Reliability/Data Quality - Acute Toxicity

Reliability: 3 - Not Valid

Reliability Remarks: Mortalities were observed in the limit test. Further acute

toxicity testing is recommended.

Key Study Sponsor

Indicator:

Reference - Acute Toxicity

Reference: This summary is based on a study from a TSCATS submission

OTS0505452 (Document ID: 88-8100369) conducted by Food and

Drug Research Laboratories, for Buffalo Color Corporation:

Acute Inhalation Toxicity of Dodecenyl Succinic Anhydride in

Sprague-Dawley Rats with Cover Letter Dated 04/08/82. (Study

produced on March 24, 1981)

 Acute Toxicity

CAS Number : 25377-73-5

Sponsored Chemical Name

:

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Acute Toxicity

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test Substance

Comments:

Purity not specified

Sponsored Chemical Result

Type:

Measured

Method - Acute Toxicity

Route of Administration: Oral

Type of Exposure: Gavage

Species: Rat

Mammalian Strain: Other
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Other Strain:

Gender: Male

Number of Animals per

Dose:

5

Dose: 1, 2, 4, 8, 16 g/kg

Year Study Performed: 1978

Method/Guideline

Followed:

OECD 401

GLP: Not Applicable

Method/Guideline and

Test Condition Remarks:

Single administration of the test material was given

intragastrically to five fasted male rats at each dose

level. The animals were observed for signs of toxicity or

behavioral changes on the day of treatment and throughout the

14-day observation period. Individual weights were recorded

immediately prior to dosing and prior to termination. The

surviving animals were euthanized at the conclusion of the

observation period. Gross autopsies were performed on all

animals.

Test Results - Acute Toxicity

Concentration (LC/LD) : LC/LD % Value

Description

Value/Lower

Concentration

Upper

Concentration

Units

LC 50 % = 2900 mg/kgbw

Number of Deaths ( Male

):

15

Number of Deaths ( Female

):

0

Number of Deaths ( Total

):

15

Results Remarks: During the first three days of study all animals treated at

the 4, 8 and 16 g/kg dose levels died. No deaths were

observed at the 1 and 2 g/kg dose levels. No clinical signs

of toxicity were observed at 1 g/kg. At 2 g/kg the animals

were lethargic and had an oily appearance for up to 48 hours

post dosing. All animals at the 4, 8 and 16 g/kg dose levels

were severely depressed prior to death. No body weight

effects occurred at 1 or 2 g/kg. Body weight data were not

available at higher dose levels due to the observed

mortality. No test material related macroscopic findings were

evident.

Conclusion: LD50 (males) = 2.9 g/kg

Reliability/Data Quality - Acute Toxicity

Reliability: 2 - Valid With Restrictions
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Reliability Remarks: Purity not specified

Key Study Sponsor

Indicator:

Reference - Acute Toxicity

Reference: HPV submission for Alkenyl Succinic Anhydrides category,

received by EPA from Petroleum Additives Panel Health &

Environmental Research Task Group on November 22,2002; HPV

submission references "Unpublished confidential business

information" updated 2/23/01 (RTA-074). 

 Repeated-Dose Toxicity

CAS Number : 25377-73-5

Sponsored Chemical

Name :

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Repeated-Dose Toxicity

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test

Substance Comments:

Sponsored Chemical

Result Type:

Method - Repeated-Dose Toxicity

Route of

Administration:

Type of Exposure:

Species:

Mammalian Strain:

Gender:

Number of Animals per

Dose:

Dose:

Year Study Performed:

Method/Guideline

Followed:

GLP:

Exposure Period:

Frequency of

Treatment:

Post-Exposure Period:
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Method/Guideline and

Test Condition

Remarks:

Test Results - Repeated-Dose Toxicity

Concentration (LOAEL/

LOAEC/ NOAEL/

NOAEC) :

LOAEL/

LOAEC/

NOAEL/

NOAEC

Population Value

Description

Value/Lower

Concentration

Upper

Concentration

Units

Results Remarks:

Conclusion:

Reliability/Data Quality - Repeated-Dose Toxicity

Reliability:

Reliability Remarks: As of February 2010, no data were available for this endpoint.

Key Study Sponsor

Indicator:

Reference - Repeated-Dose Toxicity

Reference:

 Genetic Toxicity in vivo

CAS Number : 25377-73-5

Sponsored Chemical Name

:

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Genetic Toxicity in vivo

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test Substance

Comments:

Sponsored Chemical Result

Type:

Method - Genetic Toxicity in vivo

Type of Study:

Type of Test:

Route of Administration:
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Type of Exposure:

Species:

Strain:

Gender:

Dose:

Year Study Performed:

Method/Guideline

Followed:

GLP:

Duration of Treatment/

Exposure Period and

Units:

Frequency of Treatment:

Positive, Negative, and

Solvent

Control Substance(s):

Number of Animals per Sex

and Dose Group:

Method/Guideline and

Test Condition Remarks:

Test Results - Genetic Toxicity in vivo

Systemic Toxicity:

Genotoxic Effect:

Results Remarks:

Conclusion:

Reliability/Data Quality - Genetic Toxicity in vivo

Reliability:

Reliability Remarks: As of February 2010, no data were available for this

endpoint.

Key Study Sponsor

Indicator:

Reference - Genetic Toxicity in vivo

Reference:

 Genetic Toxicity in vitro

CAS Number : 25377-73-5

Sponsored Chemical

Name :

2,5-Furandione, 3-(dodecenyl)dihydro-
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Test Substance - Genetic Toxicity in vitro

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test

Substance

Comments:

Purity not specified

Sponsored Chemical

Result Type:

Measured

Method - Genetic Toxicity in vitro

Type of Study: Bacterial gene mutation assay

Concentrations: 0.3, 1, 3.3, 10, 100 μg/plate without activation and 100, 333,

1000, 3333, 10,000 μg/plate with activation

Year Study

Performed:

Method/Guideline

Followed:

Other

GLP: No Data

Postive, Negative, and

Solvent

Control Substance(s):

Concurrent solvent control substance: DMSO

Positive control substances were not specified

Method/Guideline and

Test Condition

Remarks:

Method/guideline followed: Ames et al. 1975, with and without

metabolic activation. Plate incorporation method.

Liver S9 homogenate was prepared from male Sprague-Dawley rats and

Syrian golden hamsters that had been injected with Aroclor 1254 at

500 mg/kg body weight. For each plate receiving microsomal

enzymes, 0.5 mL of S9 mix was added.

For testing in the absence of S9 mix, 100 μL of the tester strain

and 50 μL of the solvent or test chemical were added to 2.5 mL of

molten selective top agar at 45 ± 2 oC. When S9 was used, 0.5 mL

of S9 mix, 50 μL of tester strain, and 50 μL of solvent or test

chemical were added to 2.0 mL of molten selective top agar at 45

± 2 oC. After it was vortexed, the mixture was overlaid onto the

surface of 25 mL of minimal bottom agar. After the overlay had

solidified, the plates were incubated for 48 h at 37 ± 2

oC. Five doses of test chemical, together with the appropriate

concurrent solvent (DMSO) and positive controls (not specified),

were tested in triplicate on each tester strain without metabolic

activation and also with activation by induced rat and hamster

liver S9 preparations.

The doses that were tested in the mutagenicity assay were selected

based on the levels of cytotoxicity observed in a preliminary dose

range-finding study using strain TA100. Ten dose levels of the

chemical, one plate per dose, were tested in both the presence and

the absence of induced hamster S9. If no toxicity was observed, a

total maximum dose of 10 mg of test chemical per plate was

used. The criteria used to evaluate a test were as follows: for

a test article to be considered positive, it had to induce at

least a doubling (TA98, TA100, and TA1535) in the mean number of

revertants per plate of at least one tester strain. This increase

in the mean revertants per plate had to be accompanied by a dose

response to increasing concentrations of the test chemical. If

the study showed a dose response with a less than 3-fold increase

on TA1537 or TA1538, the response had to be confirmed in a repeat

experiment. 

Test Results - Genetic Toxicity in vitro
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Details on Cytogenetic

Assay:

Statistics:

Effect : Species Other

Species

Strain Other

Strain

Metabolic

Activation

Genotoxic

Effect

Conclusion

Bacteria S.

typhimurium

TA 98

With and

Without

Negative Negative

Bacteria S.

typhimurium

TA 100

With and

Without

Negative Negative

Bacteria S.

typhimurium

TA 1535

With and

Without

Negative Negative

Bacteria S.

typhimurium

TA 1537

With and

Without

Negative Negative

Bacteria S.

typhimurium

TA 1538

With and

Without

Negative Negative

Results Remarks: Positive and negative controls responded appropriately; Cytotoxic

concentration: None specified

Conclusion: The test substance did not cause an increase in mutation frequency

in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 or

TA1538 with or without metabolic activation.

Reliability/Data Quality - Genetic Toxicity in vitro

Reliability: 2 - Valid With Restrictions

Reliability Remarks: Purity not specified. Although the findings from this study were

presented in a review article and a citation to a previous

publication of the data was not provided, the primary data from

the study were made available in a "Supporting Information" source

at http://pubs.acs.org. 

Key Study Sponsor

Indicator:

Reference - Genetic Toxicity in vitro

Reference: Seifried et al. (2006) A compilation of two decades of

mutagenicity test results with the Ames Salmonella typhimurium and

L5178Y mouse lymphoma cell mutation assays. Chemical Research in

Toxicology 19, 627-644.

 Genetic Toxicity in vitro

CAS Number : 25377-73-5

Sponsored Chemical

Name :

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Genetic Toxicity in vitro

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test

Substance

Comments:

Purity not specified
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Sponsored Chemical

Result Type:

Measured

Method - Genetic Toxicity in vitro

Type of Study: Mammalian cell gene mutation assay

Concentrations: 0.017, 0.022, 0.026, 0.031, 0.035 μg/mL without activation and

0.035, 0.08, 0.13, 0.17, 0.22, 0.26, 0.31 μg/mL with activation

Year Study

Performed:

Method/Guideline

Followed:

Other

GLP: No Data

Postive, Negative,

and Solvent

Control

Substance(s):

Solvent control: DMSO

Positive Control (without metabolic activation): ethyl

methylsulfonate at 4.7 x 10-6 M (or methyl methanesulfonate at 10 -

20 μg/mL)

Positive Control (with metabolic activation): 3-methylcholanthrene

at 1.86 x 10-5 M (or dimethylbenz[a]-anthracene at 0.5 - 4 μg/mL)

Method/Guideline

and

Test Condition

Remarks:

The toxicity of each chemical was determined both with and without

liver S9 prepared from Aroclor 1254-induced male Sprague-Dawley

rats. S9 mix was prepared according to the procedure of Clive et

al. (1979). Cells at a concentration of 6 x 105/mL (6 x 106 cells

total) were exposed for 4 h to a range of concentrations from

0.0005 to 10,000 μg/mL. The cells were then washed, resuspended in

growth medium, and incubated at 37 ± 1 °C for 48 h. The rate of

cell growth was determined for each of the treated cultures and

compared to the rate of growth of the solvent controls. The doses

of chemical selected for testing were within the range yielding

approximately 0 - 90% cytotoxicity. For each assay, there were 2 -

4 solvent (DMSO) controls, a positive control of ethyl

methylsulfonate at 4.7 x10-6 M (or methyl methanesulfonate at 10 -

20 μg/mL) for the test without metabolic activation, and a positive

control of 3-methylcholanthrene at 1.86 x 10-5 M (or

dimethylbenz[a]-anthracene at 0.5 - 4 μg/mL) for the test with

metabolic activation.

The mutagenicity assay was performed according to the procedure

described by Clive and Spector (1975). A total of 1.2 x 107 cells

in duplicate cultures were exposed to the test chemical, positive

control, and solvent control for 4 h at 37 ± 1 °C, washed twice

with growth medium, and maintained at 37 ± 1 °C for 48 h in logphase growth to allow recovery and mutant expression. Cells in the

cultures were adjusted to 3 x 105/mL at 24 h intervals. They were

then cloned (1 x 106 cells/plate for mutant selection and 200

cells/plate for viable count determinations) in soft agar medium

containing Fischer's medium, 20% horse serum, 2 mM sodium pyruvate,

0.02% pluronic F-68, and 0.23% granulated agar (BBL, Inc.,

Cockeysville, MD). Resistance to trifluorothymidine (TFT) was

determined by adding TFT (final concentration, 3 μg/mL) to the

cloning medium for mutant selection. The 100x stock solution of TFT

in saline was stored at -70 °C and was thawed immediately before

use. Plates were incubated at 37 ± 1 °C in 5% CO2 in air for 10-

12 days and then counted with an Artek automated colony counter

(Artek 982, DynaTech) or ProtoCol colony counter (Synbiosis,

Frederick, MD). Only colonies larger than ~ 0.2 mm in diameter

were counted. Mutant frequencies were expressed as mutants per 106

surviving cells. 

Although there are several different methods for evaluating mouse

lymphoma data, results from this study were interpreted using a

doubling of the mutant frequency over the concurrent solventtreated control value as an indication of a positive effect,
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together with evidence of a dose-related increase. Doubling of the

mutant frequency was previously reported as representing a positive

effect. Only doses yielding total growth values of 10% were used

in the analysis of induced mutant frequency. Doses yielding less

than 10% total growth were used in determining dose response.

The size of mutant mouse lymphoma colonies was also determined

using an Artek 982 colony counter/sizer or the ProtoCol colony

counter. An internal discriminator was set to step sequentially to

exclude increasingly larger colonies in approximate increments of

0.1 mm in colony diameter. The size range used was from ~0.2 to

1.1 mm.

Test Results - Genetic Toxicity in vitro

Details on

Cytogenetic Assay:

Statistics:

Effect : Species Other

Species

Strain Other

Strain

Metabolic

Activation

Genotoxic

Effect

Conclusion

Mammalian

Cell Line

Mouse

Lymphoma

L5178Y

Cells

With and

Without

Negative Negative

Results Remarks: Positive and negative controls responded appropriately 

Genotoxicity result: Negative with and without metabolic activation

using the evaluation criteria that are described above. The

Seifried et al. (2006) publication also presented mutagenicity

conclusions that were stated to be "new" evaluations based on

'current international "harmonization" recommendations'. However,

these "new" evaluations were considered to be uninterpretable and

are not considered further because this publication neither

presented the criteria used for the "new" evaluations nor cited

literature that present such criteria. 

Cytotoxic concentration: ≥ 0.031 μg/mL without activation,

≥ 0.13 μg/mL with activation

Conclusion: The test substance was negative for mutagenicity in mouse lymphoma

cells with and without metabolic activation. 

Reliability/Data Quality - Genetic Toxicity in vitro

Reliability: 2 - Valid With Restrictions

Reliability Remarks: Test substance purity was not specified. Although the findings

from this study were presented in a review article and a citation

to a previous publication of the data was not provided, the primary

data from the study were presented in "Supporting Information"

documents at http://pubs.acs.org.

Key Study Sponsor

Indicator:

Reference - Genetic Toxicity in vitro
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Reference: Seifried et al. (2006) A compilation of two decades of mutagenicity

test results with the Ames Salmonella typhimurium and L5178Y mouse

lymphoma cell mutation assays. Chemical Research in Toxicology 19,

627-644.

 Reproductive Toxicity

CAS Number : 25377-73-5

Sponsored Chemical

Name :

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Reproductive Toxicity

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test

Substance Comments:

Sponsored Chemical

Result Type:

Method - Reproductive Toxicity

Route of

Administration:

Type of Exposure:

Species:

Mammalian Strain:

Gender:

Number of Animals per

Dose:

Dose:

Year Study Performed:

Method/Guideline

Followed:

GLP:

Exposure Period:

Frequency of

Treatment:

Post-Exposure Period:

Method/Guideline and

Test Condition

Remarks:

Pre-Mating Exposure /

Males:

Pre-Mating Exposure /

Females:
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Test Results - Reproductive Toxicity

Concentration (LOAEL/

LOAEC/ NOAEL/

NOAEC) :

LOAEL/

LOAEC/

NOAEL/

NOAEC

Population Value

Description

Value/Lower

Concentration

Upper

Concentration

Units

Results:

Results Remarks:

Conclusion:

Reliability/Data Quality - Reproductive Toxicity

Reliability:

Reliability Remarks: As of February 2010, no data were available for this endpoint.

Key Study Sponsor

Indicator:

Reference - Reproductive Toxicity

Reference:

 Developmental Toxicity/Teratogenicity

CAS Number : 25377-73-5

Sponsored Chemical

Name :

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Developmental Toxicity/Teratogenicity

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test

Substance Comments:

Sponsored Chemical

Result Type:

Method - Developmental Toxicity/Teratogenicity

Route of

Administration:

Type of Exposure:

Species:
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Mammalian Strain:

Gender:

Number of Animals per

Dose:

Dose:

Year Study Performed:

Method/Guideline

Followed:

GLP:

Exposure Period:

Frequency of

Treatment:

Post-Exposure Period:

Method/Guideline and

Test Condition

Remarks:

Test Results - Developmental Toxicity/Teratogenicity

Concentration (LOAEL/

LOAEC/ NOAEL/

NOAEC) :

LOAEL/

LOAEC/

NOAEL/

NOAEC

Population Value

Description

Value/Lower

Concentration

Upper

Concentration

Units

Results Remarks:

Conclusion:

Reliability/Data Quality - Developmental Toxicity/Teratogenicity

Reliability:

Reliability Remarks: As of February 2010, no data were available for this endpoint.

Key Study Sponsor

Indicator:

Reference - Developmental Toxicity/Teratogenicity

Reference:

 Skin Irritation
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CAS Number : 25377-73-5

Sponsored Chemical Name

:

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Skin Irritation

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test Substance

Comments:

Light yellow, clear, viscous liquid; MW: 266; Solubility:

reacts with water and alcohols, soluble in certain oils and

industrial solvents

Sponsored Chemical Result

Type:

Measured

Method - Skin Irritation

Species: Other

Other Species: Guinea Pig

Mammalian Strain: Other

Other Strain: Albino

Type of Coverage: Occlusive

Preparation of Test Site: Shaved

Gender: Female

Number of Animals per

Dose:

Amount/Concentration

Applied:

pure compound (400 mg) or 10% solution in corn oil

Year Study Performed: 1964

Method/Guideline

Followed:

No Data

GLP: No Data

Exposure Period: 24 Hours

Total Volume applied and

Units:

0.4 ml

Control Group Type: No Data

Vehicle Used: Yes

Vehicle Name: Corn Oil

Vehicle Amount and Units:

Post-Exposure Period: 14 Days

Grading Scale:

Method/Guideline and Patch tests were performed on female, albino guinea pigs
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Test Condition Remarks: weighing 387 to 395 g, using 0.4 mL of the indicated

concentrations of the test solution. 

Undiluted material was applied to closely clipped abdominal

skin of albino guinea pigs by means of cotton-gauze patches

(2 x 2 cm) that were held in contact with the skin by means

of a 3-in. Elastoplastic bandage. The patches were removed

24 hours after application, and the animals were observed for

a period of at least 14 days; when damage occurred,

observations were continued until the damaged areas

healed. When a response was elicited with the undiluted

material, tests were repeated using 10% and 1% solutions. 

Test Results - Skin Irritation

Grade:

Primary Irritation Index:

Lesions:

Erythema:

Edema:

Results Remarks: With the pure compound, there was a slight edema which

persisted for 3 days, a scab which was evident on the 8th

day, and complete healing on the 14th day. The 10% solution

(corn oil) produced no effects.

Interpretation of Results:

Conclusion:

Reliability/Data Quality - Skin Irritation

Reliability:

Reliability Remarks:

Key Study Sponsor

Indicator:

Reference - Skin Irritation

Reference: Longley et al. 1964; AMRL (1964) Toxic Hazard Study of

Selected Missile Propellants Document Number(s): AD 441 640.

AMRL-TDR-64-28.

 Eye Irritation

CAS Number : 25377-73-5

Sponsored Chemical Name

:

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Eye Irritation

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test Substance

Comments:

Light yellow, clear, viscous liquid; MW: 266; Solubility:

Reacts with eater and alcohols, soluble in certain oils and

industrial solvents
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Sponsored Chemical Result

Type:

Measured

Method - Eye Irritation

Species: Other

Other Species: Guinea Pig

Mammalian Strain: Other

Other Strain: Albino

Gender: No Data

Number of Animals per

Dose:

Amount/Concentration

Applied:

50 mg

Year Study Performed: 1964

Method/Guideline

Followed:

No Data

GLP: No Data

Exposure Period:

Total Volume applied and

Units:

50 mg

Control Group Type: No Data

Vehicle Used: No

Vehicle Name:

Vehicle Amount and Units:

Post-Exposure Period:

Grading Scale:

Tool:

Method/Guideline and

Test Condition Remarks:

Undiluted material was instilled into the conjunctival sac of

albino guinea pigs. Effects were noted at 1 min, 5 min, 1

hour and 24 hours after exposure, and daily thereafter for a

total of at least 14 days. When damage occurred,

observations were continued until healing was completed. 

Test Results - Eye Irritation

Overall Grading Score:

Overall Irritation Score:

Primary Irritation Index:

Lesions:
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Cornea:

Iris:

Conjunctivae (Chemosis):

Conjunctivae (Redness):

Results Remarks: The pure compound produced slight swelling, with a very

slight opacity in the cornea and a moderate discharge which

lasted for 1 day. There appeared to be no effects persisting

beyond the 2nd post-exposure day. 

Interpretation of Results:

Conclusion:

Reliability/Data Quality - Eye Irritation

Reliability:

Reliability Remarks:

Key Study Sponsor

Indicator:

Reference - Eye Irritation

Reference: Longley et al. 1964; AMRL (1964) Toxic Hazard Study of

Selected Missile Propellants Document Number(s): AD 441 640.

AMRL-TDR-64-28.

 Skin Sensitization

CAS Number : 25377-73-5

Sponsored Chemical Name

:

2,5-Furandione, 3-(dodecenyl)dihydroTest Substance - Skin Sensitization

Test Substance: (25377-73-5) 2,5-Furandione, 3-(dodecenyl)dihydroTest Substance

Purity/Composition

and Other Test Substance

Comments:

98% purity; test substance referred to as "C12 ASA"

Sponsored Chemical Result

Type:

Measured

Method - Skin Sensitization

Test Type: In Vivo

Study Type: Other

Species: Guinea pig

Mammalian Strain: Hartley

Route of Induction: Dermal
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Route of Challenage

Exposure:

Dermal

Gender: Both M/F

Number of Animals per

Dose:

20

Concentration: Irritation test: 1%, 2.5%, 5%, 10%, 25%, 50% solution in

acetone or undiluted

Induction: 25% w/v in acetone

Primary challenge: 5% w/v in acetone

Rechallenge: 3% w/v in acetone

Year Study Performed: 1986

Method/Guideline

Followed:

Other

GLP: Yes

Exposure Period: 6 Hours

Induction Frequency of

Treatment:

once/week for 3 weeks

Challenge Exposure

Period:

6 Hours

Challenge Frequency of

Treatment:

once

Total Volume applied and

Units:

0.3 ml

Control Group Type: Other

Vehicle Used: Yes

Vehicle Name: Acetone

Vehicle Amount and Units:

Positive Control

Substance:

Post-Exposure Period: 48

Negative Control

Substance:

Hours

Method/Guideline and

Test Condition Remarks:

Method/Guideline Followed: Ritz and Buehler, 1980

No. of animals/dose: 4 male, 4 female for irritation study;

10 male, 10 female for test article; 5 male, 5 female for two

naive control groups

In the irritation test, a single administration of the test

material was applied dermally to sites clipped of hair on

four male and four female guinea pigs. Each animal had 4

sites exposed to a different concentration of test article on

a gauze patch. Sites were covered with a Hill Top chamber,

which was covered with tape and a rubber dam. After 6 hours

of application, the occlusion was removed, and the animals

returned to their cages. On the day following application,

the clipped sites were depilated with chemical hair remover,

and the sites scored for severity of response at 24 hours and

48 hours. The animals were observed for signs of erythema and

edema and scored either 0 (no reaction), +/- (slight patchy
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erythema), 1 (slight confluent or moderate patchy edema), 2

(moderate erythema), and 3 (severe erythema with or without

edema).

For induction of sensitization, the upper left quadrant of

the backs of guinea pigs were clipped of hair. On the

following day, moistened patches were applied, to the test

group, the animals restrained as previously described, and

the animals returned to their cages. Patches moistened with

test article were applied to the skin in the same manner once

a week for three applications. The same site was clipped on

the day before application, and the restraint periods were

six hours on each occasion.

For primary challenge two weeks after the last of the

induction applications, a fresh application site was prepared

by clipping the lower left quadrant of the backs of test and

naïve control animals. The next day, challenge patch was

applied to each guinea pig in the test and control groups.

Each animal was restrained for 6 hours as before, and the

animals returned to their cages. On the next day, sites were

depilated and scored for severity of response at least two

hours later and for a 48 hour reading. Scores of "1" or

greater in the test group were considered to be indicative of

sensitization providing grades of less than 1 were found in

the naïve control group. If the naïve group had grades of "1"

or greater, the reactions in the test group that exceeded the

most severe reactions in the control group were presumed to

be indicative of sensitization.

For rechallenge, eight days after the primary challenge, all

of the original animals were single patch rechallenged. Ten

previously unexposed naïve animals were identically treated to

serve as a new naïve control group. The right rear quadrant

was used for rechallenge. Depilation and observation

procedures were the same as described for primary challenge.

Individual weights were recorded immediately prior to dosing

and prior to termination. The surviving animals were

euthanized at the conclusion of the observation period.

Test Results - Skin Sensitization

Measurement Period 

and Units:

Percent Sensitized 

Test Substance:

Percent Sensitized 

Positive Control:

Percent Sensitized 

Negative Control:

Sensitization Score:

Results Remarks: No deaths were observed in the test. The incidence of grade

"2" responses or greater in the test group exposed to 25% for

induction, and 5% at primary challenge was greater for the

test animals (13 of 20) compared to the naïve challenge group

(0 of 10). The incidence and severity of responses in the

test group were more pronounced than the responses of the

naïve group, suggesting sensitization had occurred.

At rechallenge with 3% test article in acetone, the incidence

of grade "1" responses or greater in the test group (17 of

20) was greater than that in the naïve control group (0 of

10). The incidence and severity of responses were more

pronounced in the test group indicating that a sensitization

response had been elicited.
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Interpretation of Results: Sensitizing

Conclusion: The test article, when administered to guinea pigs according

to the method of Ritz and Buehler, caused delayed contact

hypersensitivity of the skin.

Reliability/Data Quality - Skin Sensitization

Reliability: 1 - Valid Without Restrictions

Reliability Remarks:

Key Study Sponsor

Indicator:

Reference - Skin Sensitization

Reference: HPV submission for Higher Alkenyl Succinic Anhydrides

category, received by EPA from Albemarle Corporation on April

5, 2006; HPV submission references the following:

Buehler, E.V., "Delayed Contact Hypersensitivity Study in

Guinea Pigs of Dodecenyl Succinic Anhydride C12 ASA" for

Ethyl Corporation, Hill Top Research Project No. 86-0873-21,

Hill Top Research, Inc., 1986.

Ritz, H.L, and Buehler, E.V., (1980), In Current Concepts in

Cutaneous Toxicity, (V.A. Drill and T.Lazar, eds.) pp. 25-40,

Academic Press, New York.