SRC TR

- 11

- 071

HPV4 CHEMICAL DATA ADEQUA CY REVIEW (REVISED)

Plumbane, tetraethyl

- , CAS No. 78

- 00

- 2

Prepared by:

Carlye Austin, Teresa Manyin, and Joan D. Garey

Chemical, Biological and Environmental Center

SRC, Inc.

7502 Round Pond Road

North Syracuse, NY 13212

Contract No. EP

- W

- 09

- 027

Task FG007.0.009.001

Submitted to:

OPPT/RAD/HPVCB (7403M)

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue

Washington, D.C. 20460

Debra Milligan , Project Officer

Meena Sonawane, Work Ass ignment Manager

David Brooks, Alternate Work Assignment Manager

August 5

, 2011HPV4 Chemical Data Adequacy Review (Revised)

Plumbane, tetraethyl

- , CAS No. 78

- 00

- 2

August 2011

DRAFT

Submitted to:

High Production Volume Chemicals Branch

Risk Assessment Division

Office of Pollution Prevention and Toxics

Environmental Protection Agency

WAM: Meena Sonawane

Alternate WAM: David Brooks

1200 Pennsylvan ia Avenue, NW

Washington, DC 20460

- 0001

Prepared By:

SRC , Inc.

Chemical, Biological and Environmental Center

2451 Crystal Drive, Suite 804

Arlington, VA 22202Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

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1 A. PREPARATION OF THE DATA ADEQUACY ASSESSMENTS

A

- 1. Source material used for assessment

For this unsponsored chemical, a comprehensive literature search was performed to

identify available toxicity data for the following SIDS endpoints:

Acute toxicity to fish

Acute toxicity to Daphnia

Toxicity to aquatic plants

Acute (oral, dermal, inhalation) toxicity

Repeated

- dose toxicity

Reproductive toxicity

Developmental toxicity

Gene mutation

Chromosomal aberrations

Studies relevant to non

- SIDS endpoints (e.g., eye and skin irritation; neurotoxicity) conducted

via oral, inhalation, or dermal routes were also identified through literature searching.

The following sources were searched for toxicity data:

PubMed

- B ibliographic database that contains references to journal articles in the life

sciences with a concentration on biomedicine

T OXNET

- N ational L ibrary of M edicine databases on toxicology, hazardous chemicals,

environmental health, and toxic releases; includes:

**•** TOXLINE with BIOSIS and NTIS ;

**•** Development and Reproductive Toxicolog y File (DART) ;

**•** Chemical Carcinogenesis Research Information System (CCRIS)

- Carcinogenicity and mutagenicity test results for over 8000

**•** chemicals) ;

**•** Hazardous Substances Data Bank (HSDB)

- Comprehensive, peer

reviewed toxicology data for about 5000 che micals ;

**•** Genetic Toxicology Data Bank (GENE

- TOX)

- Peer

- reviewed genetic

toxicology test data for over 3000 chemicals.

TSCATS

- U npublished technical reports submitted by industry to the EPA under the

Toxic Substances Control Act]

Registry of toxic effect s of chemical substances (RTECs)

Environmental Fate Database (EFDB)

ECOTOX

- EPA’s peer

- reviewed ecotoxicology databaseDraft HPV4 Chemical Data Adequacy Review CAS No. 78

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2 EPA’s Integrated Risk Information System (IRIS) website

Agency for Toxic Substances and Disease Registry (ATSDR) website

National To xicology Program (NTP) website

International Program on Chemical Safety Concise International Chemical Assessment

Documents (IPCS INC HE M or CICADs)

European Chemical Substances Information System (ESIS)

- source of IUCLID Datasets

Any available IUCLID Datasets found through the ESIS website and robust summaries

submitted to EPA by former sponsors on the assigned chemicals were retrieved. Original

sources were obtained for any relevant toxicity data found for the assigned chemicals.

While IUCLID D ata set s sometimes contained studies of interest, certain study

descriptions contained insufficient detail to assess adequacy. In these cases, the primary source

of the study, if available and accessible, was obtain ed and review ed.

A

- 2. Evaluating data ad equacy

Using standard OECD testing guidelines and professional judgment as guides, available

toxicity studies for the unsponsored chemical were reviewed for adequacy. Summaries were

prepared for all relevant data found, even if little or no study detail was available. Each study

was summarized according to a standard format and assigned a Klimisch reliability code; all

study summaries for the chemical were combined into a single summary document. For studies

already assigned Klimisch codes (e.g., studie s summarized in IUCLID datasets), an explanation

was provided if the reviewer’s assessment of data adequacy differed from the pre

- assigned

Klimisch code. A table summarizing data availability/adequacy for each SIDS endpoint is

included at the end of the s ummary document.

B. SPECIFIC INFORMATION ON THE AVAILABLE TOXICITY DATA

The available data for each of the SIDS toxicity endpoints are evaluated on the following

pages. Studies for a common endpoint are grouped together in the document and an endpo int

adequacy assessment is provided near the top of the first page of the summaries for that

endpoint. If the data available for the endpoint is determined to be inadequate, a basis for that

conclusion is supplied. NOTE: If no relevant studies were iden tified for the chemical , only the

data availability/adequacy summary table was completed for the report

.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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3 B

- 1. ACUTE TOXICITY TO FISH

Summary of endpoint: Adequate

Study 1: Acute toxicity flow

- through study in European plaice

Title: The acute toxici ty and bioaccumulation of some lead alkyl compounds in marine animals

This study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: T etraethyl lead, CAS No. 78

- 00

- 2

Remarks: 98% pure, supplied by Ellesmere Por t Research Laboratories of the Associated Octel

Company Limited

METHOD

Method/guideline followed: Not specified

Test type: Acute Toxicity to Fish

– Flow

- through

GLP compliant?: Not specified

Year study was performed: 1980

Test species: Pleuronect es platessa (European plaice; saltwater fish)

. Mean length: 5.2 cm;

mean weight: 2.8 g. Source: Tor Bay, S. Devon; obtained via otter trawl.

Analytical monitoring: Yes

Exposure duration: 96 hours

Concentrations tested: 0, 0.02 to 0.2 mg Pb /L

Test met hod/conditions remarks: All fish were maintained in flowing sea

- water for a

minimum of 7 days prior to test item exposure. Seawater (salinity 34.9‰) was pumped directly

from the sea and supplied at a constant temperature (15 oC) to the test system. At th e design

flow rate of 100 mL/min, the 90% replacement time was 7.5 hours.

Stock solutions were prepared by agitating 22 liters of water with 10 grams of tetraethyl lead for

4 hours, allowing the excess to settle for 2 hours, and then pumping the top 20 l iters into a sealed

stock vessel isolated from direct sunlight. A concentration of 0.02 to 0.2 mg Pb/L tetraethyl lead

was maintained with a variation of ±10%.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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4 Ten fish were transferred to a test vessel and maintained in flowing seawater for 24 hours, at

which time a pre

- selected amount of the stock solution was fed continuously into the vessel for a

period of 96 hours. A control vessel was included. Test vessels were regularly monitored for

mortality. Water samples were taken twice daily to analyze te traethyl lead content.

Temperature, dissolved oxygen, and pH were measured daily. Test animals were fed prior to but

not during exposure.

RESULTS

Endpoint value(s): The 96

- hour LC 50 value was 0.23 mg Pb/L.

Results remarks: The LC 50 value was calculat ed according to the methods of Doudoroff et al.

(1951)

.

CONCLUSIONS

The study authors reported that the results show that the plaice is more resistant to the effects of

tetraethyl lead than to tetramethyl lead.

STUDY RELIABILITY

Klimisch code = [2]. Reliable with restrictions

. No guideline or method was cited, GLP

compliance is unknown, individual data on mortality were not provided, and the exact tested

concentrations were unclear. Dissolved oxygen, pH, and total organic carbon were not specified.

Additionally, the test was performed with a non

- standard marine species.

REFERENCE

Maddock, B.G. and D. Taylor. 1980. The acute toxicity and bioaccumulation of some lead alkyl

compounds in marine animals. In: M. Branika and Z. Konrad (eds.), Lead in the Marine

Environment. Proc. Int. Experts Discussion on Lead Occurrence. Fate and Pollution in the

Marine Environment, Rovinj, Yugoslavia : 233

- 261 . Pergamon, Oxford, UK.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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5 Study 2: Acute toxicity study in multiple fish species

Title: None specified

This study is: Adequate Not Adequate

Test duration is less than the OECD

- recommended length of 96 hours and tests were conducted

using non

- preferred fish species. Additionally, the IUCLID summary, which was mostly in a

language other than English, lacked study details.

TEST SUBSTANCE

Identity: T etraethyl lead, CAS No. 78

- 00

- 2

Remarks: Purity not specified

METHOD

Method/guideline followed: Not specified

Test type: Acute Toxicity to Fish

– Flow

- through

G LP compliant?: The study pre

- dates GLP.

Year study was performed: 1977

Test species: Gobius niger (black goby), Trachurus trachurus (Atlantic horse mackerel), Mugil

cephalus (striped mullet), Atherina boyeri (sand smelt), Trachinus draco (greater weever )

Analytical monitoring: Not specified

Exposure duration: 30 minutes

Concentrations tested: Not specified

Test method/conditions remarks: The IUCLID summary of the study was mostly in a language

other than English.

RESULTS

Endpoint value(s): Not spe cified.

Results remarks: The IUCLID summary of the study was mostly in a language other than

English.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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6 CONCLUSIONS

The IUCLID summary of the study was mostly in a language other than English.

STUDY RELIABILITY

Klimisch code = [3]. Invalid

. Test dur ation is less than the OECD

- recommended length of 96

hours and tests were conducted using non

- standard fish species. Additionally, the IUCLID

summary, which was mostly in a language other than English, lacked study details.

The IUCLID summary noted an a ssigned Klimisch code of 2 for the study.

REFERENCE

Primary reference (not available): Giaccio, M. 1977. Quad. Merceol. 16: 55

- 62.

Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

ht tp://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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7 Study 3: Acute toxicity study in bluegill sunfish

Title: Toxicity of various refinery materials to fresh water fish.

This study is: Adequate Not Adequate

Test duration is less than the OECD

- recommended length of 96 hours; no analytical monitoring

was performed; loading rate exceeded the OECD

- recommended limit.

TEST SUBSTANCE

Identity: T etraethyl lead, CAS No. 78

- 00

- 2

Remarks: Purity not specified

METHOD

Method/guideline f ollowed: Not specified

Test type: Acute Toxicity to Fish

– Static

GLP compliant?: The study pre

- dates GLP.

Year study was performed: 1954

Test species: Bluegill sunfish ( Lepomis macrochirus ), obtained from the Pennsylvania State

Hatchery (Torresdale, PA) and Hiram People’s Hatchery (New Providence, PA). Average

length: 7 cm. Average weight: 5 g.

Analytical monitoring: No

Exposure duration: 48 hours

Concentrations tested: Not specified

Test method/conditions remarks: The test chemical was added to the 5

- gallon test jar at the

start of the test period. No subsequent additions were made during the course of the test. Test

jars were filled to the 15

- liter mark and placed in a 20 oC thermostatically

- controlled water bath.

Carbon

- filtered Philadelp hia tap water was used. Fish were acclimatized to the test water and

temperature for 10 days prior to the test period. Ten fish per jar were tested. Based on the

average fish weight of 5 g and the number of fish per unit volume of test solution (10 fish /15 L),

the loading rate was 3.3 g fish/L, which exceeds the OECD

- recommended maximum loading

rate of 1 g for static tests. Characteristics of dilution water: total alkalinity as CaCO 3 = 38

- 81

ppm; pH = 6.9

- 7.5; total hardness as CaCO 3 = 84

- 163 ppm; speci fic conductivity = 228

- 301

micromhos; dissolved solids = 154

- 210 ppm; sulfates as SO 4 = 56

- 98 ppm; chlorides as Cl = 3

- 26 ppm. Dissolved oxygen concentration was maintained at 5 ppm or greater throughout the testDraft HPV4 Chemical Data Adequacy Review CAS No. 78

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8 by gentle aeration.

Mortality was recor ded after 24 and 48 hours. The LC 50 was obtained by interpolation from a

graph of the logarithm of the concentration versus the percentage mortality.

RESULTS

Endpoint value(s): The 48

- hr LC 50 value was 1.4 mg lead/L. The 24

- hour LC 50 value was 2.0

mg l ead/L.

Results remarks: None.

CONCLUSIONS

No conclusions were specified.

STUDY RELIABILITY

Klimisch code = [3]. Invalid

. Test duration is less than the OECD

- recommended length of 96 hours; no analytical monitoring

was performed; loading rate excee ded the OECD

- recommended limit.

The IUCLID summary noted an assigned Klimisch code of 2 for the study.

REFERENCE

Turnbull, H. et al. 1954. Toxicity of various refinery materials to fresh water fish. Ind. Eng.

Chem. 46: 324

- 333.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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9 Study 4: Acute toxic ity study in bluegill sunfish

Title: None specified

This study is: Adequate Not Adequate

The IUCLID summary lacked sufficient information to assess data adequacy.

TEST SUBSTANCE

Identity: T etraethyl lead, C AS No. 78

- 00

- 2

Remarks: Purity not specified

METHOD

Method/guideline followed: Not specified

Test type: Acute Toxicity to Fish

GLP compliant?: Th e study pre

- dates GLP.

Year study was performed: 1964

Test species: Bluegill sunfish ( Lepomis macroch irus )

Analytical monitoring: Not specified

Exposure duration: 96 hours

Concentrations tested: Not specified

Test method/conditions remarks: None specified

RESULTS

Endpoint value(s): The 96

- hour LC 50 value was 0.2 mg/L.

Results remarks: None.

CONC LUSIONS

None specified.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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10 STUDY RELIABILITY

Klimisch code = [4]. Not assignable

. The IUCLID summary lacked sufficient information to

assess data adequacy.

REFERENCE

Primary reference (not available): Makina, J.F. 1964. Toxicology of petrochemicals in the

aquatic environment

– water and sewage works, vol 3, pp. 456

- 460.

Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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11 Study 5: Acute toxicity stu dy in bluegill sunfish

Title: Initial submission: 96

- hr LC 50 to Bluegill Sunfish

This study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: T etraethyl lead, CAS No. 78

- 00

- 2

Remarks: Composition of test it em (w/w): 61.3% tetraethyl lead; 35.68% 1,2

- dibromoethane;

0.026% blue dye; 2.93% kerosene and inerts; 0.06% antioxidant AO

- 29.

METHOD

Method/guideline followed: Not specified

Test type: Acute Toxicity to Fish

– Static

GLP compliant?: Th e study pre

- da tes GLP.

Year study was performed: 1976

Test species: Lepomis macrochirus (Bluegill sunfish); 3.6 cm standard length.

Analytical monitoring: Not indicated

Exposure duration: 96 hours

Concentrations tested: 0, 0.010, 0.025, 0.050, 0.075, 0.10, 0.25, 0. 5 mg/L

Test method/conditions remarks: The test material, as either a 0.1 or 0.01% solution in

acetone, was introduced into all

- glass vessels containing ten bluefish in 15 liters of water. Fish

were not fed for 48 hours prior to testing, nor during expos ure. No aeration was provided during

the test. Dissolved oxygen and pH were measured at the beginning of exposure. Calculation of

the 96

- hour LC 50 was via straight line graphical interpolation. An acetone control was included,

and prepared by adding, t o clean supply water, a volume of acetone equal to the greatest volume

of test solution used. A negative water control was also included.

RESULTS

Endpoint value(s): The 96

- hour LC 50 value was 0.15 mg/L.

Results remarks: The test temperature was mainta ined at 20 ± 0.2 oC. The pH measurements

across tested concentrations ranged from 7.7 to 8.0 and dissolved oxygen ranged from 8.6 to 8.7

ppm. Mortality was 100% at 0.25 and 0.50 mg/L, 10% at 0.10 mg/L, and 0% at all other testedDraft HPV4 Chemical Data Adequacy Review CAS No. 78

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12 concentrations.

CONCLUSI ONS

Tetraethyl lead exhibits extreme acute toxicity to bluegill sunfish.

STUDY RELIABILITY

Klimisch code = [2]. Reliable with restrictions

. No guideline or method was cited, and GLP

compliance is unknown. Additionally, it is unclear whether analytica l monitoring was performed

and total organic carbon was not specified.

REFERENCE

TSCATS submission (OTS0546521, Doc ID 88

- 920010136, received 10/27/92): Haskell

Laboratory, DuPont Chemical Company. 1976. Initial submission: 96

- hr LC 50 to Bluegill

Sunfi sh with Cover Letter Dated 101592.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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13 Study 6: Acute toxicity study in fathead minnows

Title: Initial submission: Report of 96

- hr LC 50 of Lead, Tetraethyl in Fathead Minnows

This study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: T etraethyl lead, CAS No. 78

- 00

- 2

Remarks: Composition of test item (w/w): 61.3% tetraethyl lead; 35.68% 1,2

- dibromoethane;

0.026% blue dye; 2.93% kerosene and inerts; 0.06% antioxidant AO

- 29.

METHOD

Method/guideline followed: Not specified

Test type: Acute Toxicity to Fish

– Static

GLP compliant?: Th e study pre

- dates GLP.

Year study was performed: 1975

Test species: Pimephales promelas (Fathead minnow); 3.7 cm standard length.

Analytical monitoring: Not indicated

Exposur e duration: 96 hours

Concentrations tested: 0, 0 .005, 0.0075, 0.01, 0.025, 0.05, 0.075, or 0.1 mg/L

Test method/conditions remarks: The test material, as a 10, 0.1, or 0.01% solution in acetone,

was introduced into all

- glass vessels containing ten fathea d minnows in 15 liters of water. Fish

were not fed during exposure. No aeration was provided during the test, but test vessels were

vigorously aerated for 30 minutes prior to introduction of fish and test material. The pH was

measured at the beginning o f exposure. Calculation of the 96

- hour LC 50 was via straight line

graphical interpolation. An acetone control was included, and prepared by adding, to clean

supply water, a volume of acetone equal to the greatest volume of test solution used. A negative

water control was also included.

RESULTS

Endpoint value(s): The 96

- hour LC 50 value was 0.037 mg/L.

Results remarks: The test temperature was maintained at 20 ± 0.2 oC. The pH was 7.8.

Mortality was 100% at the two highest test concentrations, 90% at the third

- highestDraft HPV4 Chemical Data Adequacy Review CAS No. 78

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14 concentration, and 0% at all other tested concentrations.

CONCLUSIONS

Tetraethyl lead exhibits extreme acute toxicity to fathead minnows.

STUDY RELIABILITY

Klimisch code = [2]. Reliable with restrictions

. No guideline or method was cited, and GLP

compliance is unknown. Additionally, it is unclear whether analytical monitoring was

performed, and dissolved oxygen concentrations and total organic carbon were not measured.

REFERENCE

TSCATS submission (OTS0555568, Doc ID 88

- 920010086, received 10/27/92): Haskell

Laboratory, DuPont Chemical Company. 1975. Initial submission: Report of 96

- hr LC 50 of

Lead, Tetraethyl in Fathead Minnows with Cover Letter Dated 101592.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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15 Study 7: Acute toxicity study in European seabass larvae

Title: A cute toxicity of alkyl leads to some marine organisms

This study is: Adequate Not Adequate

The test duration was less than the OECD

- recommended length of 96 hours. Additionally, the

test substance was a formulation ( composition not specified); the tested concentrations were

unclear; a non

- standard fish species was tested; and missing experimental details included

loading rate, pH, salinity, dissolved oxygen concentration, total organic carbon levels, and

whether the t est was conducted in static or flow

- through chambers.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Purity not provided; test substance described as a commercial product, “TEL

- CB”

METHOD

Method/guideline followed: Not spec ified

Test type: Acute Toxicity to Fish

GLP compliant?: The study pre

- dates GLP.

Year study was performed: 1978

Test species: 6

- mm larvae of Morone labrax (European seabass)

Analytical monitoring: No

Exposure duration: 48 hours

Concentrations tested : Not specified

Test method/ conditions remarks: The tetraethyl lead solution was prepared by adding 2 ml of

product to 1 L of f iltered natural seawater (0.45 μm) and slowly stirring magnetically for 1 hour.

The upper one fourth of the saturated solution was used for preparing experimental dilutions in

natural filtered seawater . Analytical measurement by atomic absorption s pectrophotometry gave

a content of 2 mg total lead/L for the stock solution. The experiment was carried out in the dark,

at 20 oC.

RE SULTS

Endpoint value(s): The 48

- hr LC 50 was 65 ppb Pb. One

- hundred percent mortality was seenDraft HPV4 Chemical Data Adequacy Review CAS No. 78

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16 after 48 hours at 130 ppb Pb.

Results remarks: All larvae died almost immediately at concentrations of 650 ppb Pb. There

were no mortalities at 10 ppb Pb.

CONCLUSIONS

Alkyl leads show higher toxicity than inorganic lead.

STUDY RELIABILITY

Klimisch code = [3]. Invalid. The test duration was less than the OECD

- recommended length of

96 hours. Additionally, the tested concentrations were unclear; a non

- stan dard fish species was

tested; and missing experimental details included loading rate, pH, salinity, dissolved oxygen

concentration, total organic carbon levels, and whether the test was conducted in static or flow

through chambers.

REFERENCE

Marchetti, R . 1978. Acute toxicity of alkyl leads to some marine organisms. Marine Pollution

Bulletin, 9: 206

- 207.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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17 B

- 2. ACUTE TOXICITY TO DAPHNIA

Summary of endpoint: Adequate

Study 1: Acute toxicity flow

- through study in brown shrimp

Title: The acute toxici ty and bioaccumulation of some lead alkyl compounds in marine animals

This study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: T etraethyl lead, CAS No. 78

- 00

- 2

Remarks: 9

METHOD

Method/guideline follow ed: Not specified

Test type: Acute Toxicity to Aquatic Invertebrates

– Flow

- through

GLP compliant?: Not specified

Year study was performed: 1980

Test species: Crangon crangon (brown shrimp)

. Mean length: 4.8 cm; mean weight: 1.1 g.

Source: Tor Bay, S. Devon; obtained via push net.

Analytical monitoring: Yes

Exposure duration: 96 hours

Concentrations tested: 0.0 1 to 0.2 mg Pb /L

Test method/conditions remarks: All shrimp were maintained in flowing sea

- water for a

minimum of 7 days prior to test it em exposure. Seawater (salinity 34.9‰) was pumped directly

from the sea and supplied at a constant temperature (15 oC) to the test system. At the design

flow rate of 100 mL/min, the 90% replacement time was 7.5 hours.

Stock solutions were prepared by a gitating 22 liters of water with 10 grams of tetraethyl lead for

4 hours, allowing the excess to settle for 2 hours, and then pumping the top 20 liters into a sealed

stock vessel isolated from direct sunlight. A concentration of 0.01 to 0.2 mg Pb/L tetrae thyl lead

was maintained with a variation of ±10%.

Ten shrimp were transferred to a test vessel and maintained in flowing seawater for 24 hours, atDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

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18 which time pre

- selected amount of the stock solution was fed continuously into the vessel for a

period of 9 6 hours. A control vessel was included. Test vessels were regularly monitored for

mortality. Water samples were taken twice daily to analyze tetraethyl lead content.

Temperature, dissolved oxygen, and pH were measured daily. Test animals were fed prio r to but

not during exposure.

RESULTS

Endpoint value(s): The 96

- hour LC 50 value was 0.02 mg Pb/L.

Results remarks: The LC 50 value was calculated according to the methods of Doudoroff et al.

(1951).

CONCLUSIONS

None specified.

STUDY RELIABILITY

Kli misch code = [2]. Reliable with restrictions

. No guideline or method was cited, GLP

compliance is unknown, individual data on mortality were not provided, and the exact tested

concentrations were unclear. Additionally, the test employed a non

- standard s pecies and

dissolved oxygen, pH, and total organic carbon were not specified.

REFERENCE

Maddock, B.G. and D. Taylor. 1980. The acute toxicity and bioaccumulation of some lead alkyl

compounds in marine animals. In: M. Branika and Z. Konrad (eds.), Lead in the Marine

Environment. Proc. Int. Experts Discussion on Lead Occurrence. Fate and Pollution in the

Marine Environment, Rovinj, Yugoslavia : 233

- 261 . Pergamon, Oxford, UK.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

19 Study 2: Acute toxicity flow

- through study in blue mussel

Title: The acute t oxicity and bioaccumulation of some lead alkyl compounds in marine animals

This study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: T etraethyl lead, CAS No. 78

- 00

- 2

Remarks: 98% pure, supplied by Ellesmer e Port Research Laboratories of the Associated Octel

Company Limited

METHOD

Method/guideline followed: Not specified

Test type: Acute Toxicity to Aquatic Invertebrates

– Flow

- through

GLP compliant?: Not specified

Year study was performed: 1980

Test species: Mytilus edulis (blue mussel)

. Mean length: 6.4 cm; mean weight: 28.5 g. Source:

Teign Estuary, S. Devon; obtained via hand collection.

Analytical monitoring: Yes

Exposure duration: 96 hours

Concentrations tested: 0.0 1 to 0.2 mg Pb /L

Test me thod/conditions remarks: All mussels were maintained in flowing sea

- water for a

minimum of 7 days prior to test item exposure. Seawater (salinity 34.9‰) was pumped directly

from the sea and supplied at a constant temperature (15 oC) to the test system. A t the design

flow rate of 100 mL/min, the 90% replacement time was 7.5 hours.

Stock solutions were prepared by agitating 22 liters of water with 10 grams of tetraethyl lead for

4 hours, allowing the excess to settle for 2 hours, and then pumping the top 20 liters into a sealed

stock vessel isolated from direct sunlight. A concentration of 0.01 to 0.2 mg Pb/L tetraethyl lead

was maintained with a variation of ±10%.

Ten mussels were transferred to a test vessel and maintained in flowing seawater for 24 ho urs, at

which time a pre

- selected amount of the stock solution was fed continuously into the vessel for a

period of 96 hours. A control vessel was included. Test vessels were regularly monitored for

mortality. Water samples were taken twice daily to ana lyze tetraethyl lead content.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

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20 Temperature, dissolved oxygen, and pH were measured daily. Test animals were fed prior to but

not during exposure.

RESULTS

Endpoint value(s): The 96

- hour LC 50 value was 0.10 mg Pb/L.

Results remarks: The LC 50 value was calculated according to the methods of Doudoroff et al.

(1951).

CONCLUSIONS

None specified.

STUDY RELIABILITY

Klimisch code = [2]. Reliable with restrictions

. No guideline or method was cited, GLP

compliance is unknown, individual data on mortality were not provided, and the exact tested

concentrations were unclear. Additionally, the test was conducted with a non

- standard species

and dissolved oxygen, pH, and total organic carbon were not specified.

REFERENCE

Maddock, B.G. and D. Taylor. 1980. T he acute toxicity and bioaccumulation of some lead alkyl

compounds in marine animals. In: M. Branika and Z. Konrad (eds.), Lead in the Marine

Environment. Proc. Int. Experts Discussion on Lead Occurrence. Fate and Pollution in the

Marine Environment, Ro vinj, Yugoslavia : 233

- 261 . Pergamon, Oxford, UK.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

21 Study 3: Acute toxicity study in E astern O yster

Title: Bioaccumulation and Depuration of Lead by Eastern Oysters ( Crassostrea virginica )

Exposed to a Tetraethyl Lead Motor Fuel Antiknock Compound

This study is: Adequate Not Adequate

The concentration of tetraethyl lead in the test substance was not specified.

TEST SUBSTANCE

Identity: TEL Motor Antiknock

- Red

- 01, a tetraethyl lead motor fuel antiknock compoun d

Remarks: Concentration of tetraethyl lead not specified; lead content: 0.6247 g Pb/mL; clear red

liquid; solvent/carrier: reagent grade absolute ethanol

METHOD

Method/guideline followed: Methods of Butler et al. (1960) and Butler (1965)

Test type: Acute Toxicity to Aquatic Invertebrates

– shell deposition test (flow

- through)

GLP compliant?: The study pre

- dates GLP.

Year study was performed: 1976

Test species: Eastern oyster ( Crassostrea virginica ), 2

- 4 cm from umbo to distal valve edge,

wild

- cau ght (Pensacola, FL)

Analytical monitoring: Yes

Exposure duration: 96 hours

Concentrations tested: Nominal: 0 (solvent control), 1.0, 10, 56, 100, 200 μg Pb/L; measured:

0, 1.0, 5.2, 36, 72, 131 μg Pb/L

Test method/conditions remarks: Oysters were hel d in tanks of flowing, natural seawater of

ambient salinity and temperature for a minimum of two weeks before testing. Oysters were

cleaned of attached organisms and ground by hand on a fine

- grit grinding wheel to remove

approximately 2

- 5 mm of peripheral shell. Six groups of ten oysters each were exposed to each

test concentration for 96 hours. The test was conducted in a glass system that was covered,

where feasible, to reduce volatilization of the test substance. The system was 18 L, received

seawate r at a rate of 30 L/hour, and ~99% replacement occurred every 3 hours. New shell

growth was measured to the nearest 0.1 mm using a binocular dissecting scope equipped with a

micrometer.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

22 RESULTS

Endpoint value(s): The 96

- hour EC 50 value for shell growt h was > 1 but < 5.2 μg Pb/L.

Results remarks: The percentage reduction of new shell growth of exposed oysters, as

compared to control oysters was 43, 85, 85, 85, and 100% at concentrations of 1.0, 5.2, 36, 72,

and 131 μg Pb/L, respectively. Salinity was 30

- 32‰ and temperature was 28

- 30 °C.

CONCLUSIONS

Shell growth of oysters exposed to the test substance in seawater was reduced by more than 50%

in concentrations of tetraalkyl lead ≥ 5.2 μg Pb/L during an acute exposure.

STUDY RELIABILITY

Klimisch cod e = [3]. Invalid

. The concentration of tetraethyl lead in the test substance was not

specified.

REFERENCE

TSCATS submission (OTS0200597, Doc ID 88

- 7800249, received 12/10/79): Haskell

Laboratory, EI DuPont de Nemours & Company. 1978. Bioaccumulation and Depuration of

Lead by Eastern Oysters ( Crassostrea virginica ) Exposed to a Tetraethyl Lead Motor Fuel

Antiknock Compound with Attachments and Cover Letter Dated 120379, conducted by EG&G

Bionomics, Marine Research Laboratory, Appendix A.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

23 Study 4: Acute toxicity study in brine shrimp

Title: Acute toxicity of alkyl leads to some marine organisms

This study is: Adequate Not Adequate

The test substance was a formulation; composition was not specified. Addition ally, the tested

concentrations were unclear; a non

- standard species was tested; and missing experimental details

included loading rate, pH, salinity, dissolved oxygen concentration, total organic carbon levels,

and whether the test was conducted in static or flow

- through chambers.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: None provided

METHOD

Method/guideline followed: Not specified

Test type: Acute Toxicity to Aquatic Invertebrates

GLP compliant?: The study pre

- dat es GLP.

Year study was performed: 1978

Test species: 24

- hour

- old nauplii of Artemia salina (brine shrimp)

Analytical monitoring: No

Exposure duration: 48 hours

Concentrations tested: Not specified

Test method/ conditions remarks: The tetraethyl lead s olution was prepared by adding 2 ml of

product to 1 L of f iltered natural seawater (0.45 μm) and slowly stirring magnetically for 1 hour.

The upper one fourth of the saturated solution was used for preparing experimental dilutions in

natural filtered seaw ater . Analytical measurement by atomic absorption s pectrophotometry gave

a content of 2 mg total lead/L in the stock solution. The experiment was carried out in the dark,

at 20 oC.

RESULTS

Endpoint value(s): The 48

- hr LC 50 was 85 ppb Pb. One

- hundred pe rcent mortality was seen

after 48 hours at 260 ppb Pb.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

24 Results remarks: Almost immediate 100% mortality occurred at 770 ppb Pb. No effect was

seen after 6 hours at 500 ppb Pb.

CONCLUSIONS

Alkyl leads show higher toxicity than inorganic lead.

STUDY R ELIABILITY

Klimisch code = [3]. Invalid. The test substance was a formulation; composition was not

specified. Additionally, the tested concentrations were unclear; a non

- standard species was

tested; and missing experimental details included loading rate , pH, salinity, dissolved oxygen

concentration, total organic carbon levels, and whether the test was conducted in static or flow

through chambers.

REFERENCE

Marchetti, R. 1978. Acute toxicity of alkyl leads to some marine organisms. Marine Pollution

Bulletin, 9: 206

- 207.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

25 B

- 3. TOXICITY TO AQUATIC PLANTS

Summary of endpoint: Inadequate

Study 1: Acute toxicity study in marine diatom

Title: The acute toxicity and bioaccumulation of some lead alkyl compounds in marine animals

This study is: Adequate Not Adequate

The exposure period appears to have been only 6 hours in duration; OECD guidelines specify a

duration of 72 hours. Additionally, no guideline or method was cited, GLP compliance is

unknown, a non

- standa rd test method was used, and the exact tested concentrations were unclear.

TEST SUBSTANCE

Identity: T etraethyl lead, CAS No. 78

- 00

- 2

Remarks: 98% pure, supplied by Ellesmere Port Research Laboratories of the Associated Octel

Company Limited

MET HOD

Method/guideline followed: Based on a technique developed from the organic productivity

assessment method of Steeman

- Nielsen (1952).

Test type: Toxicity to Algae

– Static

GLP compliant?: Not specified

Year study was performed: 1980

Test species: Phaeodactylum tricornutum (marine diatom). Source: Plymouth collection; sub

culture on modified Erd

- Schrieber.

Analytical monitoring: Yes

Exposure duration: 6 hours

Concentrations tested: Not specified

Test method/conditions remarks:

Seawater (salinit y 34.9‰) was pumped directly from the sea and supplied at a constant

temperature (15 oC) to the test system. Stock solutions were prepared by agitating 22 liters of

water with 10 grams of tetraethyl lead for 4 hours, allowing the excess to settle for 2 ho urs, and

then pumping the top 20 liters into a sealed stock vessel isolated from direct sunlight.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

26 A standardized quantity of algae was incubated for 6 hours in the presence of a range of

concentrations of the test item and a standard amount of C 14

- labeled carbonate. The

accumulation of C 14 by the control cultures indicates the “normal” activity of the algae which

can be compared to activity of algae exposed to the test item.

RESULTS

Endpoint value(s): The 6

- hour EC 50 value was 0.10 mg Pb/L, based on a r eduction in

photosynthetic activity.

Results remarks: The EC 50 value was calculated according to the methods of Doudoroff et al.

(1951)

CONCLUSIONS

None specified.

STUDY RELIABILITY

Klimisch code = [3]. Invalid

. The exposure period appears to have been only 6 hours in

duration; OECD guidelines specify a duration of 72 hours. Additionally, no guideline or method

was cited, GLP compliance is unknown, a non

- standard test method was used, and the exact

tested concentrations were unclear.

REFERENCE

Maddock, B.G. and D. Taylor. 1980. The acute toxicity and bioaccumulation of some lead alkyl

compounds in marine animals. In: M. Branika and Z. Konrad (eds.), Lead in the Marine

Environment. Proc. Int. Experts Discussion on Lead Occurrence. Fate and Pollution in the

Marine Environment, Rovinj, Yugoslavia : 233

- 261 . Pergamon, Oxford, UK.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

27 Study 2: Toxicity study in diatom

Title: Not specified

This study is: Adequate Not Adequate

The IUCLID summary, which was mo stly in a language other than English, contains insufficient

information to assess data adequacy.

TEST SUBSTANCE

Identity: T etraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guideline followed: Not specified

Test type: Toxic ity to Algae

GLP compliant?: Not specified

Year study was performed: 1992

Test species: Cyclotella meneghiniana f. unipunctata (diatom)

Analytical monitoring: Not specified

Exposure duration: 24 hours

Concentrations tested: Not specified

Test metho d/conditions remarks: Growth rate was measured.

RESULTS

Endpoint value(s): Not specified

Results remarks: The IUCLID summary of the study was mostly in a language other than

English.

CONCLUSIONS

The IUCLID summary of the study was mostly in a language other than English.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

28 STUDY RELIABILITY

Klimisch code = [4]. Not assignable

. The IUCLID summary, which was mostly in a language

other than English, contained insufficient details to assess data adequacy.

The IUCLID dataset summary reported an assigned Klimisch code of 2.

REFERENCE

Primary reference (unavailable): Giri, B.S. and N.A. Devi. 1992. Indian J Exp Biol 30: 201

-

204.

Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http:// ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

29 Study 3: Toxicity study in green algae

Title: Acute toxicity of alkyl leads to some marine organisms

This study is: Adequate Not Adequate

The test duration was less than the OECD

- rec ommended length of 72 hours. Additionally, the

test substance was a formulation (composition not specified); the tested concentrations were

unclear; a non

- standard species was tested; and missing experimental details included pH,

salinity, and dissolved o xygen concentration.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: None provided

METHOD

Method/guideline followed: Not specified

Test type: Toxicity to Algae

GLP compliant?: The study pre

- dates GLP.

Year study was perfo rmed: 1978

Test species: Dunaliella tertiolecta (green algae)

Analytical monitoring: No

Exposure duration: 48 hours

Concentrations tested: Not specified

Test method/ conditions remarks: The tetraethyl lead solution was prepared by adding 2 ml of

produc t to 1 L of f iltered natural seawater (0.45 μm) and slowly stirring magnetically for 1 hour.

The upper one fourth of the saturated solution was used for preparing experimental dilutions in

natural filtered seawater . Analytical measurement by atomic absorp tion s pectrophotometry gave

a content of 2 mg total lead/L in the stock solution. The experiment was carried out at 20 oC

using closed vessels to avoid gas

- phase leaching of the volatile compound. The toxicity to algae

was measured as the reduction of ph otosynthetic activity by the 14 C method.

RESULTS

Endpoint value(s): The 48

- hr EC 50 was 150 ppb. One

- hundred percent reduction ofDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

30 photosynthesis was seen after 48 hours at 300 ppb.

Results remarks: No effects on photosynthesis were observed at concentra tions less than 100

ppb Pb. Complete inhibition of photosynthetic activity was observed at 500 ppb after 6 hours.

CONCLUSIONS

Alkyl leads show higher toxicity than inorganic lead.

STUDY RELIABILITY

Klimisch code = [3]. Invalid. The test duration was less than the OECD

- recommended length of

72 hours. Additionally, the test substance was a formulation (composition not specified); the

tested concentrations were unclear; a non

- standard species was tested; and missing experimental

details included pH, sal inity, and dissolved oxygen concentration.

REFERENCE

Marchetti, R. 1978. Acute toxicity of alkyl leads to some marine organisms. Marine Pollution

Bulletin, 9: 206

- 207.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

31 B

- 4. ACUTE TOXICITY

Study 1: Acute oral toxicit y study in rats

Summary of endpoint: Adequate

Title: The Effects of Fasting on the Acute Oral Toxicity of Nine Chemicals in the Rat

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2, supplied b y E.I. du Pont de Nemours

Remarks: Purity 98.5%, containing 1% ethyl chloride. Tested as a 0.10

- 0.20% suspension.

METHOD

Method/guideline followed: Not specified

Test type: Acute oral

GLP compliant?: Not specified

Year study performed: 1984

Test s pecies: Male Crl

- CD rats (Charles River Breeding Laboratory, North Wilmington, MA),

60 days old, weighing 220

- 280 grams

Number of animals/sex/dose: 10 males/dose level

Route of administration: Oral

Vehicle: Corn oil

Doses/concentrations tested: 15, 20, 22, 26, 30, 35, or 40 mg/kg for fasted rats; 17, 22, or 28

mg/kg for non

- fasted rats

Statistical methods used: LD 50 values were estimated by probit analysis.

Test method/conditions remarks: Rats received a single oral gavage dose of the test substance.

Seven groups of 24

- hour fasted rats and three groups of non

- fasted rats were tested. A post

dosing 14

- day observation period was included, during which rats were weighed and observed

daily.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

32 RESULTS

Endpoint value(s): The oral LD 50 value was 29 mg/kg for fasted rats and 20 mg/kg for non

fasted rats.

Results remarks: Mortality (out of 10 rats at each concentration) was 0, 0, 3, 7, 6, 4, and 9 at

15, 20, 22, 26, 30, 35, and 40 mg/kg, respectively, for fasted rats and 3, 6, and 10 at 17, 22, and

28 mg/kg , respectively, for non

- fasted rats. At 22 mg/kg (the only dose level common to both

fasted and non

- fasted groups), the number of deaths among non

- fasted rats was greater. Time of

death in both fasted and non

- fasted groups was similar, with delayed death s occurring in both

groups. The mean time to death was greater in the low

- dose groups. Clinical signs of toxicity

included tremors, convulsions, weakness, diarrhea, and weight loss. Surviving fasted rats

showed only an immediate transient weight loss, w hereas non

- fasted rats had a mild to moderate

decrease followed by recovery two to three days post

- dosing.

CONCLUSIONS

Tetraethyl lead would be considered extremely toxic in both fasted and non

- fasted rats. LD 50

values in fasted and non

- fasted rats were not statistically different.

STUDY RELIABILITY

Klimisch code = [ 2 ]

. Reliable with restrictions. The study appears generally acceptable,

although it is missing information including guideline followed and GLP compliance, and only

male rats were tested.

REFERENCE

Dashiell, O.L. and G.L. Kennedy. 1984. The effects of fasting on the acute oral toxicity of nine

chemicals in the rat. J. Appl. Toxicol., 4: 320

- 325.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

33 Study 2: Acute oral toxicity study in rats

Title: None specified

The study is: Adequate Not Adequate

The IUCLID summary lacked sufficient information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guideline followed: Not specified

Test type: Acute oral

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1972

Test species: Rat

Number of animals/sex/dose: Not specified

Route of administration: Oral

Vehicle: Not specified

Doses/concentrations tested: No t specified

Statistical methods used: Not specified

Test method/conditions remarks: Not specified

RESULTS

Endpoint value(s): The oral LD 50 value was 12.3 mg/kg.

Results remarks: Not specifiedDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

34 CONCLUSIONS

Not specified

STUDY RELIABILITY

Klimisch code = [4]. Not assignable

. The IUCLID summary lacked sufficient information to

assess data adequacy.

REFERENCE

Primary reference (unavailable): Experientia, vol 28, p. 923. 1972.

Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

35 Study 3: Acute oral toxicity study in rats

Title: None specified

The study is: Adequate Not Adequate

The IUCLID summary, which wa s mostly in a language other than English, lacked sufficient

information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guideline followed: Not specified

Test type: Acut e oral

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1963

Test species: Rat

Number of animals/sex/dose: Not specified

Route of administration: Oral

Vehicle: Not specified

Doses/concentrations tested: Not specified

Statistical metho ds used: Not specified

Test method/conditions remarks: The IUCLID summary of the study was mostly in a language

other than English.

RESULTS

Endpoint value(s): The oral LD 50 value was 35 mg/kg.

Results remarks: The IUCLID summary of the study was mostl y in a language other than

English.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

36 CONCLUSIONS

The IUCLID summary of the study was mostly in a language other than English.

STUDY RELIABILITY

Klimisch code = [4]. Not assignable

. The IUCLID summary, which was mostly in a language

other than English, lacked sufficient information to assess data adequacy.

The IUCLID summary reported an assigned Klimisch code of 2.

REFERENCE

Primary reference (unavailable): Magistretti, M. et al. 1963. Med Lavoro 54: 486

- 495.

Secondary reference: IUCLID Dataset f or CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

37 Study 4: Acute oral toxicity study in rats

Title: The LD 50 value of tetraethyl lead

The study is: Adequate Not Adequate

The study tested an insufficient number of animals per dose level. Additionally, information was

missing on guideline followed and mortality by sex.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: 98% pu re solution, obtained from Ventor Corporation, Beverly, MA. Dissolved in

100% pure peanut oil.

METHOD

Method/guideline followed: Not specified

Test type: Acute oral

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1972

Test species: Sp rague

- Dawley albino rats, weighing from 150 to 250 g (females) and 350 to 425

g (males)

Number of animals/sex/dose: 2/sex/group

Route of administration: Oral

Vehicle: Peanut oil

Doses/concentrations tested: The test item was dissolved in peanut oil to obtain a concentration

of 7.32 mg/mL. Pure peanut oil was added as necessary to bring the volume administered up to

2 mL. Dose levels were 10, 13, 16.9, or 21.97 mg/kg.

Statistical methods used: Weil’s method of moving averages was used.

Test method/c onditions remarks: Animals received a single oral gavage dose. All animals

were kept in the same 12

- hr

- light

- cycled, temperature

- controlled room. Animals were examined

daily for 14 days post

- dosing.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

38 RESULTS

Endpoint value(s): The oral LD 50 value was 14.18 mg/kg.

Results remarks: Mortalities were as follows: 1/4 at 10 mg/kg, 0/4 at 13 mg/kg, 4/4 at 16.9

mg/kg, and 4/4 at 21.97 mg/kg. All animals displayed neurological signs including lethargy,

irritability, and ataxia. Violent jumping, trembling, a nd thrashing following a loud noise, plus

aggressiveness and fighting, were also observed. Aggressiveness was seen mostly in the 16.9

and 21.97 mg/kg groups beginning on day 5 post

- dosing. This was followed by convulsions,

intermittent uncontrolled thras hing, and finally death beginning on day 6 post

- dosing.

CONCLUSIONS

None specified

STUDY RELIABILITY

Klimisch code = [3]

. Invalid. The study tested an insufficient number of animals per dose level.

Additionally , information was missing on guideline followed and mortality by sex.

The IUCLID summary reported an assigned Klimisch code of 2.

REFERENCE

Schroeder, T. e t al

. 1972. The LD 50 value of tetraethyl lead. Experientia, 28: 425

- 426.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

39 Study 5: Acute oral toxicity study in rats

Title: None specified

The study is: Adequate Not Adequate

Th e IUCLID summary lacked sufficient information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHO D

Method/guideline followed: Not specified

Test type: Acute oral

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1973

Test species: Rat

Number of animals/sex/dose: Not specified

Route of administration: Oral

Vehicle: Not specified

D oses/concentrations tested: Not specified

Statistical methods used: Not specified

Test method/conditions remarks: Not specified

RESULTS

Endpoint value(s): The oral LD LO value was 30 mg/kg.

Results remarks: Not specified

CONCLUSIONS

Not specifiedDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

40 S TUDY RELIABILITY

Klimisch code = [4]. Not assignable

. The IUCLID summary lacked sufficient information to

assess data adequacy.

REFERENCE

Primary reference (unavailable): Japanese Journal of Industrial Health, 15: p. 3. 1973.

Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

41 Study 6: Acute oral toxicity study in rats

Title: None specified

The study is: Adequate Not Adequate

The IUCLID summary, which was mostly in a language other than Englis h, lacked sufficient

information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guid eline followed: Not specified

Test type: Acute oral

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1974

Test species: Rat

Number of animals/sex/dose: Not specified

Route of administration: Oral

Vehicle: Not specified

Doses/concentra tions tested: Not specified

Statistical methods used: Not specified

Test method/conditions remarks: The IUCLID summary of the study was mostly in a language

other than English.

RESULTS

Endpoint value(s): None specified

Results remarks: The IUCLID sum mary of the study was mostly in a language other than

English.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

42 CONCLUSIONS

The IUCLID summary of the study was mostly in a language other than English.

STUDY RELIABILITY

Klimisch code = [4]. Not assignable

. The IUCLID summary, which was mostly in a l anguage

other than English, lacked sufficient information to assess data adequacy.

The IUCLID summary indicated an assigned Klimisch code of 2.

REFERENCE

Primary reference (unavailable): Avery D.D. et al. 1974. Pharmacol. Biochem. Behav. 2: 473

-

479

. Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

43 Study 7: Acute oral toxicity study in rats

Title: Tetraethyllead and tetramethyllead

The study i s: Adequate Not Adequate

No LD 50 value was specified in the report.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Dissolved in peanut oil to yield a concentration of 1.813 mg/mL; toluene added (as a

stabilizer) at 0.321 mL per 100 mL peanut oil

METHOD

Method/guideline followed: Not specified

Test type: Acute oral

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1964

Test species: Charles River cesarean

- derived albino ra ts (22 days old)

Number of animals/sex/dose: 6/sex/dose

Route of administration: Oral

Vehicle: Peanut oil/toluene

Doses/concentrations tested: 0, 1.7, or 17 mg/kg

Statistical methods used: Not specified

Test method/conditions remarks: Animals were h oused in stainless steel wire cages and

observed for 9 days pre

- dosing. Pre

- dosing hematological data were obtained. Four male and

for female rats were sacrificed for histologic examination pre

- dosing.

Animals received single oral gavage doses of the test item, were observed for 144 days post

dosing, and then sacrificed. Terminal measurements included body weight, organ weights, lead

content in tissues, and histopathology.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

44 RESULTS

Endpoint value(s): None specified

Results remarks: At 17 mg/kg, 4/6 males and 1/6 females died within 5 days of dosing. All rats

displayed irritability, hypermotility, tremors, spasticity, and arched backs, and some became

prostrate. All lost weight within the first week. Within 2 weeks of administration, the surviving

rats appeared normal. At 1.7 mg/kg, there were no deaths or abnormalities observed. No

adverse effects on terminal body weight were observed.

Some slight organ weight changes were seen with respect to controls, but no statistical analysis

was provided . Pathological changes included hypoplasia and hypotrophy of hepatocytes, neural

degeneration, and hypertrophy of myocardial fibers. The liver was found to contain the greatest

lead content, relative to other organs.

CONCLUSIONS

Not specified

STUDY RE LIABILITY

Klimisch code = [3]. Invalid. No LD 50 value was specified in the report.

The IUCLID summary indicated an assigned Klimisch code of 2.

REFERENCE

Schepers, G.W.H. 1964. Tetraethyllead and tetramethyllead. Arch. Environ. Health, 8: 277

-

2 95.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

45 Study 8: Acute oral toxicity study in rats

Title: Acute Oral Toxicity Study of Tetraethyllead

The study is: Adequate Not Adequate

Insufficient information was available to assess data adequacy; details missing included test

substance purity, doses tested, test conditions, and mortality at each dose. Additionally, only one

sex of rats was tested.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Described as Haskell #9380 (TEL MM

- I)

ME THOD

Method/guideline followed: Not specified

Test type: Acute oral

GLP compliant?: Th e study pre

- dates GLP.

Year study performed: 1975

Test species: Young adult male ChR

- CD rats

Number of animals/sex/dose: 10/dose

Route of administration: Oral

Veh icle: Corn oil

Doses/concentrations tested: 5 or 50 mg/kg

Statistical methods used: Not specified

Test method/conditions remarks: Animals received single oral gavage doses of the test

substance, and were then observed for 14 days.

RESULTS

Endpoint va lue(s): The acute oral LD 50 value was >5 but <50 mg/kg.

Results remarks: All rats died at 50 mg/kg. No mortality was observed at 5 mg/kg. At 50Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

46 mg/kg, piloerection and tremors were seen two days after dosing, as well as weight loss, and

finally death 2 to 3 days post

- dosing. At 5 mg/kg, initial weight loss was observed.

CONCLUSIONS

Tetraethyl lead was classified as highly toxic.

STUDY RELIABILITY

Klimisch code = [4]. Not assignable

. Insufficient information was available to assess data

adequacy; details missing included test substance purity, doses tested, test conditions, and

mortality at each dose. Additionally, only one sex of rats was tested.

REFERENCE

TSCATS submission (OTS0571634, Document ID 88

- 920009976, received 10/15/92). Haskell

La boratory, DuPont Chemical Company. 1975. Special Oral Test of Lead, Tetraethyl in Rats

with Cover Letter Dated 101592.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

47 Study 9: Acute oral toxicity study in rats

Title: None specified

The study is: Adequate Not Adequate

The IUCLID summary, which was mostly in a language other than English, lacked sufficient

information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guideline followed: Not specified

Test type: Acute oral

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1976

Test species: Rat

Number of animals/sex/dose: Not specified

Route of administration: Oral

Vehicle: Not specified

Doses/concentrations tested: Not specified

Statistical methods used: Not specified

Test method/conditions remarks: The IUCLID summary of the study was mostly in a language

other than English.

RESULTS

Endpoint value(s): None specified

Results remarks: The IUCLID summary of the study was mostly in a language other than

English.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

48 CONCLUSIONS

The IUCLID summary of the study was mostly in a language other than English.

STUDY RELIABILITY

Klimisch code = [4]. Not assignable

. The IUCLID summary, which was mostly in a langua ge

other than English, lacked sufficient information to assess data adequacy.

The IUCLID summary reported an assigned Klimisch code of 2.

REFERENCE

Primary reference (unavailable): Czech et al. 1976. Pharmacol Biochem Behav 5: 387

- 389.

Secondary re ference: In IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

49 Study 10: Acute oral toxicity study in rats

Title: Teratogenic evaluation of lead compounds in mice and rats

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: 98% pure, supplied by Houston Chemical Company, Freeport, TX

METHOD

Method/guideline followed: Not speci fied

Test type: Acute oral

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1975

Test species: COBS random

- bred albino rats

Number of animals/sex/dose: 10/dose, sex not specified

Route of administration: Oral gavage

Vehicle: Not specif ied

Doses/concentrations tested: 35.12, 52.67, and 79.01 mg/kg

Statistical methods used: The methods of Litchfield and Wilcoxon (1949) were used.

Test method/conditions remarks: Single graded oral doses were given to groups of 10 animals

and 14

- day LD 5 0 values were calculated.

RESULTS

Endpoint value(s): LD 50 = 53 ± 8 mg/kg

Results remarks: Mortalities were 1/10, 5/10, and 10/10 at 35.12, 52.67, and 79.01 mg/kg

respectively. Clinical signs at 52.67 mg/kg included hypoactivity from 6 to 24 hours. Cli nical

signs seen at 79.01 mg/kg included hypoactivity (from 6 hours until death), tremors, from 5 to 24

hours, or until death), and clonic convulsions (from 2 to 5 hours or until death).Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

50 CONCLUSIONS

None specified

STUDY RELIABILITY

Klimisch code = [2]. Reliable with restrictions. The sex of test animals was not specified.

REFERENCE

Kennedy, G.L. et al. 1975. Teratogenic evaluation of lead compounds in mice and rats. Food.

Cosmet. Toxicol., 13: 629

- 632.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

51 Study 11: Acute oral toxicity study in mic e

Title: Teratogenic evaluation of lead compounds in mice and rats

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: 98% pure, supplied by Houston Chemical Company, Freeport, TX

METHOD

Method/guideline followed: Not specified

Test type: Acute oral

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1975

Test species: CD

- 1 random

- bred albino mice

Number of animals/sex/dose: 10/dose, sex not specified

Route of administration: Oral gavage

Vehicle: Not specified

Doses/concentrations tested: 35.12, 52.67, 79.01, and 118.5 mg/kg

Statistical methods used: The methods of Litchfield and Wilcoxon (1949) were used.

Test method/conditions remarks: Single graded oral doses were given to groups of 10 animals

and 14

- day LD 50 values were calculated.

RESULTS

Endpoint value(s): LD 50 = 65 ± 3.5 mg/kg

Results remarks: Mortalities were 0/10, 2/10, 10/10, and 10/10 at 35.12, 52.67, 79.01, and

118.5 mg/kg , respectively. Clinical signs at 52.67 mg/kg included hypoactivity from 6 to 24

hours. Clinical signs seen at 79.01 mg/kg included hypoactivity (from 6 hours or 2 hours until

death) and tremors (from 5 to 24 hours, or until death). Clinical signs seen at 118.5 mg/kg

consisted of hypoactivity (from 2 hours until death), tremors (from 3 to 12 hours or until death)Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

52 and clonic convulsions (from 2

- 3 to 5 hours).

CONCLUSIONS

None specified

STUDY RELIABILITY

Klimisch code = [2]. Reliable with restrictions . The sex of test animals was not specified.

REFERENCE

Kennedy, G.L. et al. 1975. Teratogenic evaluation of lead compounds in mice and rats. Food.

Cosmet. Toxicol., 13: 629

- 632.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

53 Study 12: Acute oral toxicity study in rats

Title: Estimation of acu te oral toxicity in rats by determination of the approximate lethal dose

rather than the LD 50

The study is: Adequate Not Adequate

Only one rat per dose level was tested.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: 98.5% pure, obtained from EI du Pont de Nemours and Co., Inc.

METHOD

Method/guideline followed: Not specified

Test type: Acute oral

GLP compliant?: Not specified

Year study performed: 1986

Test species: Crl:CD male rats, from Charles River Breeding Laboratory (North Wilmington,

MA), weighing between 230 and 257 grams and approximately 60 days old

Number of animals/sex/dose: 1 male/dose

Route of administration: Oral

Vehicle: Corn oil

Doses/concentrations tested: The tes t began by dosing at 670 mg/kg, and the dose was raised or

lowered as needed in accord with the concentration gradients of Deichmann and LeBlanc (1943).

Dose levels were 12, 17, 26, 40, and 670 mg/kg.

Statistical methods used: Not stated

Test method/co nditions remarks: A single oral dose was administered via gavage. A 14

- day

post

- dosing observation period was included.

RESULTS

Endpoint value(s): The approximate lethal dose was 26 mg/kg.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

54 Results remarks: Animals dosed with 12 or 17 mg/kg survived. A ll others died.

CONCLUSIONS

Tetraethyl lead was classified as highly toxic.

STUDY RELIABILITY

Klimisch code = [3]. Invalid. Only one animal was tested per dose level.

REFERENCE

Kennedy, G.L. et al. 1986. Estimation of acute oral toxicity in rats by determination of the

approximate lethal dose rather than the LD 50 . J of Appl

. Toxicol

. , 6(3): 145

- 148.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

55 Study 13: Acute inhalation toxicity study in male rats

Title: Initial submission: Department of Transportation Inhalation Toxicity Studies of

Tet raethyllead in Rats

The study is: Adequate Not Adequate

The duration of exposure (1 hour) was insufficient to assess inhalation toxicity; the OECD

recommended exposure duration is 4 hours. Additionally, test substanc e purity was not

specified.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Described as Haskell #8997 (TEL

- Av.)

METHOD

Method/guideline followed: Not specified

Test type: Acute inhalation

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1972

Test species: Male ChR

- CD rats, initial body weight of 250 grams

Number of animals/sex/dose: 10 males/dose

Route of administration: Inhalation

Vehicle: Air

Doses/concentrations tested: 125, 201, 241, 243, 259, 277, 29 9, and 435 ppm (0.985, 1.38,

1.89, 1.91, 2.03, 2.17, 2.35, and 3.4 mg/L)

Statistical methods used: Not specified

Test method/conditions remarks: House air was passed through a fritted bubbler immersed in

the test material. The resulting vapor mixture w as then diluted with air just prior to introduction

into the chamber. Each exposure duration was 1 hour and utilized 10 rats. Samples for analysis

were collected by drawing chamber air through a fritted bubbler immersed in iodine

monochloride solution wh ich has been shown to collect these organic compounds. The resulting

iodine monochloride

- organic lead solutions were analyzed by atomic absorption.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

56 It appears as though a number of different formulations of the test item were tested, although this

is not entirely clear from the available summary.

RESULTS

Endpoint value(s): The inhalation LC 50 value was >125 but <200 ppm.

Results remarks: All rats died at 435, 299, 277, and 241 ppm. Nine rats died at 259 ppm, 5 rats

died at 201 ppm, and 1 rat died at 2 43 ppm. There were no mortalities at 125 ppm. Three rats

that died several days after exposure to 277 ppm were examined for gross pathology, which

revealed congestion, edema, and hemorrhage in the lungs.

CONCLUSIONS

Tetraethyl lead was classified as hi ghly toxic.

STUDY RELIABILITY

Klimisch code = [3]. Invalid

. The duration of exposure (1 hour) was insufficient to assess

inhalation toxicity; the OECD

- recommended exposure duration is 4 hours. Additionally, test

substance purity was not specified.

RE FERENCE

TSCATS submission (OTS0571595, Document ID 88

- 920009938, received 10/27/92). Haskell

Laboratory, Dupont Chemical Company. 1975. Initial submission: Department of

Transportation Inhalation Toxicity Studies of Tetraethyllead in Rats with Cover Le tter Dated

101592.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

57 Study 14: Acute inhalation toxicity study in rats

Title: Further studies on the toxicity of some tetra and trialkyl lead compounds

The study is: Adequate Not Adequate

The exposure duration wa s only 1 hour; the OECD

- recommended exposure duration is 4 hours.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Pure sample

METHOD

Method/guideline followed: Not specified

Test type: Acute inhalation

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1961

Test species: Adult albino rats (175

- 230 g)

Number of animals/sex/dose: 12 to 20 rats/group (number per sex not indicated)

Route of administration: Inhalation; 1

- hr exposure period

Vehicle: Air

Doses/c oncentrations tested: 0.095, 0.19, 0.37, 0.77, 1.58, 2.77, 4.84 mg/L (nominal);

0.08, 0.17, 0.34, 0.66, 1.5, 2.64, 3.87 mg/L (analytical mean); approximate dose in mg/kg: 4.8,

10.2, 20.4, 39.6, 90, 158, and 232 mg/kg, respectively.

Statistical methods use d: The LC 50 value was calculated according to the method of Weil

(1952).

Test method/conditions remarks: The 1

- hour inhalation exposures were carried out in an all

glass chamber. Groups of four rats were exposed head

- only to a pure solution of tetraeth yl lead

which was injected into the chamber by a mechanically

- driven syringe. Air flow was maintained

at 50 L/min.

RESULTS

Endpoint value(s): The 1

- hour inhalation LC 50 value is 0.85 mg/L, based on mean measuredDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

58 concentrations.

Results remarks: 4.84 mg/L: Eight rats died in less than 6 hours and the remaining rats died in

less than 12 hours. Rats were intensely cyanotic at death.

2.77 mg/L: All rats died in less than 24 hours.

1.58 mg/L: Three rats died in 24 hours and the rest died within 72 hours.

0.77 mg/L: All rats showed excitable sparring behavior; one rat died after 2 days; 2 rats showed

continuous tremors leading to death in 14 days.

0.37 and 0.19 mg/L: All rats were affected with mild signs of poisoning with slow recovery.

0.095 mg/L: Very mild signs of poisoning, with full recovery.

CONCLUSIONS

Not specified

STUDY RELIABILITY

Klimisch code = [3]. Invalid

. The exposure duration was only 1 hour ; the OECD

- recommended

exposure duration is 4 hours

.

REFERENCE

Cremer, J.E. and S. Callawa y. 1961. Further studies on the toxicity of some tetra and trialkyl

lead compounds. Brit. J. Ind. Med., 18: 277

- 282.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

59 Study 15: Acute inhalation toxicity study

Title: None specified

The study is: Adequate Not Ad equate

Th e IUCLID summary lacked sufficient information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guideline followed: Not specified

Test type: Acute inhalation

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1973

Test species: Mouse

Number of animals/sex/dose: Not specified

Route of administration: Inhalation

Vehicle: Not specified

Doses/concentrations tested: Not specified

Statistical methods used: Not specified

Test method/conditions remarks: The duration of exposure was 7 hours.

RESULTS

Endpoint value(s): The inhalation LC LO value was 0.65 mg/L.

Results remarks: Not specified

CONCLUSIONS

Not specifiedDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

60 STUDY RELIABILITY

Klimisch code = [4]. Not assignable

. The IUCLID summary lacked sufficient information to

assess data adequacy.

REFERENCE

Primary reference (unavailable): Japanese Journal of Industrial Health, 15: 3. 1973.

Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2 , available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

61 Study 16: Acute dermal toxicity study in dogs and guinea pigs

Title: None specified

The study is: Adequate Not Adequat e

Th e IUCLID summary lacked sufficient information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guideline followed: Not specified

Test type: Acute dermal

GLP complian t?: The study pre

- dates GLP.

Year study performed: 1973

Test species: Dogs and guinea pigs

Number of animals/sex/dose: Not specified

Route of administration: Dermal

Vehicle: Not specified

Doses/concentrations tested: Not specified

Statistical method s used: Not specified

Test method/conditions remarks: Not specified

RESULTS

Endpoint value(s): Two dermal LD LO values were provided for dogs: 547 and 830 mg/kg. The

dermal LD LO for guinea pigs was 995 mg/kg.

Results remarks: Not specifiedDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

62 CONCLUSIO NS

Not specified

STUDY RELIABILITY

Klimisch code = [4]. Not assignable

. The IUCLID summary lacked sufficient information to

assess data adequacy.

REFERENCE

Primary reference (unavailable): Japanese Journal of Industrial Health, 15: 3. 1973.

Sec ondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

63 B

- 5. REPEATED

- DOSE TOXICITY

Summary of endpoint: Inadequate

Study 1: Oral 14

- day repeated

- dose toxicity study in female mice

Title: Evaluation of tetraethyl l ead: Immunology

The study is: Adequate Not Adequate

The study is inadequate to assess repeated

- dose toxicity because the exposure duration was only

14 da ys; OECD test guidelines specify a minimum exposure period of 28 days. Additionally, no

LOAEL or NOAEL is identified.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Lot #68573; supplied by the Radian Corporation.

METHOD

Metho d/guideline followed: Not specified

Test type: Repeated

- dose/Immunological toxicity

GLP compliant?: Not stated

Year study performed: 1985

Test species: Female B6C3F1 mice from Charles River Breeding Laboratories; 5

- 6 weeks of

age, weighing 17 to 19 g

.

Number of animals/sex/dose: 8/group

Route of administration: Oral gavage

Vehicle: Corn oil

Exposure duration: 14 days

Doses/concentrations tested: 0, 0.5, 1, or 2 mg/kg

Statistical methods used: Data were tested for homogeneity using the Bartlett ’s Chi Square

Test; for data that were homogeneous, a one

- way ANOVA was performed. If the ANOVA

showed significance, then a Dunnett’s Multiple Range T

- test was performed. If the data wereDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

64 non

- homogeneous, a non

- parametric ANOVA, Kruskal

- Wallis test, and Wilcoxon Rank Sum

Test were performed.

Test method/conditions remarks: Mice received oral gavage doses daily for 14 consecutive

days. Body weights were measured on days 1, 8, and 15 of the study. Animals were observed at

the time of dosing for any clini cal signs. Mice were necropsied 24 hours after the last exposure.

Organ weights (brain, liver, lung, spleen, thymus, and kidneys) were measured. Gross and

histopathological analyses were performed on selected organs (liver, spleen, lungs, thymus,

mesent eric lymph nodes, and kidneys). Hematological and clinical chemistry analyses were

performed.

Immunological tests included spleen IgM antibody response to a T

- dependent antigen (sheep red

blood cells), mixed lymphocyte response to DBA/2 mouse spleen cell s, delayed hypersensitivity

response to keyhole limpet cyanin, and serum complement levels.

RESULTS

Endpoint value(s): None specified

Results remarks: The high dose produced nervous system toxicity (tremors, beginning on day 5

of exposure and progressin g to paralysis). Dose

- dependent decreases in erythrocyte count,

hematocrit, hemoglobin, and peripheral blood leukocytes (lymphocytes and neutrophils) were

seen. There was a slight but significant increase in BUN. Histopathological evaluation was

negativ e with respect to lymphoid tissue, but a mild chronic hepatitis was seen at 1 and 2 mg/kg.

Body weights decreased in a dose

- dependent fashion, reaching statistical significance at 2 mg/kg.

No significant effects were observed on organ weights.

There wer e no effects on IgM antibody response, mixed lymphocyte response, and

hypersensitivity response. Serum complement levels, as measured by total hemolytic activity,

were decreased dose

- dependently.

CONCLUSIONS

None specified

STUDY RELIABILITY

Klimisch c ode = [3]. Invalid. The exposure duration was only 14 days; OECD test guidelines

specify a minimum exposure period of 28 days. Additionally, no LOAEL or NOAEL is

identified.

REFERENCE

Luster. M.I. 1986. Evaluation of tetraethyl lead: Immunology. Re port to National Toxicology

Program. June 1, 1986. NIEHS, RTP. Contract No. ES 55094.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

65 Study 2: Oral 13

- week repeated

- dose toxicity study in male rats

Title: None specified

The study is: Adequate Not Adequate

Th e IUCLID summary lacks sufficient information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guideline followed: Not specified

Test type: R epeated

- dose toxicity

GLP com pliant?: Not stated

Year study performed: 1987

Test species: Male Sprague

- Dawley rats

Number of animals/sex/dose: Not indicated

Route of administration: Oral gavage

Vehicle: Not indicated

Exposure duration: 5 times/week for 13 weeks

Doses/concentr ations tested: 0, 0.2, or 2 mg/kg

Statistical methods used: Not stated

Test method/conditions remarks: Not specified

RESULTS

Endpoint value(s): None specified

Results remarks: Symptoms included decreased food intake and body weight, hyperexcitabili ty,

irritability, tremor, and coma. Pathological changes included brain and spinal cord lesions andDraft HPV4 Chemical Data Adequacy Review CAS No. 78

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- 2

66 eosinophile inclusions in the proximal renal tubule.

CONCLUSIONS

None specified.

STUDY RELIABILITY

Klimisch code = [4]. Not assignable. The IUCLID su mmary lacks sufficient information to

assess data adequacy.

REFERENCE

Primary reference (unavailable): Franklin C.A. et al. , 1987. Trace Subst. Environ. Health 21:

286

- 296.

Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

67 Study 3: Oral 21

- week repeated

- dose toxicity study in rats

Title: Tetraethyllead and tetramethyllead

The study is: Adequate Not Adequate

No e ndpoint value was specified in the report, and parameters investigated were non

- standard.

Also, the study report did not specify which effects were seen at which concentrations or the

statistical significance of effects

.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Dissolved in peanut oil to yield a concentration of 1.813 mg/mL; toluene added (as a

stabilizer) at 0.321 mL per 100 mL peanut oil

METHOD

Method/guideline followed: Not specified

Test type: Repeated

- dose toxic ity

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1964

Test species: Charles River cesarean

- derived albino rats (22 days old)

Number of animals/sex/dose: 6/sex/dose for treated groups; 8/sex/dose for control group

Route of administrat ion: Oral gavage

Vehicle : Peanut oil/toluene

Exposure duration : 21 weeks

Doses/concentrations tested: 0, 0.0017, or 0. 17 mg /kg

Statistical methods used: Not specified

Test method/conditions remarks: Animals were housed in stainless steel wire cages a nd

observed for 9 days pre

- dosing. Pre

- dosing hematological data were obtained. Four male and

for female rats were sacrificed for histologic examination pre

- dosing.

Animals received daily oral gavage doses of the test item 5 times/week to a total of 1 00 doses.

All rats were sacrificed during the first or second day after administration of the last dose.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

68 Terminal measurements included body weight, organ weights, lead content in tissues, and

histopathology.

RESULTS

Endpoint value(s): None specified

Results remarks: Peripheral hyperemia was noted in high

- dose rats. Irritability of the animals

increased as the experiment proceeded. No adverse effects on terminal body weight were

observed. Some slight organ weight changes were seen with respect to co ntrols, but no statistical

analysis was provided.

Pathological changes included swollen friable liver with hypotrophy and hypoplasia of the

hepatocytes; epithelial hyperplasia of the thyroid gland; fatty degeneration of the thymus;

hypertrophy of the pa rathyroids; hyperemia and edema of the central nervous system; neural

degeneration; and pulmonary edema.

The liver and kidneys had the highest accumulation of lead, relative to other organs.

CONCLUSIONS

Tetraethyl lead caused significant lesions in vari ous organs and selective distribution of lead in

tissues.

STUDY RELIABILITY

Klimisch code = [3]. Invalid. No endpoint value was specified in the report, and parameters

investigated were non

- standard. Also, the study report did not specify which effect s were seen at

which concentrations or the statistical significance of effects.

REFERENCE

Schepers, G.W.H. 1964. Tetraethyllead and tetramethyllead. Arch Env Health, 8: 277

- 295.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

69 Study 4: Oral repeated

- dose toxicity study in rats

Title: None sp ecified

The study is: Adequate Not Adequate

The IUCLID summary, which was mostly in a language other than English, lacked sufficient

information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guideline followed: Not specified

Test type: Repeated

- dose toxicity

GLP compliant?: Not specified

Year study performed: 1980

Test species: Rats

Number of animals/sex/dose: Not specified

Route of administration: Oral gavage

Vehicle:

Exposure duration : Not specified

Doses/concentrations tested: 5 and 10 mg/kg

Statistical methods used: Not specified

Test method/conditions remarks: The IUCLID summary of the study was mostly in a language

othe r than English.

RESULTS

Endpoint value(s): None specified

Results remarks: The IUCLID summary of the study was mostly in a language other thanDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

70 English.

CONCLUSIONS

The IUCLID summary of the study was mostly in a language other than English.

STUDY RE LIABILITY

Klimisch code = [4]

. Not assignable. The IUCLID summary, which was mostly in a language

other than English, lacked sufficient information to assess data adequacy.

The IUCLID summary specified a reliability rating of 2.

REFERENCE

Primary refe rence (unavailable): Seawright A.A. et al. 1980. In Holmstedt et al. Mechanism of

Toxicity and Hazard Evaluation. Elsevier/North Holland, 71

- 74.

Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

71 Study 5: Oral 6

- month repeated

- dose study in rhesus monkeys

Title: Chronic oral administration of alkyl lead solutions to the rhesus monkey

The study is: Adequate Not A dequate

Only one test concentration was employed, as well as a non

- standard test species and insufficient

number of animals per treatment group.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Not specified

METHOD

Method/guide line followed: Not specified

Test type: Repeated

- dose toxicity

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1979

Test species: Rhesus monkeys ( Macaca mulatta ), weighing 2.1

- 3.3 kg; wild

- caught

Number of animals/sex/dose: 2/sex/dose

Route of administration: oral gavage

Vehicle: Toluene/ethanol

Exposure duration : 6 months

Doses/concentrations tested: 0 ( toluene/ethanol vehicle control), 6 μg Pb/kg/day

Statistical methods used: Analysis of variance and Newman

- Keuls’ multiple compari son

procedure were used.

Test method/conditions remarks: Each monkey was housed in a wall

- mounted cage, in a room

maintained at a temperature of 22 oC in normal daylight conditions. Monkeys were given daily

gavage doses of 4 mL/kg of the test substance f or 6 months at a dose level equivalent to 6 μg

Pb/kg/day . Clinical signs and food consumption were monitored daily throughout. Body

weights were measured weekly. Neurological and ophthalmoscopic examinations were made

throughout. Hematological and bloo d biochemical examinations were made before and after 13Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

72 and 26 weeks of treatment. Twenty

- four hour urine samples were examined. Lead content of

blood, urine, and feces was estimated at weekly intervals for the first 8 weeks, and thereafter at

2

- week in tervals. Post

- mortem examinations included weighing of brain, pituitary, heart, lungs,

liver, spleen, pancreas, thymus, prostate or uterus, kidneys, adrenals, and gonads, and a wide

range of tissues were prepared for histological examination. Samples of all major tissues were

analyzed for lead content.

RESULTS

Endpoint value(s): None specified

Results remarks: There were no effects of treatment except for elevated blood, urine, and feces

lead levels, and elevated lead in tissues.

CONCLUSIONS

The admi nistration of tetraethyl lead to rhesus monkeys for long periods was without effect on

the clinical, behavioral, and pathological parameters monitored.

STUDY RELIABILITY

Klimisch code = [ 3 ]

. Invalid

. Only one test concentration was employed, as well as a non

standard test species and insufficient number of animals per treatment group.

REFERENCE

Heywood R. et al. 1979. Chronic oral administration of alkyl lead solutions to the rhesus

monkey. Toxicol. Lett., 4: 119

- 125.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

73 Study 6: Inhalation repeated

- d

ose toxicity study in rats

Title: Inhalation of tetramethyllead and tetraethyl lead

The study is: Adequate Not Adequate

The exposure regimen and parameters investigated were non

- standard.

TEST SUBSTANCE

Ident ity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: 99.3% purity; supplied by the Ethyl Corporation.

METHOD

Method/guideline followed: Not specified

Test type: R epeated

- dose toxicity

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1963

Test species: CFN rats obtained from Carworth Farms, NY; 3 months old at test initiation

Number of animals/sex/dose: 10/sex/concentration for control group; 5/sex/concentration for

treated groups

Route of administration: Inhalation

Vehicle: Air

Exposur e duration: 0 and 12 mg/m 3 : 150 7

- hour exposure periods; 22 mg/m 3 :14 7

- hour

exposure periods; 46 mg/m 3 : 5 7

- hour exposure periods.

Doses/concentrations tested: 0, 12, 22, or 46 mg/m 3

Statistical methods used: Not stated

Test method/conditions remarks : The vapor was generated by bubbling dry nitrogen through

the liquid contained in a glass cylinder fitted with sintered disks for dispersing the gas through

the liquid. Rats were confined in 32

- liter glass bell jars. The vapor and supplemental air were

introduced at a rate of 32 liters/minute. Three or more samples of test atmosphere were taken

during each 7

- hour period of exposure.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

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74 Tissues and excreta were analyzed for lead content, and pathological changes in viscera were

investigated.

RESULTS

Endp oint value(s): None specified

Results remarks: At 22 mg/m 3 , 4/5 males and 5/5 females died. At 46 mg/m 3 , 3/5 males and

5/5 females died. There were no mortalities at 0 and 12 mg/m 3 . Clinical signs included

irritability when handled, uncoordinated movem ents, combativeness, convulsions, and coma

followed by death. Tetraethyl lead was found to be concentrated mostly in the lungs, liver, and

kidneys; the lead content in the brain was 10 μg/g (exposure concentration not specified).

Pathological findings in cluded brain damage (neocortex, medulla oblongata, and brain stem),

including cell shrinkage, vacuolization, and extended neuronal necroses with glioses in both

hemispheres of the brain; swollen hepatocytes; swelling and necrosis of the proximal renal

tubu les; and hemorrhages and inflammation of the lungs.

CONCLUSIONS

Tetraethyl lead was more toxic to rats than tetramethyl lead.

STUDY RELIABILITY

Klimisch code = [3]. Invalid. The exposure regimen and parameters investigated were non

standard.

REFER ENCE

Davis, R.K. et al. 1963. Inhalation of tetramethyllead and tetraethyllead: A comparison of the

effects in rats and dogs. Arch. Environ. Health, 6: 473

- 479.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

75 Study 7: Inhalation repeated

- dose toxicity study in dogs

Title: Inhalation of tetramet hyllead and tetraethyllead

The study is: Adequate Not Adequate

The exposure regimen, test species, and parameters investigated were non

- standard; additionally,

only one or two animals were tested per concentration.

T EST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: 99.3% purity; supplied by the Ethyl Corporation.

METHOD

Method/guideline followed: Not specified

Test type: R epeated

- dose toxicity

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1963

Test species: Purebred b eagle dogs, obtained from Cherry Hill Kennels, OH or Cornell Dog

Farm, NY; initial weight: 5.9 to 13.2 kg.

Number of animals/sex/dose: 0 and 12 mg/m 3 : 2/concentration, 22 and 42 mg/m 3 :

1/concentration; sex n ot specified

Route of administration: Inhalation

Vehicle: Air

Exposure duration: 0 mg/m 3 : more than 130 7

- hour exposures; 12 mg/m 3 : 24 and 29 7

- hour

exposure periods for a smaller (5.9 kg) and larger (10.2 kg) dog, respectively; 22 mg/m 3 :30 7

- hour expo sure periods; 42 mg/m 3 : 7 7

- hour exposure periods.

Doses/concentrations tested: 0, 12, 22, or 42 mg/m 3

Statistical methods used: Not stated

Test method/conditions remarks: The vapor was generated by bubbling dry nitrogen through

the liquid contained in a glass cylinder fitted with sintered disks for dispersing the gas through

the liquid. Dogs were subjected to the inhalation of the test item in insulated 600

- liter plywood

chambers which were supplied with air at a rate of 600 liters/minute; the air w as dehumidified toDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

76 50% relative humidity and the temperature was 77 to 81 oF. Three or more samples of test

atmosphere were taken during each 7

- hour exposure period.

Tissues and excreta were analyzed for lead content, and pathological changes in viscera w ere

investigated.

RESULTS

Endpoint value(s): None specified

Results remarks: It appears that all dogs died, although this is not explicitly stated in the report.

Clinical signs included tremors, muscle twitching, hyperactivity, and coma followed by dea th.

Tetraethyl lead was found to be concentrated mostly in the liver and kidneys. The lead

concentration in the brain was 2.0 μg/g (exposure concentration not specified). Pathological

findings included brain damage (neocortex, medulla oblongata, and bra in stem), including cell

shrinkage, vacuolization, and extended neuronal necroses with glioses in both hemispheres of the

brain; swollen hepatocytes; swelling and necrosis of the proximal renal tubules; and hemorrhages

and inflammation of the lungs.

CON CLUSIONS

Tetraethyl lead was more toxic to dogs than to rats.

STUDY RELIABILITY

Klimisch code = [3]. Invalid. The exposure regimen, test species, and parameters investigated

were non

- standard; additionally, only one or two animals were tested per conc entration.

REFERENCE

Davis, R.K. et al. 1963. Inhalation of tetramethyllead and tetraethyllead: A comparison of the

effects in rats and dogs. Arch. Environ. Health, 6: 473

- 479.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

77 B

- 6. GENETIC TOXICITY

– GENE MUTATION

Summary of endpoint: Adequat e for gene mutations; inadequate for chromosomal aberrations

Study 1: Mutagenicity study in Salmonella

Title: Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals

The study is: Adequate Not A dequate

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: Supplier: ICN Pharmaceuticals

METHOD

Method/guideline followed: According to Haworth et al. (1983)

Test type: Preincubation assay

GLP compliant?: Not specified

Year stu dy performed: 1986

Test species: Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 , obtained

from Dr. Bruce Ames

Metabolic activation: With and without

Concentrations tested: 0, 1.0, 3.3, 10.0, 33.3, 100 μg/plate with 95% ethanol as a solve nt; 0, 10,

33, 100, 333, 1000 μg/plate with DMSO as a solvent

Statistical methods used: The chemical was considered to be mutagenic if there was a dose

related, reproducible increase in the number of revertants over the background level, even if the

incr ease was less than two

- fold. If no increase in the number of revertants was observed, the

chemical was considered to be non

- mutagenic. The response was considered to be equivocal if

there was an absence of a clear

- cut dose

- related increase in revertants, if the dose

- related

increases in revertants were not reproducible, or if the response was of insufficient magnitude to

support a determination of mutagenicity.

Test method/conditions remarks:

Preparation of S

- 9 fraction: Male Sprague

- Dawley rats and mal e Syrian hamsters were routinely

used for the preparation of the liver fractions. Aroclor 1254 (200 mg/ m L in corn oil) was

administered i.p. at 500 mg/kg 5 days prior to decapitation or cervical dislocation . The animalsDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

78 were deprived of food for 12

- 24 h o u r s immediately preceding death; otherwise food and water

were provided ad libitum . The livers were removed aseptically, washed in ice

- cold 0.15 M KC l

, and minced and homogenized (3 m L of 0.15 M KC l per g of wet tissue) . The S

- 9 fraction was

obtained by centrifugation of the liver homogenate f or 10 min at 9,000 g at 4°C. The S

- 9 fraction

was dispensed into freezing ampoules and stored in a

- 70°C freezer, or in liquid nitrogen. The S

9 mix was prepared immediately prior to each assay and consisted of the fo llowing, per

milliliter: S

- 9 fraction, 0.10 mL ; 0.04 M MgC1 2 , 0.02 m L ; 1.65 M KC1, 0.02 m L ; 0.04 M P

nicotinamide adenine dinucleotide phosphate (NADP), 0.10 m L ; 0.05 M glucose

- 6

- phosphate,

0.10 m L ; 1.0 M NaH 2 P O 4 , (pH 7.4), 0.10 m L ; and distilled water, 0.56 m L

.

Preincubation assay: All chemicals were assayed for mutagenicity in the preincubation assay

. To each of 13 x 100

- mm test tubes maintained at 37 o C were added in the following order: 0.5

m L of S

- 9 mix or 0.1 M PO 4 buffer (pH 7.4), 0.05 m L of the overnight culture, and 0.05 m L of

solvent or chemical dilution. The mixture was mixed and allowed to incubate without shaking at

37 o C for 20 min, at which time 2.5 or 2.0 m L of molten ( 45°C) top agar supplemented with 0.5

rnM L

- histidine and 0.5 mM D

- biotin were added. The contents of the tubes were mixed and

poured onto 25 m L of minimal glucose bottom agar in 15 x 100

- mm plastic petri dishes . When

the top agar had solidified, the plates were inverted and incubated at 37 oC for 48 hours.

Concurre nt solvent and positive controls were tested with and without the metabolic activation

systems. At least five dose levels were tested, with three plates per dose level. All assays were

repeated (as described above) no less than 1 wk after completion of the initial test.

Controls: The following mutagens were used as concurrent positive controls in the absence of

activation : sodium azide for TA1535 and TA100, 4

- nitro

- o

- phenylenedia m ine for TA98, and 9

-

aminoacridine for TA97 and TA1537; 2

- a m inoanthracene was used with all strains with hamster

and rat liver metabolic activation systems.

RESULTS

Genotoxicity result: Negative with and without metabolic activation

Cytotoxic concentration (if applicable): Slight cytotoxicity at 100 μg/plate in 95% ethanol

Res ults remarks: Positive and negative controls responded appropriately

CONCLUSIONS

None specified

STUDY RELIABILIT Y

Klimisch code = [1]. Reliable without restrictions.

REFERENCEDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

79 Mortelmans et al. 1986. Salmonella Mutagenicity Tests: II. Results Fr om the Testing of 270

Chemicals. Environmental Mutagenesis, 8 (Suppl. 7): 1

- 119.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

80 B

- 7. REPRODUCTIVE TOXICITY

Study 1: Reproductive toxicity study in mice

Summary of endpoint: Adequate. Although the reproductive study of tetraethyl lead in mice

(Stu dy 1) is not adequate, sufficient, reliable studies on the neurodevelopmental toxicity of lead

, as reviewed in the U.S. EPA document Air Quality Criteria for Lead, Vol I of II (U.S. EPA

2006), exist to support a determination of adequacy for the reproducti ve toxicity endpoint based

on a weight

- of

- evidence approach.

Reference: U.S. EPA 2006. Air Quality Criteria for Lead. Volume I of II. EPA/600/R

5/144aF, October 2006. Available on

- line at

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=158823#Download

Title: Not specified

The study is: Adequate Not Adequate

The IUCLID summary, which is mostly in a language other than Engl ish, does not contain

sufficient information to assess data adequacy.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: None specified

METHOD

Method/guideline followed: Not specified

Test type: Fertility study

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1971

Test species: Mouse

Number of animals/sex/dose: Not specified

Route of administration: Oral feed

Exposure duration: Not specified

Doses/concentrations tested: 6.48, 32 mg/kgDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

81 Vehicle: Not specified

Statistical methods used: Not specified

Test method/conditions remarks: The IUCLID summary of the study was mostly in a language

other than English.

RESULTS

Endpoint value(s): Not specified

Results remarks: The IUCLID summary of the study was mostly in a language other than

English.

CONCLUSIONS

The IUCLID summary of the study was mostly in a language other than English.

STUDY RELIABILITY

Klimisch code = [ 4 ]

. Not assignable. The IUCLID summary, which is mostly in a language

other than English, do es not contain sufficient information to assess data adequacy.

REFERENCE

Primary reference (unavailable): Kennedy, G.L. and D. Arnold. 1971. Newsletter Environ Mut

Soc 5: 370.

Secondary reference: IUCLID Dataset for CAS No. 78

- 00

- 2, available at

http://ecb.jrc.ec.europa.eu/esis/Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

82 B

- 8. DEVELOPMENTAL TOXICITY

Summary of endpoint: Adequate

Study 1: Developmental toxicity study in mice

Title: Teratogenic evaluation of lead compounds in mice and rats

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: 98% pure, supplied by Houston Chemical Company, Freeport, TX

METHOD

Method/guideline followed: Not speci fied

Test type: Teratogenicity

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1975

Test species: CD

- 1 random

- bred albino female mice, impregnated at the Charles River Breeding

Laboratories, Wilmington, MA

Number of animals/sex/dose: 20

Route of administration: Oral gavage

Exposure duration: Gestation day 5 to 15

Doses/concentrations tested: 0, 0.01, 0

. 1, 1.0

, and 10 mg /kg

Vehicle: Corn oil

Statistical methods used: Not specified

Test method/conditions remarks: Animals received or al gavage doses daily from gestation day

5 through 15. Animals were weighed daily. Due to the toxicity observed at 10 mg/kg, treatment

at this level was discontinued after 3 daily doses. Animals were sacrificed by cervical

dislocation on day 18 of gesta tion and the uterine horns were examined for implantation sites,

resorption sites, and viable fetuses. A complete examination of each fetus was conducted and,Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

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83 following removal of excess amniotic fluid, each was weighed. Fetuses were divided into two

equ al groups (randomly assigned in each litter) for evaluation of skeletal development or of

internal development.

RESULTS

Endpoint value(s): None specified, but the LOAEL appears to be 1 mg/kg for systemic toxicity

(based on weight loss) and for developmen tal toxicity (increased number of resorptions and

decreased fetal growth). The NOAEL for teratogenicity appears to be 10 mg/kg, the highest

dose level tested.

Results remarks: Animals given up to 0.10 mg/kg showed no clinical signs and displayed

normal w eight gains during pregnancy. Mice treated with 1 mg/kg gained 25% less weight

during gestation than controls. Mice exhibited hypoactivity, tremors, and convulsions along with

severe body weight loss after 3 daily doses of 10 mg/kg, and subsequent dosing was

discontinued.

The number of pregnancies was sharply reduced in mice given 10 mg/kg (5 pregnant females,

compared to 16 in control group). Many of these high

- dose females were observed to be full of

brown liquid without any traces of fetal tissues. The mean number of resorption sites per female

was 0.8, 0.7, 0.9, 2.1, and 1.6 at 0 (vehicle control), 0.01, 0.1, 1.0, and 10 mg/kg, respectively.

The mean number of fetuses/litter was 10.9, 11.7, 11.9, 10.2, and 10.0 at 0 (vehicle control),

0.01, 0.1, 1. 0, and 10 mg/kg, respectively.

No evidence for a teratogenic response to lead was obtained from the gross examination of mice.

Three of 362 fetuses (0.8%) displayed external anomalies, consisting of one exencephaly, one

runt, and one cleft palate. Three abnormal fetuses, all displaying torsion of the rear limbs, were

recovered from one litter at 0.10 mg/kg. Skeletal examination revealed slight delays in

ossification in fetuses from females exposed to 1 or 10 mg/kg. Internal evaluation revealed no

significant effects.

Growth of fetuses, as indicated by terminal body weights, was reduced at d oses ≥ 1.0 mg/kg.

CONCLUSIONS

It is concluded that no teratogenic response is produced in mice following in utero exposure to

maximally tolerated doses of tetraethyl lead.

STUDY RELIABILITY

Klimisch code = [2]. Reliable with restrictions. Apparently, no statistical evaluation of

teratogenicity data was performed.

REFERENCE

Kennedy, G.L. et al. 1975. Teratogenic evaluation of lead compounds in mice and rats. FoodDraft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

84 Cosmet. Toxicol., 13: 629

- 632.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

- 2

85 Study 2: Developmental toxicity study in rats

Titl e: Teratogenic evaluation of lead compounds in mice and rats

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: 98% pure, supplied by Houston Chemical Compan y, Freeport, TX

METHOD

Method/guideline followed: Not specified

Test type: Teratogenicity

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1975

Test species: COBS random

- bred albino female rats, impregnated at the Charles River Breedin g

Laboratories, Wilmington, MA

Number of animals/sex/dose: 20

Route of administration: Oral gavage

Exposure duration: Gestation day 6 to 16

Doses/concentrations tested: 0, 0.01, 0

. 1, 1.0

, and 10 mg /kg

Vehicle: Corn oil

Statistical methods used: Not specified

Test method/conditions remarks: Animals received oral gavage doses daily from gestation day

6 through 16. Animals were weighed daily. Due to the toxicity observed at 10 mg/kg, treatment

at this level was discontinued after 3 daily doses. Anim als were sacrificed by cervical

dislocation on day 20 of gestation and the uterine horns were examined for implantation sites,

resorption sites, and viable fetuses. A complete examination of each fetus was conducted and,

following removal of excess amniot ic fluid, each was weighed. Fetuses were divided into two

equal groups (randomly assigned in each litter) for evaluation of skeletal development or of

internal development.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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86 RESULTS

Endpoint value(s): None specified, but the LOAEL appears to be 1 mg/kg f or systemic toxicity

(based on weight loss) and for developmental toxicity (increased number of resorptions and

decreased fetal growth). The NOAEL for teratogenicity appears to be 10 mg/kg, the highest

dose level tested.

Results remarks: Animals given up to 0.10 mg/kg showed no clinical signs and displayed

normal weight gains during pregnancy. Rats treated with 1 mg/kg gained 70% less weight

during gestation than controls. Rats exhibited hypoactivity, tremors, and convulsions along with

severe body weig ht loss after 3 daily doses of 10 mg/kg, and subsequent dosing at this dose level

was discontinued.

The number of pregnancies was sharply reduced in rats given 10 mg/kg (7 pregnant females,

compared to 16 in control group). Many of these high

- dose female s were observed to be full of

brown liquid without any traces of fetal tissues. The mean number of resorption sites per female

was 0.8, 0.7, 0.9, 2.3, and 1.2 at 0 (vehicle control), 0.01, 0.1, 1.0, and 10 mg/kg, respectively.

The mean number of fetuses/ litter was 11.5, 11.9, 11.9, 10.5, and 9.9 at 0 (vehicle control), 0.01,

0.1, 1.0, and 10 mg/kg, respectively.

One fetus at 0.01 mg/kg was non

- viable, and one fetus at 0.10 mg/kg had malrotation of a

hindlimb. All other fetuses appeared normal, ind icating a lack of a teratogenic response. No

internal findings were observed in fetuses. Upon skeletal examination, delayed ossification was

seen in offspring at 10 mg/kg.

Growth of fetuses, as indicated by terminal body weights, was reduced at doses ≥ 1.0 mg/kg.

CONCLUSIONS

It is concluded that no teratogenic response is produced in rats following in utero exposure to

maximally tolerated doses of tetraethyl lead.

STUDY RELIABILITY

Klimisch code = [2]. Reliable with restrictions. Apparently, no st atistical evaluation of

teratogenicity data was performed.

REFERENCE

Kennedy, G.L. et al. 1975. Teratogenic evaluation of lead compounds in mice and rats. Food

Cosmet. Toxicol., 13: 629

- 632.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

- 00

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87 Study 3: Developmental toxicity study in rats

Title: Eff ects of organolead compounds on rat embryonic and fetal development

The study is: Adequate Not Adequate

The duration of exposure was insufficient; the OECD

- recommended duration extends from

gestation day 6 to 15 for r odents.

TEST SUBSTANCE

Identity: Tetraethyl lead, CAS No. 78

- 00

- 2

Remarks: >99% pure; provided by The Ethyl Corporation, Ferndale, MI

METHOD

Method/guideline followed: Not specified

Test type: Developmental toxicity

GLP compliant?: The study pre

- dates GLP.

Year study performed: 1972

Test species: Pregnant Simonsen Sprague

- Dawley rats

Number of animals/sex/dose: 3 to 8/group

Route of administration: Oral gavage

Exposure duration: Gestation day 9

- 11 or 12

- 15

Doses/concentrations tested: 0

, 7.5, 15, or 30 mg/kg

Vehicle: Corn oil

Statistical methods used: Statistical analyses were made by binomial expansion. Quantitative

data were analyzed by ANOVA and individual means compared using the group t

- test.

Test method/conditions remarks: Ani mals received oral gavage doses daily from gestation

days 9 through 11, or gestation days 12 through 14. Rats were sacrificed on gestation day 22 and

the total number and position of live, dead, or resorbed fetuses were recorded. Fetuses were

weighed and examined for gross malformations; the transumbilical and crown

- rump lengths

were measured. One half of each litter was placed in alcohol and the other half in Bouin

solution. Soft tissue and skeletal examinations for anomalies were performed.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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88 RESULTS

Endpoint value(s): None specified, but the LOAEL appears to be 7.5 mg/kg for systemic

toxicity (based on weight loss) and for developmental toxicity (based on decreased fetal body

weights).

Results remarks: Clinical signs of toxicity ranged from hyperex citability and weight loss at

lower levels to tremors, aggressiveness, spasticity, and paralysis at higher dose levels. The

highest dose level resulted in death of all dams. At 30 mg/kg, 5/5 rats dosed on days 9 through

11 died, and 4/4 rats dosed on days 12

- 14 died. One rat dosed at 15 mg/kg on days 12

- 14 also

died.

An increased number of resorbed fet uses was observed at the highest dose level allow ing

survival (15 mg/kg) with tetraethyl lead administered on days 9, 10, and 11 of gestation.

Retardatio n of fetal growth was also evident. Body weights of fetuses were significantly

decreased, compared with controls, at 7.5 and 15 mg/kg (for both dosing periods). Chan ges in

transumbilical and crow n

- rump length and the length of the long bones in the fetus paralleled

changes in body weight. Growth

- retarded fetuses were otherwise norm al in external appearance.

No gross malformation was observed in any control or treated fetus. There were no gross

deformities of skeletal structures and no significant soft t issue malformations.

CONCLUSIONS

It was concluded that the observed embryotoxic and fetal toxic effects were secondary to the

maternal toxicity rather than a direct effect of tetraethyl lead on the developing rat.

STUDY RELIABILITY

Klimisch code = [3] . Not reliable. The duration of exposure was insufficient; the OECD

recommended duration extends from gestation day 6 to 15 for rodents. Additionally, d ata for

transumbilical and crown

- rump length were not provided.

REFERENCE

McClain, R.M. and B.A. Bec ker. 1972. Effects of organolead compounds on rat embryonic and

fetal development. Toxicol. Appl. Pharmacol., 21: 265

- 274.Draft HPV4 Chemical Data Adequacy Review CAS No. 78

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89 B

- 9. CAS No. 78

- 00

- 2: Summary of Endpoints

Endpoint Study Information

Available Acceptable Data Gap

Aquatic Effects

Acute Toxicity to Fish Yes Yes No

Acute Toxicity to Daphnia Yes 1 Yes No

Toxicity to Aquatic Plants Yes No Yes

Health Effects

Acute Toxicity Yes Yes No

Repeated

- Dose Toxicity Yes No Yes

Gene Mutation Yes Yes No

Chromosomal Aberrations No

- Yes

Reproductiv e Toxicity Yes 2 Yes No

Developmental Toxicity Yes Yes No

1 No studies of plumbane, tetraethyl on Daphnia were located; however

, three studies were

located on other aquatic invertebrate species. These studies tended to indicate h igh toxicity to

aquatic invertebrates.

2 Although the reproductive study of tetraethyl lead in mice (Study 1) is not adequate, sufficient,

reliable studies on the neurodevelopmental toxicity of lead, as reviewed in the U.S. EPA

document Air Quality Criter ia for Lead, Vol I of II (U.S. EPA 2006), exist to support a

determination of adequacy for the reproductive toxicity endpoint based on a weight

- of

- evidence

approach.

Reference: U.S. EPA 2006. Air Quality Criteria for Lead. Volume I of II. EPA/600/R

5/ 144aF, October 2006. Available on

- line at

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=158823#Download