UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

Tuesday, March 30 , 2010

MEMORANDUM

SUBJECT: Acute Toxicity Review for EPA Reg. No.: 85808

- R

- STABICIDE 71

DP Barcode: 373957

FROM: Leon Johnson, Biologist

Chemistry and Toxicology Team

Product Science Branch

Antimicrobials Division (7510P)

THRU : Karen Hicks, Team Leader

Chemistry and Toxicology Team

Product S cience Branch

Antimicrobials Division (7510P)

TO: Marshall Swindell, PM 33/ Demson

Regulatory Management Branch

Antimicrobials Division (7510P)

Applicant: Schulke & Mayr GmBH

Robert

- Koch

- Str. 41

22851 Norderstedt

Germany

FORMULATION FROM LABEL:

Active Ingredient(s) : % by wt.

N , N’

- methylenebis ( 5

- methyloxazolidin ) 99.09

Other Ingredient( s) : 0.91

Total: 100.001) BACKGROUND :

Schulke & Mayr GmbH has applied for registration of their new Industrial Bactericide

product STABICIDE 71 “ EPA Reg. No. 85808

- R “. Schulke & Mayr has re submitted

the acute oral toxicity stu dy (MRID 479596

- 01 ) and the acute dermal toxicity study

(MRID 479596

- 02 ) in response to acute toxicity data deficiences noted in a

previously submitted acute oral and dermal toxicity study.

2) RECOMMENDATIONS: PSB findings are:

a) The acute oral toxici ty study MRID# 479596

- 01 is acceptable.

b) The acute dermal toxicity study MRID# 479596

- 02 is acceptable.

c) MBO is a new active ingredient and EPA does not have any data to support the

acute inhalation claim. MBO has the potential to be aerosolized and inhaled and

therefore there is the potential for deep lung deposition by the handler. This

scenario could lead to a more toxic effect being caused by MBO lower in the

respiratory tract. Depending on MBO particle size, it may be possible for the

particles to reach the deep lung before they hydrolyze. A waiver for the acute

inhalation toxicity study is denied.

d) The primary eye irritation study does not meet the requirements of GLP and

differs in the following ways:

i. No Study Director

ii. No Quality Assur ance inspections performed

There are a number of issues with the primary eye irritation study. However, the

lab has assessed the product as being severely irritating to the eye and this would

place the product in category one for toxicity. This clas sification is acceptable for

registering this product.

e) The primary skin irritation study does not meet the requirements of GLP and

differs in the following ways:

i. No study Director

ii. No Quality Assurance inspectio ns were performed

There are a number of concerns about the primary skin irritation study.

However, the lab has assessed the product as being severely irritating to the

Skin and this would place the product in c ategory one for toxicity. This

Classification is acceptable for registering this product.

f) The dermal sensitization is acceptable.The acute toxicity profile for File Symbol 85808

- R is currently:

Study MRID Number To xicity

Category Status

Acute Oral Toxicity 475972

- 03 III A cceptable

Acute Dermal Toxicity 47597204 II A cceptable

Acute Inhalation Toxicity Waiver Request

- Denied

Primary Eye Irritation 475972

- 05 I Acceptable

Primary Skin Irritation 475972

- 05 I Sel f

- validated

Dermal Sensitization 475972

- 06 Non

- sensitizer Acceptable

3) PRECAUTIONARY LABELING:

Precautionary labeling for MBO cannot be determined until the acute inhalation

toxicity study has been satisfied.DATA REVIEW FOR ACUTE ORAL TOXICITY TESTING (§ 81

- 1, 870.1100)

(ACUTE TOXI C CLASS METHOD)

Testing Laboratory : Laboratory for Pharmacology and Toxicology, Hamburg, Germany

Study Director : Dr. Phil Leuschner

Quality Assurance (40 CFR §160.12) : A Quality Assurance (QA) statement was

included. A Good Laboratory Compliance Statement was included, st a ting that this study

meets the requirements of 40 CFR PART 160. This study was performed according to:

Good Laboratory Practice’ Regulations of the EC enacted in Germany in the’

Chemikaliengesetz [ Chemicals Act ] curr ent edition; United States Food and Drug

Administration Good Laboratory Practice Regulations

- 21 Code of Federal Regulations,

Part 58, current edition. The following regulations were also considered ‘ OECD

Principles of Good Laboratory Practice’ ( as revis ed in1997 ) ENV/MC/CHEM (98) 17,

January 21 st , 1998

.

Test Material : N,N

- Methylene

- bis(5

- methyloxazolidine)

(batch no. 24773) ( clear, colourless liquid )

Dosage : 200 and 2000 mg/kg b.w.

Species : 12 rats, Sprague

- Dawley

Sex : 6 Males and 6 Females

Age : Males: 36 days old; Females: 48 days old

Weight : Males: 183

- 197grams, Females:173

- 187grams

Source : Charles River Deutschland GmbH ,Sandhofer Weg 7,D

- 97633 Sulzfeld

Housing : Temperature Range : 22° C ± 3°

Relative Humidity : 55± 15%

Photoperiod : 150 lux at approx.1.5 m room height/darkened for 12 hours

Acclimation : at least 5 days

Conclusion :

1. Acute Oral LD 50 (mg/kg) : Male and Female Rats 632 mg/kg

2. Toxicity Category : III Classificat ion : acceptable

Procedure (Deviations from §81

- 1) :

No procedure deviations noted. Produc t Manager : Marshall Swindell Reviewer : Leon Johnson

MRID No. : 479596

- 01 Study Completion Date : Mar. 07, 2002

Lab Study No. : 14816/01Results :

Dosage (mg/kg) (Number Deaths/Number Tested)

Males Females Combined

2000 3/3 3/3 6/6

200 0/3 0/3 0/6

Observati ons :

200 mg/kg Dose level (6 animals ): All animals survived. No signs of intolerance

reactions were noted.

2000 mg/kg Dose level ( 6 animals ) : All animals died. Reduced motility, ataxia,

reduced muscle tone and dysponea were exhibited between 15 minut es and 24 hours.

Gross Necropsy :

Gross necropsy revealed no specific pathological findings.DATA REVIEW FOR ACUTE DERMAL TOXICITY TESTING (§81

- 2, 870.1200)

Testing Laboratory : Laboratory for Pharmacology and Toxicology, Hamburg, Germany

Author : Dr. Phil Leuschner

Quality Assurance (40 CFR §160.12) : A Quality Assurance (QA) statement was

in cluded. A Good Laboratory Compliance Statement was included, stating that this study

meets the requirements of 40 CFR PART 160. This study was performed according to:

Good Laboratory Practice’ Regulations of the EC enacted in Germany in the’

Chemikalienges etz [ Chemicals Act ] current edition; United States Food and Drug

Administration Good Laboratory Practice Regulations

- 21 Code of Federal Regulations,

Part 58, current edition. The following regulations were also considered ‘ OECD

Principles of Good Labor atory Practice’ ( as revised in1997 ) ENV/MC/CHEM (98) 17,

January 21 st , 1998.

Test Material : N,N

- Methylene

- bis(5

- methyloxazolidine)

(batch no. 24773) ( clear, colourless liquid )

Dosage : 200 mg/kg, 750mg/kg and 2000 mg/kg b.w.

Species : 30 rats, Sprag ue

- Dawley

Sex : 15 Males and 15 Females

Age : Males: 33 days to 43 days old; Females:44 days to 56 days old

Weight : Males: 215

- 267grams, Females:198

- 230grams

Source : Charles River Deutschland GmbH,Sandhofer Weg 7,D

- 97633 Sulzfeld

Hou sing : Temperature Range : 22° C ± 3°

Relative Humidity : 55± 15%

Photoperiod : 150 lux at approx.1.5 m room height/darkened for 12 hours

Acclimation : at least 5 days

Summary :

1. LD 50 (mg/kg) :

2. The estimated LD 50 is 1700 mg/kg at 24 hours and 790 mg/kg at 14 days

3. Tox. Category : II Classification : Acceptable Product Manager : Marshall Swindell Reviewer : Leon Johnson

MRID No. : 479596

- 02 Study Compl etion

Date : Mar 07, 2002

Lab Study No. : 14817/01

Males= 1700@24 hours, 1200@ 14 days

Females= >2000@ 24 hours, 760@14 day s

Combined= 1700@24 hours, 790@ 14 daysProcedure (Deviation From §81

- 2) :

No procedure deviations noted.

Results :

Reported Mortality

DOSAGE

(mg/kg) (NUMBER DEATHS/NUMBER TESTED)

Males Females Combined

250 0/5 0/5 0/10

750 0/5 1/5 1/10

2000 5/5 5/5 10/10

Observations : 250 mg/kg Dose Level ( 10 animals ):

A ll animals survived. No sign s of intolerance reactions were noted.

750 mg/kg Dose Level ( 10 animals ):

Males and females exhibited signs of reduced motility, ataxia, dyspnoea and muscle

tonus. One female died by day one.

2000 mg/kg Dose Level ( 10 animals ):

All animals died . Males and females exhibited reduced motility, ataxia, tremors and

dyspnoea by day one.

Gross Necropsy Findings :

250 mg/kg Dose Level ( 10 animals ):

G ross necropsy revealed no abnormalities.

750 mg/kg Dose Level ( 10 animals ):

G ross necropsy reve aled no abnormalities.

2000 mg/kg Dose Level ( 10 animals ):

G ross necropsy revealed no abnormalities in males and severe necrosis in two females.