### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

**Antimicrobials Division (AD)**

Friday, October 14, 2011

MEMORANDUM

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

- R

DP Barcode: D393665

Product Name: Stabicide 71

From: Ian Blackwell, Biologist

Chemistry and Toxicology Team

Product Science Branch

Antimicrobials Division (7510P)

Through: Karen Hicks, Team Leader

Chemistry and Toxicology Team

Product Science Branch

Antimicrobials Division (7510P)

To : Marshall Swindell, PM 33/ Demson Fuller

Regulatory Management Branch

Antimicrobials Division (7510P)

Applicant: Schulke & Mayr GmbH

FORMULATION FROM LABEL:

Active Ingredient(s) : % by wt.

N , N’

- methylenebis (5

- methyloxazolidin) (MBO) 99.09

Other Ingredient(s) : 0.91

Total: 100.00

### I BACKGROUND : Schulke and Mayr GmbH have submitted a supplement to an

acute inhalation toxicity study that the Chemistry and Toxicology Team (CTT)

reviewed on 4/20/2011. The results of that 4/20 /2011 revi ew were:

Study MRID Number Toxicity

Category Status

Acute Oral Toxicity 475972

- 03 III Acceptable

Acute Dermal Toxicity 475972

- 04 II Acceptable

Acute Inhalation Toxicity 482860

- 02 ? Supplementary

Primary Eye Irritation 475972

- 05 I Acceptable

Primary S kin Irritation 475972

- 05 I Acceptable

Dermal Sensitization 475972

- 06 Non

- sensitizer Acceptable

The acute inhalation toxicity study was graded supplementary (needing the

submission of additional information before it could be accepted) due to the

followi ng:

A. The report does not state whether the test material was tested neat or diluted.

The registrant needs to clarify this.

B. The size of the exposure chamber was not reported.

C. The lab did not conduct the assay by analyzing the chamber concentration of t he

active ingredient, N, N’

- methylenebis (5

- methyloxazolidin). Instead the report

states, “Formaldehyde was used as the lead compound for analysis.” We do

realize that MBO is a reaction product from paraformaldehyde and 2

- hydroxypropylamine. CTT knows from the Product Chemistry review of 85808

- R, that one method of measuring MBO concentration is by reacting it with

hydroxylamine hydrochloride. The report does not state how the assay went

from measuring the atmospheric aerosol concentration 85808

- R to h aving gaseous

formaldehyde in the impingers. These things need to be clarified.

D. The test facility did not determine the Mass Median Aerodynamic Diameter

(MMAD) of the aerosol. The report appears to state that due to evaporation of

the aerosolized produc t, they could not measure the MMAD. CTT does not

understand why they could determine a test material concentration (mg/L), but,

could not determine an MMAD. The lab needs to explain this.

E. As there was an issue with vaporization of the aerosol, CTT must ask if the lab

intentionally vaporized the test material for testing.

To correct the study deficiencies listed above, Schulke and Mayr GmbH consultant

Technology Sciences Group has submitted a revised version (dated 9/1/2011) of the

acute inhalation toxi city study. The original MRID Number was 482860

- 02. The

MRID Number of the revised report is 485945

- 01.

### II RECOMMENDATIONS :

1. The acute inhalation toxicity study is unacceptable. The specific study deficiency

causing the rejection is that the laboratory did not conduct a particle size analysis

for this study. Agency guideline OPPTS 870.1300 states, “During the

development of the generating system, particle size analysis should be performed

to establish the stability of aerosol concentrations. The MMAD p article size range

should be between 1

- 4 μm.” This study did not assess the MMAD or any other

form of particle size analysis of the aerosol generated in this study

.

A. The report states, “After spraying parts of the solution immediately

evaporate. When co llecting the particle fractions of filters or impactor foils

the semi

- volatile nature of the inhalation atmosphere results in significant

loss of the particle mass and therefore leads to false results.” The product

chemistry data for this product (MRID Nu mber 475972

- 02) reports the

boiling point of this product as 204°C. With a boiling point this high, it is a

non sequitur that the product would vaporize at the tested temperature of

22°C.

B. CTT received a telephone call from a representative of Schulke an d Mayr

GmbH, Zuhal Thompkins. Ms. Thompkins stated that due to guideline

Agency guideline 830.7520, the laboratory felt that an MMAD was not

required for this acute inhalation toxicity study. This explanation is not

acceptable as 830 guidelines clearly a pply to Product Chemistry studies, not

acute toxicity studies.

The registrant must properly address the data gap for the acute inhalation toxicity

to support 85808

- R.

The acute toxicity profile for File Symbol 85808

- R is currently:

Study MRID

Numbe r Toxicity

Category Status

Acute Oral Toxicity 475972

- 03 III Acceptable

Acute Dermal Toxicity 475972

- 04 II Acceptable

Acute Inhalation Toxicity 482860

- 02 ? Data Gap

Primary Eye Irritation 475972

- 05 I Acceptable

Primary Skin Irritation 475972

- 05 I Acce ptable

Dermal Sensitization 475972

- 06 Nonsensitizer Acceptable



### III LABELING :

1. The Signal Word is “DANGER”, based upon the results of the primary eye and

skin irritation studies.2. Other than the Signal Word, CTT cannot prescribe Precautionary labeling fo r File

Symbol 85808

- R. The registrant must correct the lack of an acute inhalation

toxicity

.DATA REVIEW FOR ACUTE INHALATION TOXICITY (§81

- 3, 870.1300)

Testing Laboratory : Fraunhofer Institute for Toxicology and Experimental Medicine

Author : Prof. Dr. Dr. U Heinrich

Quality Assurance (40 CFR §160.12) : Included

Test Material : Stabicide 71, (Grotan OX)

Concentration : 0.543 and 1.189 mg/L

Species : Wistar rats, Crl:WI(WU)

Weight : Males= 241.9

- 302.7 g Females= 188.1

- 197. 8 g

Age : 8

- 10 weeks

Source : Charles River Deutschland

Summary :



### 1. LC 50 

### (mg/L) Males=

Females=

Combined=

2. The estimated LC 50 

### is

3. MMAD: μm

4. Toxicity Category: Classification: Unacceptable

Procedure (Deviation From §81

- 3) :

• No particle size determination was conducted.

Results :



### Reported Mortality

Exposure Concentration (NUMBER DEATHS/NUMBER TESTED)

Males Females Combined

0.543 (nominal=1

. 022) 0/3 0/3 0/6

1.189 (nominal=2.038) 3/3 0/3 3/6 Product Manager : 33 Reviewer : I. Blackwell

MRID No. : 485945

- 01 Revised Final Report Date : 9/1/2011

Lab Study No. : 02 G 10026Chamber Atmosphere

Dose Level MMAD GSD particles < μm

0.543 mg/L ? μm ? μm Not determined

1.189 mg/L ? μm ? μm Not determined

Chamber Environment

Chamber Volume Not reported Not reported

Airflow 17.6 L/min. 17.6 L/min.

Temperature 21.3 ± 0.1 o C 21.3 ± 0. 1 o C

Relative Humidity 61.2 ± 0.7% 63.1 ± 0.6%

Clinical Observations : Salivation, stains around mouth, coat soiled, gasping,

respiratory sounds, general condition bad, abdominal breathing.

Gross Necropsy Findings : Lungs showing areas that were r ead, partly red, spongy

and/or glassy.