Page 2 of 10 

1.0 Action Requested

The Antimicrobial Division’s (AD) Regulatory Management Branch I has requested that 

the Risk Assessment and Science Support Branch (RASSB) conduct exposure and risk 

assessments to support Lubrizol’s application for registration of Contram ST-1, which 

contains a new active ingredient N,N-Methylenebismorpholine (MBM). RASSB was also 

requested to review a worker exposure study (MRID 475558-31, UK Exposure Study) that 

was submitted by Lubrizol to support this registration. 

2.0 Summary of Findings 

The submitted data in conjunction with the data available from the literature appears to 

suggest that formaldehyde exposures from the use of Contram ST-1 in metal working fluids 

(MWF) will not exceed the EPA level of concern of 100 ppb. However, this preliminary 

conclusion is based on the assumption that the Lubrizol study was conducted under typical 

machine shop conditions. It is recommended that additional formaldehyde samples be 

collected in a several additional machine shops to verify the extremely low levels of 

formaldehyde measured during the Lubrizol study. These samples should be collected using 

sampling times of 10-15 minutes each so that results will be comparable to the LOC of 100 

ppb which is a peak value. A protocol should be submitted to EPA for review prior to the 

initiation of the study. 

 

If additional sampling indicates that formaldehyde exposures exceed the LOC under 

typical machine shop conditions, then engineering controls such as machine enclosures and 

local exhaust ventilation will be required. It will also be necessary to collect additional 

sampling to verify the performance of the machine enclosures because such systems were 

often designed for the control of oil mist and were not intended to control formaldehyde 

vapors. This is particularly true for machine enclosures connected to mist elimination 

systems where the air is recirculated back into the work area after passing through a filtration 

unit. While such systems can be effective for trapping aerosols that consist of oil mist and 

typical biocides that are essentially non-volatile, these systems are not effective for volatile 

biocides such as formaldehyde unless they are vented to the outside. 

3.0 Product Use Profile 

Contram ST-1 is a formaldehyde releasing preservative that contains a new active 

ingredient, MBM (purity of 98.5% a.i., 14 to 16% available formaldehyde). It is proposed for 

use as a preservative to control non-public health bacteria and some fungi in MWF. It is 

intended to be distributed to mixers of MWF concentrates and will be added to these 

concentrates at a rate of approximately 3.0 percent. The concentrate, which is considered to 

be a treated article, will then be sold to machine shops and diluted on site to a maximum end 

use concentration of 2000 ppm Contram ST-1 or 300 ppm free formaldehyde. 
Page 3 of 10 

4.0 Summary of Toxicological Endpoints 

MBM Acute Toxicity

Three of the six required acute toxicity studies have been submitted for MBM and their 

results are summarized in Table 1. 

Table 1 - Acute Toxicity Values for MBM 

MRID Test (species) Result Toxicity 

Category 

475713-02 Oral Toxicity (rat) LD50 - >500, <2000 mg/kg/day III 

No study submitted Dermal Toxicity (rabbit) N/A N/A 

No study submitted Inhalation Toxicity (rat) N/A N/A 

No study submitted Eye Irritation (rabbit) N/A N/A 

475713-03 Skin Irritation (rabbit) Corrosive I 

475713-04 Dermal sensitization (guinea pig) Not a Dermal sensitizer N/A 

MBM Subchronic/Chronic Toxicity

 The two submitted studies for subchronic/chronic toxicity are included in Table 2. Both 

of these studies involved oral dosing, however, and are not relevant for the assessment of the 

proposed MWF use because MWF exposures occur primary via the dermal and inhalation 

routes. For this reason and because MBM releases formaldehyde, endpoints for the 

assessment of the parent MBM dermal and inhalation exposures were not selected. Instead, 

the risk assessment of the proposed use was based on formaldehyde endpoints as discussed in 

the formaldehyde toxicity section below. 

Table 2 - Toxicology Profile for N,N-Methylenebismorpholine (MBM)

Study Doses Tested 

(mg/kg/day) 

NOAEL 

(mg/kg/day) Toxicological Effects 

Oral Prenatal 

Developmental 

-Rabbit 

(475713-07) 

0, 

10, 

30, 

100 

10 (maternal) 

100 (developmental) 

Maternal – treatment related stomach effects including 

erosion and granular aspect was observed at the LOAEL of 

30 mg/kg/day. 

Developmental – no effects were observed at the highest 

dose tested. 

90 day Oral 

Toxicity, 

Gavage – Rat 

(475713-05) 

(475713-06) 

0, 

5, 

15, 

50, 

250/150 

15 Microscopic changes to the non-glandular stomach were 

observed at the LOAEL of 50 mg/kg/day. 

 

Formaldehyde Toxicity 

Table 3 summarizes the toxicological endpoints for formaldehyde which are described in 

more detail in following memorandum: "Formaldehyde/Paraformaldehyde - Report of the 

Antimicrobials Division Toxicity Endpoint Selection Committee (ADTC)” from T. McMahon 

to S. Carlisle, dated June 24, 2008. Endpoints were selected only for assessing inhalation 

exposures to formaldehyde and it was determined that assessments of the other routes of 
Page 4 of 10 

exposure (dietary, dermal and incidental oral) would not be not required. 

In addition, the following disclaimer from the “Response to Public Comments on the 

Formaldehyde Preliminary Risk Assessment RED” from T. McMahon and T. Dole to S. 

Carlisle, dated January, 6, 2009 is provided for the non-cancer formaldehyde inhalation 

endpoint: 

OPP developed the formaldehyde inhalation non-cancer toxicological endpoint used in this 

document through the established registration process, which includes stakeholder 

consultation and public comment. However, the result has not been subjected to an interagency review or external peer review. Because of time constraints imposed by statutory 

deadline, OPP could not consider all available peer reviewed science (for example, the 

intentional human dosing toxicity studies). Thus, this value should be considered an interim 

value, developed solely for the purposes of this determination and subject to future revision 

and subsequent peer review and should not be used in other contexts as EPA's opinion of the 

best available science on the non-cancer effects of formaldehyde. 

For the purposes of this assessment, the formaldehyde endpoints are expressed as RfCs 

which are the NOAEL divided by the uncertainty factor (UF). The UF is 1 for the 

occupational exposures because the NOAEL was derived from observational studies of 

workers exposed to formaldehyde and the UF is 10 for the residential exposures to account 

for the increased sensitivity of some members of the residential population. It is also 

important to note these RfCs are for peak exposures. 

Table 3 - Summary of Toxicological Doses and Endpoint Selection for Formaldehyde

Exposure 

Scenario

Dose Used in Risk 

Assessment 

Reference 

Concentration (RfC) 

Study and Toxicological Effects

Inhalation

(all durations) NOAEL (human) = 

100 ppb 

 

RfCoccupational = 100 ppb 

RfCresidential= 10 ppb 

Where: 

RfC = NOAEL

 UF 

UF = 1 for occupational 

UF = 10 for residential 

ACGIH 2001, TLV Documentation for 

Formaldehyde 

Horvath, E.P. et al. (1986): JAMA 259(5): 701-

707. Based on complaints of eye, nose, and 

throat irritation in particle board workers at 

concentrations of formaldehyde from 0.4 – 1.0 

ppm. 

Redden, J. (2005): Section 18 Emergency 

Exemption for the use of Paraformaldehyde: U.S. 

Army Medical Research Institute of Infectious 

Diseases. 

Cancer Lifetime extra cancer unit risk estimate of 1.3 × 10-5 per μg/m3 (US EPA IRIS 

http://www.epa.gov/ncea/iris/subst/0419.htm) 

And 

CIIT modeling: Tables 8A (for residential) and B (for professional). Hockey stick-shaped CRCP 

(nonsmoking) (Conolly, 2004) 
Page 5 of 10 

5.0 Exposure Assessment 

 Occupational dermal and inhalation exposures to MBM can occur during the use of 

MWFs containing Contram ST-1. Mixer/Loader exposures will occur during the mixing of 

the MWF concentrate that contains 3 percent MBM with dilutants to produce the end use 

fluid and machinist exposures will occur while using the end us fluid for machining. 

 

 The proposed label application rate of 2000 ppm of Contram ST-1 in the end use MWF 

equates to a free formaldehyde level of approximately 300 ppm given the product 

specification of 14 to 16% available formaldehyde. Since formaldehyde has a significant 

vapor pressure (1 mm Hg at 25 C as formaldehyde in formalin), the vapor inhalation 

exposure is the primary route of exposure. Inhalation exposure to the vapor is considered to 

be protective of exposure to the MWF aerosols containing formaldehyde as well as 

formaldehyde vapors that evaporate from MWF. 

5.1 Submitted Data 

The applicant submitted a machinist exposure study which is discussed below: 

MRID 475558-31, UK Exposure Study, Performed by the Lubrizol Corporation, Completed 

February 7, 2008 

The purpose of this study was to measure worker exposures to formaldehyde and oil mist 

during the use of metal working fluids treated with Contran ST-1. This study was conducted 

at a machining facility in the UK where Contran ST-1 was used in the MWF at a target 

treatment rate of 1500 ppm as MBM. Two machines (#1, C27 and #2, C133) that used 

treated MWF and one machine (#3, V38) that used neat oil, that did not contain MBM, were 

included in the study. Both Machines C27 and C133 were computer numerical controlled 

(CNC) and they both were used to machine cast steel. The machining operations were 

milling and drilling at Machine C27 and milling, drilling, threading and trepan cutting at 

Machine C133. Both machines used low oil semi-synthetic MWF. The levels of MBM in 

the MWF were measured in samples taken from each machine and ranged from 640 to 860 

mg/liter prior to the study and 1470 to 1450 mg/liter during the study. 

From the pictures included in the study report, both machines C27 and C133 appear to be 

semi-enclosed with at least one side being open. The enclosure for Machine C27 appears to 

be connected via flexible duct to what is probably a mist eliminator while the enclosure for 

Machine C133 does not appear to be connected to a mist eliminator. 

Real time measurements of oil mist were collected using a MIE DataRAM real time 

aerosol monitor that was calibrated before the study. Real time measurements of 

formaldehyde and morpholine were also collected using an Innova Model 1412 photoacoustic 

field gas monitor using appropriate optical filters. Air samples for formaldehyde were 

collected using glass fiber filters treated with dinitrophenyl hydrazine (DNPH). The flow rate 

was one liter per minute and the sample durations ranged from 80 to 480 minutes. The 

samples were analyzed using HSE method 78 which involves desorption of the filters with 

actonitrile and analysis using HPLC with UV-VIS detection. This method has an LOQ of 

0.05 ug/sample which equates to air concentrations of 0.1 to 0.6 ug/m3

 (0.08 to 0.5 ppb) 

depending on the duration of the sample. The real time measurements and area air samples 

were taken in the vicinity of the machines near the operator positions. Personal samples were 
Page 6 of 10 

also taken on the operators of those same machines. Background area samples were taken 

near a machine that did not use biocides and in non-machining areas such as the vending area 

and cafeteria. 

The formaldehyde levels measured by the Innova instrument included many values below 

zero and were considered by the study author to be invalid. EPA agrees with this conclusion 

and also suspects that the morpholine levels may not been be accurately measured. Therefore 

the Innova instrument results are not included in this review. 

A summary of the formaldehyde air sample results and associated oil mist levels is 

included in Table 4. In general the formaldehyde levels in the machining areas of were very 

low and ranged from less than 1 ppb to 6.2 ppb with an average of approximately 2 ppb. The 

formaldehyde levels in the background areas ranged from less than 1 ppb to 2.8 ppb. The 

average oil mist levels ranged from 0.137 to 0.296 mg/m3

 and the maximum oil mist levels 

ranged from 0.211 to 0.932 mg/m3

. The highest levels occurred at machine C27. 

Table 4 – Summary of Air Sample Results from the Lubrizol Study 

Sample Type* Location Day Sample 

Duration 

(Minutes) 

Formaldehyde 

(ppb) 

Average 

Oil Mist 

(mg/m3) 

Maximum 

Oil Mist 

(mg/m3) 

Operator Position 

1 meter from machine 

1 422 

438 

0.81 

0.90 

NA NA 

Same as for Day 1 2 318 

320 

0.98 

1.30 

NA NA 

GA - Background at 

Machine V38 where no 

biocide was used 

Operator Position 3 NA NA 0.137 0.211 

GA - Background 

Vending Area 

3 80 

330 

2.77 

1.55 

NA NA 

GA – Non Machining 

Area 

Near cafeteria 25M from 

nearest machine 

NA NA NA 0.162 0.233 

Operator Position 

1 meter from machine 

1 393 

395 

1.71 

1.79 

0.241 

0.296 

0.395 

0.932 

Same as above 2 476 

480 

2.20 

1.47 

NA NA 

GA – Machine C27 

Same as above 3 452 

453 

0.90 

0.98 

0.173 0.379 

Operator Position 

2 meters from machine 

1 227 

227 

2.20 

1.55 

NA NA 

Same as above 2 480 

480 

1.63 

6.19 

0.149 

0.172 

0.231 

0.243 

GA – Machine C133 

Same as above 3 414 

410 

3.26 

1.30 

NA NA 

PBZ Machine C27 

Machine C133 

2 149 

138 

1.71 

2.20 

NA NA 

PBZ Machine C27 

Machine C133 

3 312 

295 

1.14 

1.30 

NA NA 

*GA = general area, PBZ = personal breathing zone 
Page 7 of 10 

5.2 Literature Data 

In addition to the study submitted by Lubrizol, there are studies reported in the literature 

of worker exposures to formaldehyde and oil mist during the use of MWFs. These studies 

are discussed below. 

Formaldehyde Results from the Literature 

There are a few studies in the literature which report levels of formaldehyde that is 

associated with the use of MWF. A listing of these studies is included in Table 5. In the 

Linnainmaa and Cohen studies, hexahydro-1,3,5 tris (2-hydroxyethyl)-s-triazine (HHT) was 

used as a biocide and in the remaining studies the biocide used was not reported. In the 

Lillienberg study the highest levels were recorded in a shop that had recirculating air. In the 

Suuronen study, the authors reported that ventilation measures and the use of enclosures 

varied in the workshops and some of the local exhaust equipment was found ineffective; 

however, they concluded that the overall standard of exposure control was nevertheless found 

to be reasonable good throughout the companies. Oil mist samples were also collected in ten 

shops during the Suuronen study and the results ranged from <0.010 to 0.60 mg/m3 with a 

mean of 0.14 mg/m3

. The highest concentrations of oil mist (0.60 mg/m3) were measured 

during a process with several open-face grinders that did not have local exhaust ventilation. 

Unfortunately, it is not known if the formaldehyde levels correlated with the mist levels since 

only summary data are included in the article.

Table 5 – MWF Formaldehyde Exposures Reported in the Literature 

Study Type of Operation Sampled Biocide 

Used 

Air 

Sample 

Type* 

Formaldehyde 

(ug/m3) 

Godderis, 

2007 

Secondary aluminum plant with extrusion 

presses, hot rolling mills and cold rolling 

mills 

Unknown GA 20 to 30 (n=6) 

Lillienberg, 

2008 

5 machine shops in 3 companies that 

machined steel, aluminum and iron. Data 

are listed by company. 

Unknown PBZ 87 to 154 (n=4) 

2 to 42 (n=33) 

1 to 7 (n=16) 

Suuronen, 

2008 

10 metal machine shops that made tools, 

bodies and parts for machines and vehicles. 

Formaldehyde samples were collected in 

Sep Pak cartridges with a sample duration of 

2 hours. 

Unknown PBZ 11 to 150 (n=42) 

Linnainmaa, 

2003 

Blade grinding (8 shops) General machining 

(10 Shops) 

HHT PBZ 8.1 to 179 ppb (n=21) 

Cohen, 1994 Steel rolling mills, manufactures of 

automotive transmissions, industrial 

machinery, automobiles and aluminum cans 

HHT PBZ <20 to 490 ppb (n=88) 

*GA = general area, PBZ = personal breathing zone 

Oil Mist Results from the Literature

There are several dozen studies of oil mist air exposure reported in the literature; 

however, most of these studies used filter based air sampling methods. There is a literature 

study (Obrien, 2001), however, where direct reading instruments were used to measure 

exposures in 23 small machine shops. These 23 shops were a subset of 79 shops that were 

being studied by the National Institute of Occupational Safety and Health (Piacitelli, 2001) to 
Page 8 of 10 

assess the range of worker exposures associated with a variety of existing engineering 

controls. The shops were selected to represent a range of sizes, machining operations, 

machine age, fluid types and engineering controls. Real time oil mist concentrations were 

measured using an MIE DataRAM Aerosol Photometer while concurrent air samples were 

collected using filters in either closed face cassettes or cassettes preceded by thoracic cylones. 

The air samples were analyzed for both total mass and extractable mass using a 

NIOSH/ASTM provisional method that is intended to differentiate the MWF specific 

components of the collected particulate from the non-MWF fraction (such as metals and 

background particulate). The results of the DataRAM readings and air samples are 

summarized in Table 6. A comparison of the 8 hour TWA results obtained from the 

DataRAM with the results of the air sampling indicated that the DataRAM TWAs were 

approximately 1.5 to 2.0 times greater than the corresponding air sample TWAs depending 

upon the type of MWF and fraction considered. The authors recommended that correction 

factors of 0.7 and 0.5 for straight oils and water based fluids, respectively, could be used to 

adjust the DataRAM readings to estimate results that would be obtained using air samples. 

Table 6 – Machine Shop Oil Mist Exposures 

Number of 

Shops 

Monitored 

Minimum Average 95th

Percentile 

Maximum 

Short Term DataRAM Readings (mg/m3) 

Instantaneous Peak 23 0.28 5.15 17.6 21.3 

1 Minute Peak 23 0.14 2.13 5.94 7.97 

15 Minute Peak 23 0.06 1.35 3.0 7.24 

8 Hour TWA DataRAM Readings and Air Sample Results (mg/m3) 

8 Hour TWA DataRAM Readings 23 0.04 0.55 1.25 1.82 

Closed Face Cassette/Total Mass 23 0.03 0.52 1.31 1.36 

Closed Face Cassette/Extractable Mass 23 0.01 0.45 1.13 1.30 

Cyclone/Total Mass 23 0.04 0.38 1.08 1.15 

Cyclone/Extractable 23 0.01 0.32 0.96 1.11 

Source: Obrien, 2001 

5.3 Estimated Exposure to Formaldehyde 

The submitted study indicated that formaldehyde levels in the work areas ranged from 1 

ppb to 6.2 ppb with an average of approximately 2 ppb while formaldehyde levels in the 

background areas ranged from less than 1 ppb to 2.8 ppb. The literature data and previously 

submitted studies suggest that formaldehyde exposures were much higher than those recorded 

in the Lubrizol study, particularly when HHT was used. Because Contram ST-1 was not used 

in these studies, it is not known if the difference was due a more rapid release rate of other 

formaldehyde releasers such as HHT or if the difference was due to other machine shop 

conditions such a higher work rate or less ventilation. A comparison of the oil mist data from 

the Lubrizol study vs. the data reported in a literature study (Obrien, 2001) suggests that oil 

mists levels reported in the Lubrizol study were somewhat lower than the literature data, but 

the difference was not as great as the difference was for formaldehyde. In the Obrien study, 

the average 8 hour TWA for oil mist levels was 0.55 mg/m3

 while the average oil mist level 

was 0.2 mg/m3

 in the Lubrizol study. It is important to note that the same type of instrument 

(an MIE DataRAM Aerosol Photometer) was used in both the Lubrizol and the Obrien 

studies. 
Page 9 of 10 

The submitted data in conjunction with the data available from the literature appears to 

suggest that formaldehyde exposures from the use of Lubrizol will be lower than the 

formaldehyde exposures recorded during the use of HHT and will not exceed the EPA level 

of concern of 100 ppb. However, this preliminary conclusion is based on the assumption 

that the Lubrizol study was conducted under typical machine shop conditions. It is 

recommended that additional formaldehyde samples be collected in a several additional 

machine shops to verify the extremely low levels of exposure measured during the Lubrizol 

study. These samples should be collected using sampling times of 10-15 minutes each so 

that results will be comparable to the LOC of 100 ppb which is a peak value. 

If additional sampling indicates that formaldehyde exposures exceed the LOC under 

typical machine shop conditions, then engineering controls such as machine enclosures and 

local exhaust ventilation will be required. It will also be necessary to collect additional 

samples to verify the performance of the machine enclosures, because such systems were 

often designed for the control of oil mist and were not intended to control formaldehyde 

vapors. This is particularly true for machine enclosures connected to mist elimination 

systems where the air is recirculated back into the work area after passing through a filtration 

unit. While such systems can be effective for trapping aerosols that consist of oil mist and 

typical biocides that are essentially non-volatile, these systems are not effective for volatile 

biocides such as formaldehyde unless they are vented to the outside. 

6.0 Human Studies Considerations 

All of the exposure studies mentioned in this risk assessment (Cohen, 1994, Godderis, 

2008, Lillienberg, 2008, Linnainmaa, 2003, Obrien, 2001, Piacitelli, 2001, and Suuronen, 

2008) have been determined by the OPP ethics reviewers to be observational in nature and 

did not involve intentional exposure to human subjects. 
Page 10 of 10 

7.0 References: 

Cohen, 1994. A Study of Formaldehyde Exposures from Metalworking Fluid Operations 

Using Hexahydro-1,3,5-Tris (2-Hydroxyethyl)-S- Triazine. MRID 473354-02, H. J. Cohen, 

University of New Haven, May 3, 1994 

Conolly, 2004. Human Respiratory Tract Cancer Risks of Inhaled Formaldehyde: DoseResponse Predictions Derived From Biologically-Motivated Computational Modeling of a 

Combined Rodent and Human Dataset. Conolly, R. B., Kimbell, J.S., Janszen, D., Scholsser, 

P. M., Kalisak, D., Preston, J., and Miller, F.J., Toxicological Sciences: 82 (279-296). 

Godderis, 2008. Exposure to Metalworking Fluids and Respiratory and Dermatological 

Complaints in a Secondary Aluminum Plant. Godderis, L., Deschuyffeleer, T., Roelandt, H., 

Veulemans, H., Moens, G., International Archives of Occupational and Environmental 

Health, Volume 81, pp 845-853. 

Lillienberg, 2008. Exposure to Metal Working Fluid Aerosols and Determinants of 

Exposure. Lillienburg, L., Burdorf, A., Mathiasson, L., Thorneby, L., Annuals Occupational 

Hygiene, Volume 52, Number 7, pp 597-605. 

Linnainmaa, 2003. Control of Worker’s Exposure to Airborne Endotoxins During Use of 

Metalworking Fluids. Markuu Linnainmaa, Hannu Kivirata, Juha Laitinen and Sirpa 

Laitinen, Kuopio Regional Institute of Occupational Health and National Public Health 

Institute Department of Environmental Health, Kupio, Finland, AIHA Journal 64:496-5000, 

July/August 2003. 

Obrien, 2001. An Evaluation of Short-Term Exposures to Metalworking Fluids in Small 

Machine Shops. Obrien, D.M., Piacitelli, G. M., Sieber, W. K., Hughes, R.T., Catalano, J.D., 

American Industrial Hygiene Association Journal, Volume 62, pp 342-348. 

Piacitelli, 2001. Metal Working Fluid Exposures in Small Machine Shops: An Overview. 

Piacitelli, G. M., Sieber, Obrien, D.M., W. K., Hughes, R.T., Catalano, J.D., American 

Industrial Hygiene Association Journal, Volume 62, pp 356-370. 

Suuronen, 2008. Respiratory Exposure to Components of Water-Miscible Metalworking 

Fluids. Suuronen, K., Henriks-Eckerman, M-L, Riala, R., Tuomi, T., Annuals Occupational 

Hygiene, Volume 52, Number 7, pp 604-614.