-- RECEIV'EB ' 

JuanB PerezlDClUSEPAlUS TO NCIC HPV@EPA OPPT CBtC 

1 111 612006 08:25 AM CC 2006 OEC - I 1 An 7: 32 

bcc 

Subject Fw: HPV submission 

----- Forwarded by JuanB PerezlDCIUSEPAIUS on 11/16/2006 08:25 AM ---- 

"StafFord, Fran (FM)" 

<FMStafFord@dow.com> TO NClC OPPTQEPA, Rtk Chem@EPA 

1 111 512006 05:48 PM "Cosse, Pam (P)" <PCosse@dow.com>, "Deford, Connie 

cc (CL)" cCLDeford@dow.com>, "Stott, William (WT)" 

<WStott@dow.com> 

Subject HPV submission 

Attached please find the HPV submission test plan and dossier for 

Tris(hydroxymethy1)aminomethane (77-86-1). A hard copy and CD were sent via 

Fed Ex yesterday, (Tuesday, 14 November) with an arrival to EPA by the morning 

of today, Wednesday, 15 November. However, according to Fed Ex there were 

weather conditions and a missed courier pick up which did not allow for a 

Wednesday delivery of the test plan and dossier to EPA. We were not informed 

that Fed Ex did not deliver the package until after 5:00 pm today (Wednesday, 

15 November). We apologize for this unforeseen delay of FedEx not being able 

to do the next day delivery . We made every attempt to make the November 15th 

submission day. If you have any questions please contact Pam Cosse 

989-638-9660 or Dr. William Stott 989-636-8203. 

<<Dossier Tris(hydroxymethy1)aminomethane CAS# 77-86-l.rtf>> 

<<Test Plan Tris(hydroxymethy1)aminomethane CAS# 77-86-l.doc>> 

Thank you. 

Pamela F. Cosse 

Toxicology and Environmental Research and Consulting 

Bldg 1803 > The Dow Chemical Company > Midland, MI 48674 

phone 989-638-9660 

Fran Stafford 

TERC 

1803 Bldg., Midland, MI 48764 

989-636-3010 

E-Mail: fstafford@dow.com 

Dossier Tris[hydroxymethyl]arninomethane CAS# 77-86-1 . rtf Test Plan Tris[hydroxymethyl]aminomethane CAS # 77-86-1 .doc 
AMINO ALCOHOL 

HPV Challenge Program 

TEST PLAN 

For 

Tris(hydroxymethyl)aminomethane (77-86-1) 

Submitted t6the U.S. Environmental Protection Agency 

Under the High Production Volume (HPV) Chemicals Challenge Program 

The Dow Chemical Company 

Midland, Michigan, 48674 

November 14,2006 
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TABLE OF CONTENTS '.,', 

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I. INTRODUCTION ....................................................................................................., .. :!.:.; 7

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II. IDENTIFICATION OF THE ANALOGUES.. .................................................................... 
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III. JUSTIFICATION FOR ANALOGUE DESIGNATION. ..................................................... 
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... '.',r IV. DEVELOPMENT OF ROBUST SUMMARIES AND STUDY SCORlNG CRITERIA ......... ! .: :; :; DQka6Bd: 8 


V. TEST ENDPOINT RESULTS FOR ANALOGUES. ................................... 


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..... F. PHOTODEGRADATION................................................................................................................................... " -.;. --'-:9-9 I
 G. STA~~ITY IN WATER (HYDROLYSIS) ..............................................................................................................
 H. ENVIRONMENTAL ..................................................................................................................... 3 -". ~ . 

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I. BIODEGRADATION........................................................................................................................................ I 


J. ACUTE FISH TOXICITY .............................................................. 
 .% ...............................................................
 K. AQUATICINVERTEBRATES 

L. AQUATICPLANTS....................................................................................................................................... 


EYEIRRITATIO 


SKIN SENSITIZATION.. ......................................................................................................... 
 REPEATED-DOSE TOXICITY 
 ........................................................................................................................
 GENETICTOXICITY: GENE MUTATIONS AND CHROMOSOME ABERRATION...S 
 ............................................
 CARCINOGENICI...................................................................................................................................... 
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REPRODUCTIVE TOXICITY 
 ..........................................................................................................................
 DEVELOPMENTAL TOXICITY. ......................................................................................................................
 ,::'",:',,L CONCLUSIONS.......................................................................................................... !$;i7::,c,:,,:r -: I, 
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I. INTRODUCTION 

The Dow Chemical Company has committed to sponsor TRIS AMINO in the EPA 

High Production Volume Chemical Program. 

II. IDENTIFICATION OF THE SUBSTANCE 

For more than 50 years, Tris(hydroxymethyl)aminomethane (TRIS AMINO) CAS# 77­

86-1, technically described as 2-Amino-2 (Hydroxymethyl)-1,3-Propanediol, has been 

used in applications ranging from pharmaceuticals, biological buffers, and transport of 

live aquatic species, to emulsifying agents in cosmetics. TRIS AMINO is widely 

known and used as a therapeutic biological buffer, predominantly in patients suffering a 

decrease in blood pH due to diabetes or a wide array of respiratory diseases and 

conditions. It is also used clinically as a drug for the treatment of metabolic acidosis 

where it is injected intravenously or via other routes. It is listed in both the U.S. 

Pharmacopeia and the National Formulary of drugs for therapeutic drug applications. 

TRIS AMINO is administered in human patients primarily via the intravenous route 

regardless of the cause of the acidosis. It has been rigorously evaluated in numerous 

clinical experiments with animals and humans, and has consistently shown a low 

incidence of long-term toxicological effects at effective doses with relatively few and 

minor side-effects. TRIS AMINO is also used in the anti-inflammatory Keterolac® to 

improve drug solubility. In this form, it has been approved for use in treating acute 

post-operative pain via an intramuscular injection. Keterolac

® has been widely used 

due to its outstanding pain control properties, and is a nondependency-forming 

alternative to opiates with a low occurrence of side-effects. TRIS AMINO is also listed 

in the CTFA International Cosmetic Ingredient Dictionary (page 628, entry name of 

Tromethamine), reflecting its use as an ingredient in various cosmetic formulations. 

Because of its low aquatic toxicity, TRIS AMINO is also an effective buffer used to 

regulate the pH of the water during the transport of live aquatic species. TRIS AMINO 

is also widely used as a buffer, solubilizer and neutralizing agent in cosmetic creams, 

solutions, and lotions, mineral oil and paraffin wax emulsions, polishes and cleaning 

compounds. Finally, TRIS AMINO is also often used as a buffer in various biological 

test systems and life science applications such as cell culture media. 

3 
III. JUSTIFICATION FOR THE USE OF SURROGATE SUBSTANCES TO SUPPORT 

THE SUBMISSION FOR TRIS AMINO 

Table 1: Identification of the surrogate substances 

CAS No. Chemical Acronym Chemical Name 

000077-86-1 TRIS AMINO, THAM, TA, 

TRIS, TROMETHAMINE 

Tris (hydroxymethyl) aminomethane 

(2-Amino-2-hydroxymethyl-1,3-propanediol) 

000115-69-5 AMPD 2-Amino-2-methyl-1,3-propanediol 

000124-68-5 AMP, AMP-95 2-Amino-2-methyl-1-propanol 

A common mechanism of action, based on structural and chemical similarity, is one of 

the bases that the EPA has provided under the HPV program to use structurally-similar 

substances as data surrogates (U.S. EPA, 1999). We propose to utilize surrogate 

chemicals to fill gaps in our HPV data base for TRIS AMINO. 

TRIS AMINO (2-Amino-2-hydroxymethylpropanediol) and the proposed surrogate 

compounds 2-Amino-2-methyl-1,3-propanediol (AMPD) and 2-Amino-2-methyl-1­

propanol (AMP) possess an identical molecular “backbone” structure and common 

functional groups, forming a continuum from triol to diol to mono-alcohol, 

respectively. These structures are shown in Figure 1. TRIS AMINO, AMPD and 

AMP all contain a primary amine connected to a tertiary carbon, with one or more 

terminal primary alcohol groups 

Figure 1. Representative Structures of the Surrogate Substance(s) 

Formatted: Left, Indent: First line: 

36 pt 

NH2 

OH 

HO

HO

CH3 

H2N OH 

HO

H2N

CH3 

OH 

H3C

TRIS AMINO AMPD AMP 

Table 2: Chemical Properties of TRIS AMINO and of the Surrogate Substances 

Test 

Chemical CAS No. 

Molecular 

Wt. g/mol 

Melting 

Point 

Boiling 

Point 

Vapor 

Pressure 

Partition 

Coefficient 

Water 

Solubility 

4 
(

o

C) (

o

C) (hPa) Log Kow (g/L) 

TRIS 

AMINO 

77-86-1 121.14 171-172 219-220 @ 

10 mm Hg 

3.04x10-6 -2.31 800 

AMPD 115-69-5 105.14 110 151-152 @ 

10 mm Hg 

8.71x10-3 <-3.8 2500 

AMP 124-68-5 89.14 30.5 165.5 @ 

760 mm Hg 

4.5.3x10-1 -0.63 Miscible all 

proportions 

Consistent with the general structural and chemical similarities of TRIS AMINO, 

AMPD and AMP, studies have demonstrated a similar pattern of physical chemistry, 

environmental fate, and ecological and mammalian toxicity profiles. The compounds 

are solid crystalline masses in the pure or neat state, and possess common general 

physical/chemical properties. Because of their structure, all the substances are highly 

soluble in water, have very low vapor pressures, possess relatively low partition 

coefficients (log Kow’s), and similar dissociation constants, making them likely to 

remain dissolved in the water compartment upon the event of an environmental release, 

where biodegradation is ultimately expected. MacKay Level III fugacity modeling 

predicts that TRIS AMINO and the surrogate substances will tend to partition 

predominately to water Gonsior (2006). There is also a low potential to bioaccumulate 

in aquatic organisms based on low log Kow values. The high water solubility and 

negligible vapor pressure of all three substances support the low estimated Henry’s 

Law Constants (4.54x10-8 and 6.48x10-10 Pa m3

/mol for TRIS AMINO and AMP, 

respectively, and 8.67 x10-13

atm-m3/mole for AMPD). 

Deleted: , S. 

Deleted: 

The data on fish, aquatic invertebrate, and algal toxicity, in addition to the use of TRIS 

AMINO as a buffer for live fish transport, indicate a pattern of low toxicity for this 

chemical and the surrogate substances. These materials are of low toxicity to aquatic 

organisms with EC50s greater than 100 mg/L. 

Mammalian toxicity studies have displayed similar results. The oral LD50 value for TRIS 

AMINO is 5500 mg/kg in the mouse, and its surrogates range from 2150 to greater than 

5 
5000 mg/kg in the rat and mouse. TRIS AMINO was non-irritating to eyes when a 40% 

aqueous solution was applied to the eyes of rabbits (pH 10.4 for 0.1M aqueous solution). In 

contrast, 95% AMP in water was severely irritating to the eyes, presumably due to the 

severely alkaline pH of the test solution used (pH 11.3 for 0.1M aqueous solution); however, 

more neutral cosmetic formulations containing lower concentrations of AMP are only 

minimally irritating. There is no sensitization data available for TRIS AMINO; however, 

based on the following data, TRIS AMINO is not expected to be a sensitizer. Laboratory 

animal test samples of AMP did not cause allergic skin reactions when tested in guinea pigs 

following topical or intradermal administration. In patch tests with humans, AMP and 

cosmetic formulations containing either AMP or AMPD were negative for dermal 

sensitization. 

Repeated-dose mammalian toxicity studies conducted on TRIS AMINO and the two 

surrogate chemicals indicate that the compounds are generally well-tolerated at 

concentrations as high as 500 mg/kg/day via IV infusion for TRIS AMINO and ingestion of 

up to 3200 ppm in the rodent diet (250-750 mg/kg/day for rats and mice, estimated). A 

number of human clinical trials of the IV infusion of TRIS AMINO have also been 

successfully conducted. In all studies, the only target tissue, when observed at all, has been 

the liver with AMP. Human clinical studies with Keterolac® (a major component of which 

is TRIS AMINO) have suggested that patients with decreased liver function not be given the 

drug over extended treatment periods based upon changes in several clinical chemistry 

parameters. Ingestion of relatively high dosages of AMP has caused liver histopathological 

changes in rats and dogs. The most significant toxicological activity has been a fetotoxic 

effect of AMP when ingested at relatively high levels by pregnant rats. Subsequent dermal 

exposure to comparable dosages failed to elicit a developmental effect in rats. Overall, there 

have been no consistently-noted observations or treatment-related findings among the 

numerous repeated-dose mammalian toxicity studies that have been conducted over the last 

50 years on these compounds that would indicate long-term significant toxicity of either 

compound at typical human exposure levels. Reflective of these findings is the fact that 

both TRIS AMINO and AMP display similar patterns of excretion from the body, being 

primarily eliminated unchanged via the urine over a relatively short period of time. Further, 

no evidence of either direct reactivity or metabolism to reactive species toward genetic 

6 
material has been observed. Genetic toxicity studies conducted on the TRIS AMINO and the 

surrogate substances in the presence or absence of mammalian metabolic enzymes have all 

been negative. 

Finally, TRIS AMINO and the surrogate chemicals have displayed little if any toxicity 

to humans during their long history of use as human drugs and/or in personal care 

products and cosmetics. TRIS AMINO has found use as an IV drug for the 

management of acidosis in humans for many years and the toxicity of AMPD and AMP 

have been reviewed by the Cosmetic Ingredient Review Expert Panel which concluded 

that these materials are safe as used in cosmetic formulations up to 1% (CIR, 1990). 

Based upon the properties, uses and toxicities of TRIS AMINO, AMPD and AMP, the use of 

AMPD and AMP as surrogate substances to fulfill any data gaps for TRIS AMINO is warranted. IV. 

DEVELOPMENT OF ROBUST SUMMARIES AND STUDY SCORING CRITERIA 

The Dow Chemical Company has chosen to use the IUCLID (International Uniform 

ChemicaL Information Database) format for preparation of robust summaries for the 

HPV program. Because many of the fields in the IUCLID database program are 

outside the scope of the HPV program, these fields are typically left blank in the 

IUCLID robust summary. Scoring of studies from company files or from the literature 

for reliability to fulfill the testing requirement for each endpoint used a system similar 

to that published by Klimisch et al. (1997). Studies were given a score of “1” if the 

data could be considered valid without restriction based on the completeness of the 

protocol and adequate details in reporting. Studies were given a score of “2” if the data 

and study design could be considered scientifically valid to address the endpoint but 

with restrictions due to lack of various technical or reporting details or deviations from 

current OECD guidelines. Studies were given a score of “3” if their conduct was not 

acceptable and “4” if there wasn’t enough information present to assign a reliability 

rating. However, a study receiving a score of “4” could provide supplementary 

information that could be used to address the endpoint in a weight of evidence 

evaluation in the absence of other data. 

V. TEST ENDPOINT RESULTS FOR TRIS AMINO and SURROGATE SUBSTANCES 

A summary of the data on HPV/SIDS endpoints for TRIS AMINO and structurally 

similar amino alcohols can be found in Table 3: Summary of the Endpoints. 

Comment [PFC1]: Pam does this 

reference include AMPD? 

Deleted: ¶

 ¶ 

7 
Evaluation of this data leads to the conclusions that (1) a substantial quantity of data 

currently exist to adequately represent the toxicological and ecological profile, (2) there 

is concurrence and similarity among the existing data for the various HPV/SIDS 

endpoints, (3) available data from TRIS and the structurally similar substances can be 

used to adequately represent the various HPV/SIDS endpoints that may not have been 

subjected to the same level of testing, and (4) utilization of these data support the 

conclusion that no further testing is needed for most of the HPV/SIDS categories. The 

data for each of the HPV/SIDS endpoints are discussed in the following section. 

A. Melting Point 

IUCLID 2.1: TRIS AMINO is crystalline masses in the neat or pure state with melting 

points of 171-172o

C (Merck, 1989). The data suggest that decomposition is unlikely, 

and because the melting point is well-documented in peer-reviewed literature and 

public databases, further testing for this endpoint would not be productive. 

B. Boiling Point 

IUCLID 2.2: The boiling point for TRIS AMINO is well documented (Merck, 1989). 

No further testing is planned for this endpoint. 

C. Vapor Pressure 

IUCLID 2.4: The vapor pressure for TRIS AMINO was estimated by EPIWIN 

MPBPWIN program, and although estimations are not considered reliable for this 

category, both the experimental or estimated values for the structurally similar amino 

alcohols are extremely low at 3.0x10-6 (TRIS AMINO) hPa at 20-25o

C. The vapor 

pressure, for the structurally related substances have been well-documented in either 

measured reports, published literature or chemical handbooks. This result is consistent 

with the physical/chemical nature of the amino alcohols and suggests a very low degree 

of volatility; there is no further testing planned for this endpoint. 

D. Partition Coefficient 

IUCLID 2.5: The value for TRIS AMINO is –2.31(Lhotak, 1996). The partition 

coefficient is consistent with high water solubility and which by definition would be 

8 
indicative of low log Kow values. Based on the structure, and the low log Kow values, 

no further testing of this endpoint is necessary. 

E. Water Solubility 

IUCLID 2.6.1: Measured data indicate that TRIS AMINO is highly soluble to miscible 

in water. Measured aqueous solubilities of at least 800 g/l at 25 o C for TRIS AMINO 

further document its very high water solubility (L. Troester, personal communication, 

2006). Furthermore, TRIS AMINO is sold as an aqueous solution, and is formulated as 

part of the drug Keterolac® to enhance its solubility. Sufficient data exist for this 

endpoint to characterize water solubility for the TRIS AMINO, such that no further 

testing is needed. 

F. Photodegradation 

IUCLID 3.1.1: TRIS AMINO does not absorb light >290 nm, and therefore direct 

photolysis is not possible. Indirect photolysis (hydroxyl radicals) is possible, however. 

Modeling has shown that the half-life of TRIS AMINO in the atmosphere is 

approximately 3.8 hours (West, 2004a). Since volatilization is not an important 

environmental fate process for the surrogate substances, testing for photolysis in the 

atmosphere is not relevant, and therefore no further testing for this endpoint is 

necessary. 

G. Stability in Water (Hydrolysis) 

IUCLID 3.1.2: TRIS AMINO does not possess molecular structures that contain 

functional groups subject to hydrolysis under neutral ambient conditions (Reaction 

Mechanisms in Environmental Organic Chemistry, 1994). It is commercially available 

as an aqueous mixture, further documenting high stability in water, and is reported 

stable for several years <200o

C. This testing endpoint is well characterized, and no 

additional testing is required. 

H. Environmental Transport 

IUCLID 3.3.1: Environmental transport data were obtained for the TRIS AMINO 

by estimation using the EPIWIN Level III Fugacity program (Canadian Environmental 

9 
Modeling Center). Measured water solubility data and the previously-reported values 

for vapor pressure were used as the model input. The program also used input values 

for octanol/water partition coefficients, air-water coefficients, melting point and 

molecular weight that were either calculated by other programs in the EPIWIN suite or 

used as reported in peer-reviewed literature or databases. 

The fugacity mass amount (partitioning) values obtained indicate that distribution into 

the air would be negligible (<0.1%), as would be expected for primary amino alcohols 

compounds with low volatility and high solubility in water. Likewise, the distribution 

to sediment was estimated to be <0.1%. The calculated mass amounts in the soil 

environmental compartment was <0.1%; the predicted mass amounts distributed to 

water was 100.0%, a high level that is consistent with the known high water solubility 

of members of this category (Gonsior, 2006). 

Although the values obtained using this model should not be regarded as quantitative, 

the model results are consistent with the known physical and chemical properties of 

TRIS AMINO, i.e., the known high water solubility and negligible volatility. Further 

testing for this endpoint is not needed. 

I. Biodegradation 

IUCLID 3.5: Biodegradation is the conversion of a chemical by microorganisms in 

the environment into its simpler components and ultimately to carbon dioxide and its 

other constituent molecules. Chemicals are classified as readily biodegradable by the 

Organization for Economic Development (OECD) guidelines if there is a 70% 

degradation of dissolved organic carbon within a 10-day period during a typical 28-day 

laboratory protocol. 

There is a biodegradation study, OECD 301D, for TRIS AMINO which indicates that it 

is not readily biodegradable (IWL, 1990). There is evidence based on studies with 

structurally-related compounds to suggest that TRIS AMINO would biodegrade under 

favorable conditions. There is an OECD 302C study on AMPD which showed 96.7% 

biodegradation after 22 days. It should therefore be considered inherently 

biodegradable, which indicates that it would not persist indefinitely in the environment 

10 
and that it would exhibit similar biodegradation potential based on structurebiodegradability relationships measured for similar compounds (West, 2004b). 

These data indicate that there is sufficient information on the biodegradation potential 

of TRIS AMINO and of the surrogate substances, and justifies that no additional 

testing is needed. 

J. Acute Fish Toxicity 

IUCLID 4.1: The LC50 value of TRIS AMINO for 29 species of fish was reported to 

be greater than 4400 mg/L when observed for a period of 30 days; it is used as a 

buffering agent for shipping live fish at dose levels ranging 440-1100 mg/L under 

aerated or static conditions (McFarland and Norris, 1958). AMP has been evaluated in 

96-hour LC50 testing with Lepomis macrochirus, where the LC50 under semi-static 

conditions was reported to be approximately 190 mg/L (Parekh, 1980a). No additional 

testing is required. 

K. Aquatic Invertebrates 

IUCLID 4.2: Based on toxicity trends in fish, and comparable physical-chemical 

properties, TRIS AMINO is expected to be as non-toxic to aquatic invertebrates as 

AMP. Aquatic invertebrate toxicity data are available for AMP only, and the authors 

report 48- & 96-hour LC50 values for Crangon crangon to be 179 mg/L (Young and 

Tapp, 1983). In Daphnia magna, AMP was reported with a 48-hour EC50 of 193 mg/L 

(Parekh, 1980b). No additional testing is required. 

L. Aquatic Plants 

IUCLID 4.3: TRIS AMINO was tested with Selenastrum Capricornutum, and a 

NOEC of >100 mg/L in a 96-hour growth rate test (Adams, et al., 1985). No 

additional testing is considered necessary. 

M. Acute Oral Toxicity 

IUCLID 5.1.1: Acute oral toxicity studies were conducted with TRIS AMINO using a 

gastric tube in the Swiss mouse and Wistar rat. Solutions of 20% and 5% were given 

via the gastric tube to rats and mice respectively at doses of 1000, 2000, and 3000 

11 
mg/kg as a solution. The LD50 for rats and mice are estimated to be >3000 mg/kg in 

solution. There was no toxicity noted in either species at the top dose levels, although 

abundant urine output was noted for some animals (Giroux and Beaulaton, 1962). 

Additional testing is not considered necessary. 

N. Acute Inhalation Toxicity 

IUCLID 5.1.2: There is no available data on TRIS AMINO or the surrogate substances 

for this endpoint. There is, however, a low potential for inhalation exposure based on 

known use patterns, physical state of the pure materials, and vapor pressure, and 

therefore testing is considered unnecessary. 

O. Acute Dermal Toxicity 

IUCLID 5.1.3: TRIS AMINO has been evaluated in the rat and mouse via intradermal 

injections, and the LD50 for both species exceeded 1000 mg/kg body weight, the highest 

dose tested. At that dose level, lesions were noted, but no other signs of toxicity were 

reported (Giroux and Beaulaton, 1962). AMP was evaluated in rabbits via a 24-hour 

skin patch test, and the LD50 was reported greater than 2000 mg/kg (Parekh, 1980c). 

There were no signs of systemic toxicity, however the treatment sites were necrotic 

within 2-3 days, and remained so at study termination. Treated groups exhibited a loss 

in body weight over the 14-day post-treatment period. 

No additional testing for this endpoint is considered necessary, as reliable data is 

available for TRIS AMINO and the surrogate compound AMP. 

P. Skin Irritation 

IUCLID 5.2.1: Skin irritation tests following the Draize Method have been performed 

on TRIS AMINO, although documentation is not sufficient for full assessment 

(reliability 4). It was found to be moderately irritating on abraded rabbit skin, but 

resolved within 48 hours (Baldwin, 1961). There was no noticeable irritation on 

unabraded skin sites. In a more reliable study, AMP was found to be irritating to 

rabbits, with burrowing lesions noted when applied to abraded skin sites (Machle et al., 

1940); there was mild irritation noted when applied to unabraded skin. The severity of 

irritation is directly related to the base strength of the amino alcohol. At 25°C the pKa 

12 
of TRIS AMINO is 8.03, the pKa of AMPD is 8.76, and the pKa of AMP is 9.72. 

Since limited data exists for the compound, but exists for the surrogate substances, 

additional testing is not considered necessary. 

Q. Eye Irritation 

IUCLID 5.2.2: Undiluted TRIS AMINO was found to be essentially non-irritating to 

rabbits, although documentation is not sufficient for full assessment (reliability 4). Another 

test conducted on a 40% solution of TRIS AMINO in water has shown this material to be 

non-irritating to rabbits (Power, 1975). No additional testing is necessary. 

R. Skin Sensitization 

IUCLID 5.3: While the toxicological/safety profile of TRIS AMINO has been extensively 

established for many endpoints, especially those associated with its use in the treatment of 

metabolic acidosis, no laboratory studies of skin sensitization have been reported for this 

material, and the assessment for dermal sensitization has been based on the favorable use 

experience associated with various uses, such as applications where it is an ingredient in 

formulations associated with anticipated dermal contact. In addition, structurally related 

surrogates AMPD and AMP have been negative in laboratory animal and/or human patch 

tests for sensitization. AMP did not cause allergic skin reactions when tested in guinea pigs 

following topical or intradermal administration. In patch tests with humans, cosmetic 

formulations containing either 0.22% AMP or 0.5% AMPD or 0.075% AMPD were 

negative for dermal sensitization (Kociba, 2003; CIR, 1990). Based upon extensive 

clinical use and surrogate related chemical activities no further testing is 

recommended. 

S. Repeated-Dose Toxicity 

IUCLID 5.4: TRIS AMINO was administered to various species of animals and 

humans in multiple studies and trials primarily via the intravenous route, since it is 

delivered in that manner to human patients suffering acidosis and requiring treatment. 

The test durations ranged from 10 to 99 days in rats, mice, and rabbits. In all studies, 

regardless of duration or species, the observations consistently noted were lesions and / 

or gangrene at the infusion sites, and, in many cases, increases in white blood cell 

Comment [PFC2]: Pam check 

Formatted: Not Highlight 

Formatted: Not Highlight 

Comment [PFC3]: BILL, What’s 

your call? 

Deleted: (Toxicology Profile on TRIS 

AMINO in DR-0017-3524-019 

Formatted: Font: Not Bold 

Formatted: Not Highlight 

Formatted: Font: Not Bold 

Deleted: ) 

13 
counts associated with gangrene. Sporadic kidney and liver lesions were noted in the 

longer studies. Because the studies were generally conducted at one dose level (plus 

control) comparable to human therapeutic doses, no-observed-adverse effect level 

(NOAEL’s) / lowest-observed-adverse effect level (LOAEL’s) are not useful to report. 

It is reasonable to assume, however, that since the studies were conducted under very 

likely human exposure scenarios, the relative toxicity of TRIS AMINO to humans is 

low. The assumption of low toxicity is also supported by multiple clinical trials with 

both healthy and ailing human patients treated with TRIS AMINO at similar dose 

levels. In these clinical trials, the most common observations included a transient 

decrease in respiratory rate, an increase in urine output, hyperkalemia, and 

hypoglycemia. In cases where the dose level far exceeded the recommended 

therapeutic dose, vomiting, sweating, hunger, dizziness, and diarrhea occurred in a 

small subset of the test group. There are no documented long-term effects of TRIS 

AMINO treatment, and no serious side-effects on record that are directly attributed to 

treatment with the compound. 

The surrogate chemical AMP has been more thoroughly tested in mammalian species 

via more traditional industrial safety and handling toxicity test than TRIS AMINO. The 

repeated dose toxicity of AMP has been well-studied and documented. These dietary 

studies ranged from eight weeks to one year in multiple species. The primary 

treatment-related effect noted has been histopathological changes consisting of 

increased liver weights and vacuolation of the liver in rats and dogs (Parekh, 1981; 

1981b; Griffin, 1990). No further testing of TRIS AMINO is recommended. 

T. Genetic Toxicity: Gene Mutations and Chromosome Aberrations 

IUCLID 5.5 and 5.6: TRIS AMINO was negative in a gene mutation assay in 

Saccromyces cerevisiae, and negative in the bacterial gene mutation assay with E.coli 

(Livtak and McEvoy, 1990). No additional testing is considered necessary. 

U. Carcinogenicity 

IUCLID 5.7: TRIS AMINO did not induce tumors when tested in male Syrian golden 

hamsters receiving 0.2 ml of a mixture of Tris buffer and 0.9% NaCl intratracheally into the 

lungs weekly for life (Ketkar, M. et al., 1979). The long history of safe use of TRIS 

14 
AMINO as a biological buffer in the treatment of acidosis, its use in Keterolac®, an antiinflammatory drug, and the compound’s use in cosmetics over many years suggest that 

TRIS is not carcinogenic. Repeated dose toxicity studies of TRIS and the structurally 

related primary amino alcohol, AMP, do not show any evidence of any preneoplastic 

lesions, and mutagenicity studies are all negative; a one-year study of AMP in dogs (Griffin, 

1990), indicated no evidence of carcinogenicity. These data suggest that the materials 

are not carcinogenic. No additional testing is considered necessary. 

V. Reproductive Toxicity 

IUCLID 5.8.1: There have been no reproduction studies conducted with TRIS AMINO. 

Data are available to indirectly evaluate the potential for reproductive effects from exposure 

via chronic studies that include histological examination of gonadal tissues for evidence of 

adverse effects. No adverse clinical, histological, or hematological effects were noted in 

more than a dozen repeated-dose toxicity studies conducted with AMP and AMPD that 

would indicate toxicity to the reproductive organs. Likewise, there have been no reports of 

any reproductive effects in the multiple studies conducted on human patients with TRIS 

AMINO. However, in a recent rat reproductive/developmental screening study, the HCl salt 

of AMP has been observed to be fetotoxic in rats. An OECD 421 study was conducted 

using AMP-HCl in which male and female CD rats were fed diets supplying 0 (control), 

100, 300, or 1000 mg/kg/day of AMP-HCl (Carney et al., 2005). Males were exposed for at 

least two weeks prior to breeding and continuing throughout breeding for 37 days. The 

females were exposed for two weeks prior to breeding, continuing through breeding (up to 

two weeks), gestation (three weeks), and lactation (four days). Evidence of complete litter 

resorption (100% post-implantation loss) was seen at 1000 mg/kg/day, and significant 

resorptions were seen at 300 mg/kg/day. Effects associated with, or secondary to the postimplantation loss increase at 300 mg/kg/day included decreased litter size, increased pup 

body weight, and decreased gestation body weight and body weight gain. The no-observed 

effect level (NOEL) for systemic toxicity in males was 100 mg/kg/day, but could not be 

established for females due to liver effects in the low dose group; the NOEL for 

reproductive toxicity was 100 mg/kg/day. There were no treatment related effects on 

reproductive performance in the 100 mg/kg/day group. The NOEL for general toxicity in 

males was 300 mg/kg/day, while the general toxicity NOEL for females could not be 

15 
determined, based upon the presence of very slight microscopic liver effects. The NOEL for 

reproductive effects was considered to be 100 mg/kg/day. 

Comment [PFC4]: This info is from 

the AMP SIAR. 

In light of the history of TRIS AMINO use in pharmaceuticals and no direct evidence of Formatted: Not Highlight 

Deleted: 

reproductive toxicity associated with TRIS AMINO, we believe that 

reproduction/developmental toxicity data may exist. We plan to explore this further by 

filing a Freedom of Information Act (FOIA) request with the US Food and Drug 

Administration (FDA) to determine if such testing has been conducted. In the event that we 

do not obtain this data, then we commit to conducting an OECD 421 reproductive and 

developmental screening study similar to that conducted on AMP to fully evaluate any 

Formatted: Not Highlight 

Formatted: Not Highlight 

Formatted: Not Highlight 

potential fetotoxicity of TRIS AMINO in rats. 

W. Developmental Toxicity 

IUCLID 5.82: Data are not available for TRIS AMINO. However, an OECD 414 GLP 

guideline study on AMP is available. In this study, female rats were exposed 6 hours daily 

dermally to 0, 30, 100, or 300 mg AMP/kg/day from gestation days (GD) 6-20 (Carney and 

Thorsrud, 2006). Dermal administration of 300 mg/kg/day of AMP produced significant 

effects at the test site, as evidenced by scabbing and moderate to severe scaling. The dermal 

finding of slight scaling at 30 and 100 mg/kg/day was not considered adverse, as the 

observation was transient in nature and relatively low in incidence. There was no evidence 

of test article related systemic maternal or developmental toxicity at any dose level tested. 

Under the conditions of this study, the NOAEL for maternal toxicity based on dermal effects 

was 100 mg/kg/day. The NOEL for developmental toxicity was 300 mg/kg/day, the highest 

dose level tested. While this study is believed to represent a definitive evaluation of 

potential developmental toxicity for TRIS AMINO in addition to AMP, it is believed that 

given the extensive use of TRIS AMINO as a therapeutic agent data exist within US FDA 

archives to address this endpoint (FOIA reference noted in Reproduction Section and 

below). Should no data be identified, a proposed OECD 421 reproductive and 

developmental screening study will provide an additional evaluation of any potential for 

developmental toxicity TRIS AMINO. 

Formatted: Not Highlight 

16 
VI. CONCLUSIONS 

Evaluation of the existing data leads to the conclusions that [1] a substantial quantity of 

data currently exist to adequately represent the toxicological and ecological screening 

profile of the category, [2] there is a concurrence and similarity among the existing 

data for the various HPV/SIDS endpoints [3] available data from previously studied 

structurally similar primary amino alcohols can be used to adequately represent the 

majority of the various HPV/SIDS endpoints for the compound that was not subjected 

to the same level of testing (with the exception of acute inhalation and developmental 

toxicity), and [4] utilization of these data support the conclusion that no further testing 

is needed to satisfy endpoints for HPV/SIDS with the exception of Reproductive 

toxicity. (Table 4: Test Plan Matrix). However, TRIS AMINO has a long history of 

safe use in pharmaceutical products intended for use internally in humans. We believe 

that reproduction/developmental toxicity data may exist, so the FOIA inquiry with the 

FDA will determine if such testing has been conducted. If no data is found we will then 

commit to conducting an OECD 421 reproductive and developmental screening study. 

Further, a proposed OECD 421 reproductive/developmental toxicity screening test will 

provide data on the potential developmental toxicity of TRIS AMINO. 

17 
VII. REFERENCES 

Adams, N., Goulding, K.H., and Dobbs, A.J. (1985). Toxicity of Eight Water-Soluble 

Organic Chemicals to Selenastrum capricornutum: A Study of Methods for Calculating 

Toxic Values Using Different Growth Parameters. Arch. Environ. Contam. Toxicol. 14:333­

345. 

Baldwin, R. (1961). Tris(hydroxymethyl)aminomethane Primary Skin Irritation Studies. 

Internal correspondence of The Dow Chemical Company. May 19, 1961. 

Carney, E.W. and Thorsrud, B. (2006). AMP: Dermal Developmental Toxicity Study in 

CRL:CD(SD) Rats. The Dow Chemical Company Report No: DR-0399-3940-001. 

Formatted: Font: Italic 

Deleted: 

Formatted: English (U.S.) 

Carney, E.W., Quast, J.F., and Zablotny, C.L. (2005). 2-Methyl-2-Aminopropanol 

Hydrochloride: A Reproductive / Developmental Toxicity Screening Test in CD Rats. 

Deleted: of the Dow Chemical 

Company 

Deleted: 

The 

Dow Chemical Company Report No. DR-0038-3186-001. 

CIR: Cosmetic Ingredient Review Board (1990). A Final Report on the Safety Assessment of 

Aminomethylpropanol and Aminomethylpropanediol. J. Am. Coll. of Toxicol. 9:203-228. 

Giroux, J. and Beaulaton, I. (1962). Recherches Pharmacologiques Sur Le THAM. Societe 

Pharmacie Montpellier. 21:206-217. 

Formatted: Normal, Indent: Left: 

67.5 pt 

Deleted: ¶ 

Deleted: ¶ 

Formatted: Font: Italic 

Deleted: ¶ 

Gonsior, S. (2006). Prediction of the Environmental Distribution and Transport Between 

Environmental Compartments for Tris(hydroxymethyl)aminomethane Using Level I and 

Level III Fugacity Models. Draft Report of The Dow Chemical Company. 

Griffin, T. (1990). A One-Year Oral Toxicity Study of AMP in Dogs. Coulston Research 

Incorporated, White Sands Research Center, Alamogordo, NM, USA. Amended by the 

original author on April 20, 1993. 

IWL (1990). Institut für gewerbliche Wasserwirtschaft und Leftreinhaltung e. V. IWL – 

Auftragsnummer: Lab 594. 

Ketkar, M. , Green, U., Schneider, P., and Mohr, U. (1979). Investigation on the 

carcinogenic burden by air pollution in man. Cancer Letters 6:279-284. 

Klimisch, H., Andreae, M. and Tillmann, U. (1997). A Systematic Approach for Evaluating 

Deleted: t 

Formatted: Font: Italic 

Deleted: , 

Formatted: Font: Italic 

Formatted: English (U.S.) 

Formatted: English (U.S.) 

Deleted: 

Deleted: 

18 

the Quality of Experimental Toxicological and Ecotoxicological Data. Regul. Toxicol. 

Pharmacol. 25:1-5. 

Kociba, R. (2003). Assessment of the Potential for Skin Sensitization of Structurally-Related 

Analogs Represented by 2-Amino-2-(Hydroxymethyl)-1,3-Propanediol, 2-Amino-2-Methyl1-Propanol, and 2-Amino-2-Methyl-1,3-Propanediol. Written communication. 
Lhotak, H. (1996). Participation Coefficient of Various ANGUS Products (AMPD APD). 

ANGUS Chemie GmbH. 

Livtak, K.M. and McEvoy, G.K. (1990). Ketorolac, an injectable nonnarcotic analgesic. 

Clinical Pharmacy 9:921-935. 

Machle, W., Scott, E. W. and Treon, J. F. (1940). The Physiological Response of Animals to 

Some Simple Mononitroparaffins and to Certain Derivatives of These Compounds. J. Ind. 

Hyg. Toxicol. 22:315-332. 

McFarland, W.N. and Norris, K.S. (1958). The Control of pH by Buffers in Fish Transport. 

California Fish and Game. 291-310. 

Formatted: Font: Italic 

Deleted: 

Deleted: . 

Deleted: 

The Merck Index (Eleventh Edition) (1989). Merck & Co., Inc. Rahway, NJ, USA. 

Parekh, C. (1980a). Acute Toxicity Effects of AMP-95 on Bluegill Sunfish, Ninety-six Hour 

LC50. Report DR-0309-4391-002 for the International Minerals & Chemical Corporation, 

Pharmacology Laboratories, Animal Science Research by Analytical Bio Chemistry 

Laboratories, Columbus, MO, USA. 

Parekh, C. (1980b). AMP-95 Acute Toxicity Effects on Daphnia, 48 Hr LC50. Report 

#25561 for the International Minerals & Chemical Corporation, Pharmacology Laboratories, 

Animal Science Research by Analytical Bio Chemistry Laboratories, Columbus, MO, USA. 

Parekh, C. (1980c). Dermal Toxicity of P-1826 (AMP). Report PLR-113 of Pharmacology 

Laboratories Animal Science Research, Terre Haute, IN, USA 

Formatted: Space Before: 12 pt 

Deleted: 1989. 

Formatted: English (U.S.) 

Parekh, C. (1981). A Three Month In Diet Toxicity Study of 2-Amino-2-methyl-1-propanol 

in Rats. Report of Bio/dynamics Inc, East Millstone, NJ, USA. Sponsored by the 

International Minerals & Chemical Corporation, Terre Haute, IN, USA. 

Deleted: ¶ 

Power, C. (1975). Eye Irritation, Bioassay Report #26775. Pharmacology Laboratories 

Research and Development, Commercial Solvents Corporation. May 21, 1975. 

Reaction Mechanisms in Environmental Organic Chemistry (1994). Richard A. Larson and 

Formatted: Indent: Left: 67.5 pt 

Formatted: Font: (Default) Times 

New Roman, 12 pt 

Formatted: Font: (Default) Times 

New Roman, 12 pt Eric J. Weber Lewis Publishers, Ann Arbor, MI, USA. Chapter 2 "Hydrolysis", pages 103­

167. 

US EPA (1999). The use of structure-activity relationships (SAR) in the High Production 

Volume Chemicals Challenge Program. OPPT, EPA. 

West, R.J. (2004a). A report of The Dow Chemical Company using Level I model version 

2.11, Obtained from the Canadian Environmental Modeling Centre, Trent University, 

Peterborough, Ontario, Canada. 

West, R.J. (2004b). A report of The Dow Chemical Company using BIOWIN estimation 

software. 

Deleted: , 

19 
Young, B.E. and Tapp, J.F. (1983). The Toxicity of AMP 95 to the brown shrimp (Crangon 

crangon) and plaice (Pleuronectes platessa). Report K349/B for the Central Electricity 

Generating Board, Manchester, UK by Imperial Chemical Industries, PLC. 

20 
Table 3: Summary of the Data 

Formatted Table SURROGATE SUBSTANCES 

TRIS AMINO (77-86-1) AMPD (115-69-5) AMP (124-68-5) 

PHYSICAL 

CHEMISTRY 

Melting point, °C 171-172 110 30.5 

Boiling point, °C 219-220 oC @ 

133.3hPa 

290.9 oC @ 1013hPa 

151-152 165oC @ 1013hPa 

Vapor Pressure @ 

20°C 

3.0x10-6hPa 8.71x10-3 hPa 4.5.3x10-1 hPa 

Water Solubility 

@ 25o

C 

800 g/L 2500 g/L Miscible all proportions 

Log Kow -2.31 <-3.8 -0.63 

Estimated LogD 

(log Kow @ pH 7) 

-2.22 -- -2.77 

Density 0.932 g/cm3 @ 20oC --- 0.928 g/cm

3

 @ 20oC 

ENVIRONMENTAL 

FATE 

Biodegradation Not inherently inherently Not inherently; does 

not biodegrade 

Hydrolysis Not expected Not expected Not expected 

Photodegradation Direct photolysis not 

expected. 

Direct photolysis not 

expected. 

Direct photolysis not 

expected. 

Transport 

between 

Environmental 

Compartments: 

(Fugacity Level 

III Model) 

Default 

assumption: 1000 

kg/hr released 

simultaneously 

into air, water, 

and soil. 

<0.1% to air 

68.6% to water 

31.4% to soil 

<0.1% to sediment 

--- 0.07% to air 

73.9% to water 

26.0% to soil 

0.03% to sediment 

ECOTOXICITY 

Acute Toxicity to 

Fish 

( LC50) 

Non-toxic to 29 species 

in concentrations up to 

4400 mg/L. Used as a 

buffering agent at 440­

1100 mg/L for shipping 

live fish 

96-h static LC50 in 

zebrafish is >10,000 

mg/L 

Marine LC50(96h)= 

184 mg/L in 

Pleuronectes platessa 

Freshwater LC50(48h) 

= 331mg/L in 

Formatted Table 

Formatted Table 

Formatted: Font color: Auto 

Formatted Table 

21 
Leuciscus idus 

Acute Toxicity to 

Aquatic 

Invertebrates 

(48hr LC50) 

--- --- LC50 = 179 mg/L in 

Crangon crangon 

EC50 = 193 mg/L in 

Daphnia magna 

Toxicity to 

Aquatic Plants 

72-hour growth rate 

NOEC > 200 mg/L; 96­

hour growth rate NOEC 

> 100 mg/L in 

Selenastrum 

capricornutum 

--- 72-hour EC50 = 520 

mg/L in Scenedesmus 

sp. 

TOXICOLOGICAL 

DATA 

Acute Toxicity 

(oral) 

LD50 > 3000 mg/kg in 

rats (20% solution) & 

mice (5% solution) 

LD50 was 3500 - 

4400 mg/kg in mice 

LDLo=140 mg/kg in 

mice 

LDLo= 1500 mg/kg in 

rabbits 

LD50 = 2900 + 140 

mL/kg in rats 

LD50 = 2150 mL/kg in 

mice 

LDlo = 1000-2000 

mL/kg in rabbits 

Acute Toxicity 

(dermal) mg/kg 

LD50 > 1000 mg/kg in 

rats & mice 

--- LD50 > 2000 mg/kg in 

rabbits 

Acute Toxicity 

(inhalation) 

--- --- --- 

Acute Toxicity 

(other routes) 

LD50 = 3280-4040 

mg/kg in rats via tail 

vein 

LD50 = 6000 mg/kg in 

rats via tail vein 

LD50 = 6100 mg/kg in 

mice via tail vein 

--- LC50 = 325 mg/kg in 

mice i.p. dose 

Acute Skin 

Irritation 

In rabbits, a mild 

irritant on abraded 

skin, resolved within 48 

hours 

--- In rabbits, an irritant 

in abraded (burrowing 

lesions) or intact 

(dermatitis) skin. 

Acute Eye 

Irritation 

In rabbits, saturated 

TRIS AMINO solution 

(40%) is essentially 

non-irritating. 

--- In rabbits, vision was 

destroyed if eyes were 

flushed or unflushed. 

Neat AMP is highly 

irritating likely due to 

high pH. 

Sensitization --- 0.1% negative on Intracutaneous test 

Formatted Table 

Formatted Table 

22 
Guinea Pig and a later patch test 

with guinea pigs found 

AMP to be a nonsensitizer. 

Repeated Dose 

Toxicity 

NOAEL = 500 mg/kg of 

0.3M THAM in 

Sprague-Dawley rats 

for 20 days of infusions. 

NOAEL > 0.5mg/kg of 

0.3M THAM for 4 

weeks via IV in rabbits 

20-Day dermal rabbit 

– No effects 

LOAEL < 25ppm via 

diet for 12 weeks in 

Sprague-Dawley rats 

(increased liver 

weights) 

LOAEL~1000ppm via 

diet for 8 weeks in 

Sprague-Dawley rats 

(alopecia & focal skin 

erosions) 

NOAEL > 3200ppm 

via diet for 8 weeks in 

CD-1 mice 

NOAEL = 25ppm via 

diet for 13 weeks in 

dogs (clin chemistry & 

organ weight changes 

suggesting liver as 

target organ) 

NOAEL > 110ppm via 

diet for 1 year in dogs 

Genetic ToxicityMutation 

Bacterial cell gene 

mutation assay 

(bacterial strains)- 

negative 

Not mutagenic in 4 

strains of Salmonella, 

with or without 

metabolic activation 

AMES Test – negative 

Mammalian cell gene 

mutation assay – 

negative 

Bacterial Reverse Mut. 

Assay – negative 

Genetic ToxicityChromosomal 

Aberrations 

--- --- Mouse Micronucleus 

Assay- negative 

Toxicity to 

Reproduction 

--- --- A 1 year dietary dog 

study revealed no 

gross or 

histopathologic effect 

on testes, uteri, or 

ovaries (NOAEL > 

110ppm) 

NOEL for general 

Formatted Table 

23 
toxicity in male rats 

was 300 mg/kg/day; 

the general toxicity 

NOEL for female rats 

could not be 

determined, based 

upon the presence of 

very slight microscopic 

liver effects. NOEL for 

reproductive effects is 

100 mg/kg/day. 

(OECD 421 study) 

Developmental 

Toxicity 

--- --- NOAEL for maternal 

toxicity based on 

dermal effects was 100 

mg/kg/day. The NOEL 

for developmental 

toxicity was 300 

mg/kg/day, the highest 

dose level tested. 

(Developmental study 

in rats OECD 414) 

24 
Table 4: Test Plan Matrix 

TRIS AMINO 

 (77-86-1) 

AMPD

 (115-69-5) 

AMP 

(124-68-5) 

PHYSICAL 

CHEMISTRY 

Melting point, °C 171-172

 (measured) 

A No Data 

110 

(measured)

 No Data 

30.5 

(measured) 

 No Data 

Boiling point, °C 219-220 (measured) 

A No Data 

151-152 (measured) 

 No Data 

165 (measured)

 No Data 

Vapor Pressure @ 20°C 3.0x10-6hPa 

(calculated) 

Calc No Data 

8.714x10-3 hPa 

(calculated) 

Calc No Data 

4.5.3x10-1 hPa 

(calculated) 

Calc No Data 

Water Solubility @ 25oC 800 g/L (measured) 

A No Data 

2500 g/L 

(measured) 

Exp No Data 

Miscible all 

proportions 

(measured) 

 No Data 

Log Kow -2.31(measured) 

A No Data 

<-3.8 (measured) 

No Data 

-0.63 

Calc No Data 

ENVIRONMENTAL 

FATE 

Biodegradation Not 

Inherently(measured) 

A No Data 

Inherently(measured) 

No Data 

Not inherently; does 

not biodegrade Calc 

No Data 

Hydrolysis Not expected 

NA No Data 

Not expected 

NA No Data 

Not expected 

NA No Data 

Photodegradation Direct photolysis not 

expected. 

NA No Data 

Direct photolysis not 

expected. 

NA No Data 

Direct photolysis not 

expected. 

NA No Data 

Transport between 

Environmental 

Compartments: 

(Fugacity Level III Model) 

Default assumption: 1000 

kg/hr released 

simultaneously into air, 

water, and soil. 

<0.001% to air 

68.6% to water 

31.4% to soil 

<0.1% to sediment 

Calc No Data 

--- 0.07% to air 

73.9% to water 

26.0% to soil 

0.03% to sediment 

Calc No Data 

ECOTOXICITY 

Acute Toxicity to Fish 

( LC50) 

Non-toxic 

A No Data 

LC50 (96-h) static in 

zebrafish is >10,000 

mg/L 

LC50(48h) in Bluegill 

sunfish 

Y 

Acute Toxicity to Aquatic 

Invertebrates (48hr LC50) 

R R 

EC50 in Daphnia 

magna 

Y 

Formatted: Font color: Black 

Formatted: Font color: Black 

25 
Toxicity to Aquatic Plants 72-hour growth rate 

NOEC in 

Selenastrum 

capricornutum 

A No Data 

--- 72-hour EC50 in 

Scenedesmus sp. 

No Data 

TOXICOLOGICAL 

DATA 

Acute Toxicity (oral) LD50 in rats 

A No Data 

LD50 in mice and rats LD50 in mice and rats 

N 

Acute Toxicity (dermal) 

mg/kg 

LD50 in rats & mice 

A N 

--- LD50 in rabbits 

N 

Acute Toxicity (inhalation) NA NA NA 

Acute Skin Irritation Irritant 

A N 

--- Irritant 

N 

Acute Eye Irritation Non-irritating 

A No Data 

--- Highly irritating 

likely due to high pH. 

N 

Sensitization Non-sensitizer 

R 

Non-sensitizer Non-sensitizer

 N 

Repeated Dose Toxicity 20-day IV in rats 

4-week IV in rabbits 

R 

--- Diet (12 weeks) in 

rats No Data 

Diet (8 weeks) in rats 

No Data 

Diet (8 weeks)in mice 

No Data 

Diet (13 weeks) in 

dogs No Data 

Diet (1 year) in dogs 

Y

 N, Y 

Carcinogenicity Test 

Negative for tumors 

A 

 Negative 

Genetic Toxicity-Mutation Negative 

A N 

Negative All negative

 Y 

Genetic ToxicityChromosomal Aberrations R --- Negative 

Y 

Toxicity to Reproduction 

Test (Dependent on 

FOIA result) 

--- One year dietary 

dog study

 Y 

OECD 421 in 

rats 

Y 

Developmental Toxicity Test (Dependent on 

FOIA result) 

--- OECD 414 in 

rats 

Y 

26 
Symbol 

R 

Test 

Calc 

A 

Exp 

NR

NA 

Y 

N 

No Data 

Legend 

Description 

Endpoint requirement fulfilled using Structurally related information 

Endpoint requirements to be fulfilled with testing 

Endpoint requirement fulfilled based on calculated data 

Endpoint requirement fulfilled with adequate existing data 

Endpoint requirement fulfilled via experimentation 

Not required per the OECD SIDS guidance 

Not applicable due to physical/chemical properties 

Yes (GLP) 

No (GLP) 

No data on GLP status 

27 
RECEIVED v- 

! 

OP6T CErlC 

2@6 OEC - I A!"! 7: 32 

IUCLID 

Data Set 

Existing Chemical : ID: 77-86-1 

CAS NO. : 77-86-1 

Molecular Formula : C4HllN03 

CAS Name : Tris (hydroxyrnethyl) aminomethane 

Producer related part 

Company : The Dow Chemical Company 

Creation date : 11.11.2006 

Substance related part 

Company : The Dow Chemical Company 

Creation date : 11.11.2006 

Status 

Memo 

Printing date : 14.1 1.2006 

Revision date 

Date of last update : 14.1 1.2006 

Number of pages : 60 

Chapter (profile) : Chapter: 1,2,3,4, 5,6,7, 8, 10 

Rellablllty (profile) : Reliability: without reliability, 1,2, 3, 4 

Flags (profile) : Flags: without flag, confidential, non confidential, WGK (DE), TA-Luft (DE), 

Material Safety Dataset, Risk Assessment, Directive 67/548/EEC, SlDS 
1. General Information Id 77-86-1 

Date 14.11.2006 

1.0.1 APPLICANT AND COMPANY INFORMATION 

Type : manufacturer 

Name : Dow Chemical, TERC 

Contact person : Dr. William T. Stott 

Date : 27.08.2006 

Street : 1803 Building

Town : 48674 Midland, MI 

Country : United States 

Phone : 

Telefax : 

Telex : 

Cedex : 

Email : 

Homepage : 

Source : Dow Chemical, TERC Midland, MI 

30.08.2006

1.0.2 LOCATION OF PRODUCTION SITE, IMPORTER OR FORMULATOR 

Type : manufacturer 

Name of plant : Dow Chemical 

Street : 

Town : Sterlington, Louisiana 

Country : United States 

Phone : 

Telefax : 

Telex : 

Cedex : 

Email : 

Homepage : 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

13.11.2006 (1) 

Type : manufacturer 

Name of plant : Dow Chemical 

Street : 

Town : Ibbenburen 

Country : Germany 

Phone : 

Telefax : 

Telex : 

Cedex : 

Email : 

Homepage : 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

13.11.2006 (1) 

2 / 60 
1. General Information Id 77-86-1 

Date 14.11.2006 

1.0.3 IDENTITY OF RECIPIENTS 

1.0.4 DETAILS ON CATEGORY/TEMPLATE 

1.1.0 SUBSTANCE IDENTIFICATION 

IUPAC Name : 2-Amino-2-hydroxymethyl-1,3-propanediol 

Smiles Code : OCC(N)(CO)CO 

Molecular formula : C4H11NO3 

Molecular weight 

Petrol class 

: 

: 

121.14 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

09.11.2006 (2) 

1.1.1 GENERAL SUBSTANCE INFORMATION 

Purity type : typical for marketed substance 

Substance type : organic 

Physical status : solid 

Purity : 

Colour : White 

Odour : Odorless 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

13.11.2006 (3) 

1.1.2 SPECTRA 

Type of spectra : NMR 

Result : 13-Carbon NMR spectra of TRIS were measured between 407 and 461 K. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (4) 

1.2 SYNONYMS AND TRADENAMES 

Talatrol 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

19.03.2004 (2) 

THAM 

Source : Dow Chemical, TERC Midland, MI 

3 / 60 
1. General Information Id 

Date 

77-86-1 

14.11.2006 

Reliability

19.03.2004 

: (2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

Trimethlol aminomethane 

Source 

Reliability

19.03.2004 

: 

: 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

TRIS 

Source 

Reliability

19.03.2004 

: 

: 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

TRIS AMINO ® 

Source 

Reliability

10.11.2006 

: 

: 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

Tris Buffer 

Source 

Reliability

19.03.2004 

: 

: 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

Tris(hydroxymethyl)aminomethane 

Source 

Reliability

19.03.2004 

: 

: 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

Tris-steril 

Source 

Reliability

19.03.2004 

: 

: 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

Trisamine 

Source 

Reliability

19.03.2004 

: 

: 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

Trizma 

Source 

Reliability

19.03.2004 

: 

: 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

Trometamol 

4 / 60 
1. General Information Id 77-86-1 

Date 14.11.2006 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

19.03.2004 (2) 

Tromethane 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

09.11.2006 (2) 

1.3 IMPURITIES 

Purity : typical for marketed substance 

CAS-No : 

EC-No : 

EINECS-Name : 

Molecular formula : 

Value : 

Remark : The compound is sold as 100% crystal or a 40% aqueous solution of 

tris(hydroxymethyl)aminomethane. 

Source : MSDS of the Dow Chemical Company. 2003. 

Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

09.11.2006

1.4 ADDITIVES 

Purity type : typical for marketed substance 

CAS-No : 7732-18-5 

EC-No : 231-791-2 

EINECS-Name : water 

Molecular formula : H2O 

Value : ca. 40 % v/v

Function of additive : Solvent 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

09.11.2006 (1) 

1.5 TOTAL QUANTITY 

1.6.1 LABELLING 

1.6.2 CLASSIFICATION 

1.6.3 PACKAGING 

5 / 60 
1. General Information Id 77-86-1 

Date 14.11.2006 

1.7 USE PATTERN 

Type of use : use 

Category : other: Emulsifier for cosmetics, mineral oil and wax emulsions, leather 

dressings, textiles, cleaners, pharmaceuticals, and chemical intermediate 

buffer 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

10.11.2006 (1) (2) 

1.7.1 DETAILED USE PATTERN 

1.7.2 METHODS OF MANUFACTURE 

Result : May be prepared by reduction or catalytic hydrogenation of corresponding 

nitro compound. Preparation by electrolytic reduction: McMillan, US Patent 

2,485,982 (1949 TO COMM SOLVENTS CORP), CA 44, 1836B (1950) 

Source : Hazardous Substances Data Bank. 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

13.11.2006 (5) 

1.8 REGULATORY MEASURES 

1.8.1 OCCUPATIONAL EXPOSURE LIMIT VALUES 

1.8.2 ACCEPTABLE RESIDUES LEVELS 

1.8.3 WATER POLLUTION 

1.8.4 MAJOR ACCIDENT HAZARDS 

1.8.5 AIR POLLUTION 

1.8.6 LISTINGS E.G. CHEMICAL INVENTORIES 

1.9.1 DEGRADATION/TRANSFORMATION PRODUCTS 

Type : degradation product 

CAS-No : 

EC-No : 

EINECS-Name : 

6 / 60 
1. General Information Id 77-86-1 

Date 14.11.2006 

IUCLID Chapter : 

Remark : THAM is stable at room temperature for periods as long as 12 years. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (6) 

1.9.2 COMPONENTS 

1.10 SOURCE OF EXPOSURE 

Source of exposure : Human: exposure by production 

Exposure to the : Substance 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

09.11.2006 (1) 

Source of exposure : Human: exposure through intended use 

Exposure to the : Substance 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

09.11.2006 (1) 

Source of exposure : Human: exposure of the consumer/bystander 

Exposure to the : Substance 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

09.11.2006 (1) 

1.11 ADDITIONAL REMARKS 

1.12 LAST LITERATURE SEARCH 

Type of search : Internal and External 

Chapters covered : 3, 4, 5 

Date of search : 03.11.2006 

13.11.2006 

1.13 REVIEWS 

7 / 60 
2. Physico-Chemical Data Id 77-86-1 

Date 14.11.2006 

2.1 MELTING POINT 

Value : 

Sublimation : 

Method : 

Year : 

GLP : 

Test substance : 

Source : 

Reliability : 

19.03.2004 

Value : 

Sublimation : 

Method : 

Year : 

GLP : 

Test substance : 

Source : 

Reliability : 

24.03.2004 

2.2 BOILING POINT 

Value : 

Remark : 

Source : 

Reliability : 

28.06.2004 

Value : 

Source : 

Reliability : 

24.03.2004 

2.3 DENSITY 

2.3.1 GRANULOMETRY 

2.4 VAPOUR PRESSURE 

Value : 

Decomposition : 

ca. 171 - 172 °C 

1989 

as prescribed by 1.1 - 1.4 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

ca. 171 - 172 °C 

1940 

as prescribed by 1.1 - 1.4 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(7) 

ca. 219 - 220 °C at 101.33 hPa 

@ 10mmHg 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(2) 

ca. 219 - 220 °C at 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(7) 

ca. .000003 hPa at 25 °C 

8 / 60 
2. Physico-Chemical Data Id 77-86-1 

Date 14.11.2006 

Method : other (calculated) 

Year : 2004 

GLP : 

Test substance : 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Accepted calculation method. 

28.06.2004 (8) 

2.5 PARTITION COEFFICIENT 

Partition coefficient : octanol-water 

Log pow : = -2.31 at 20 °C

pH value : 

Method : OECD Guide-line 107 "Partition Coefficient (n-octanol/water), Flaskshaking Method" 

Year : 1996 

GLP : no data 

Test substance : as prescribed by 1.1 - 1.4 

Conclusion : The calculated partition coefficient is consistent with high water solubility 

and which by definition would be indicative of low log Kow values. 

Reliability : (1) valid without restriction 

Comparable to a guideline study. 

13.11.2006 (9) 

Partition coefficient : octanol-water 

Log pow : <= -3.8 at 20 °C

pH value : 

Method : OECD Guide-line 107 "Partition Coefficient (n-octanol/water), Flaskshaking Method" 

Year : 1997 

GLP : no data 

Test substance : other TS:AMPD 

Test substance : AMPD (2-Amino-2-methyl-1,3-propanediol) CAS# 000115-69-5. Molecular 

weight = 105.14 

13.11.2006 (10) 

Partition coefficient : octanol-water 

Log pow : ca. -2.22 at °C

pH value : = 7 

Method : other (calculated) 

Year : 2004 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Model Input Parameters: 

Data Temperature (°C) = 25 

Chemical Type = 1 

Molecular Mass (g/mol) = 121.14 

Water Solubility (g/m3) = 550,000 

Vapor Pressure @ 25° C (Pa) = 3.0 x 10-4 

Melting Point ( C) = 171.5 

Estimated Henry's Law Constant (H) (Pa m3/mol) = 6.7 x 10-8 

Log Kow (Octanol-Water Partition Coefficient) = -2.22 / 1.38 

Simulated Emission (kg) = 100,000 

9 / 60 
2. Physico-Chemical Data Id 77-86-1 

Date 14.11.2006 

Conclusion : This material has very high water solubility, very low vapor pressure, and 

very low log Kow. In the absence of advective and reactive processes, 

these physical properties dictate that the material will partition exclusively 

to the water compartment at equilibrium. 

Reliability : (2) valid with restrictions 

Accepted calculation method. 

07.04.2004 (11) 

2.6.1 SOLUBILITY IN DIFFERENT MEDIA 

Solubility in : Water 

Value : ca. 800 g/l at 25 °C 

pH value : 

 concentration : at °C 

Temperature effects : 

Examine different pol. : 

pKa : 8.03 at 25 °C 

Description : 

Stable : 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

13.11.2006 (12) 

Solubility in : Water 

Value : ca. 550 other:mg/mL at 25 °C 

pH value : ca. 10.4 

 concentration : .1 other:Molar at 25 °C 

Temperature effects : 

Examine different pol. : 

pKa : at 25 °C 

Description : 

Stable : 

Deg. product : 

Method : 

Year : 1989 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

19.03.2004 (2) 

2.6.2 SURFACE TENSION 

2.7 FLASH POINT 

2.8 AUTO FLAMMABILITY 

2.9 FLAMMABILITY 

10 / 60 
2. Physico-Chemical Data Id 

Date 

77-86-1 

14.11.2006 

2.10 EXPLOSIVE PROPERTIES 

2.11 OXIDIZING PROPERTIES 

2.12 DISSOCIATION CONSTANT 

Acid-base constant 

Method

Year 

GLP 

Test substance 

: 

: 

: 

: 

: 

8.21 

1989 

Source 

Reliability

28.06.2004 

: 

: 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Data from handbook or collection of data. 

(13) 

2.13 VISCOSITY 

2.14 ADDITIONAL REMARKS 

Memo 

Source 

Reliability

13.11.2006 

: 

: 

: 

pKa= 8.3 @ 20°C; 8.03 @ 25°C; 7.8 @ 37°C 

L. Troester (2006) ANGUS data. 

(2) valid with restrictions 

Data from handbook or collection of data. 

11 / 60 
3. Environmental Fate and Pathways Id 77-86-1 

Date 14.11.2006 

3.1.1 PHOTODEGRADATION 

3.1.2 STABILITY IN WATER 

Type

t1/2 pH4 

t1/2 pH7 

t1/2 pH9 

Deg. product 

Method

 : 

: 

: 

: 

: 

: 

abiotic 

at °C 

at °C 

at °C 

Year : 

GLP : no data 

Test substance : as prescribed by 1.1 - 1.4 

Conclusion : TRIS AMINO is stable for several years at ambient temperatures according 

to ANGUS files. 

Reliability : (2) valid with restrictions 

Data from handbook or colletion of data. 

13.11.2006 (14) 

3.1.3 STABILITY IN SOIL 

3.2.1 MONITORING DATA 

3.2.2 FIELD STUDIES 

3.3.1 TRANSPORT BETWEEN ENVIRONMENTAL COMPARTMENTS 

Type : fugacity model level III 

Media : water - air 

Air : % (Fugacity Model Level I) 

Water : 100 % (Fugacity Model Level I) 

Soil : % (Fugacity Model Level I) 

Biota : % (Fugacity Model Level II/III) 

Soil : % (Fugacity Model Level II/III) 

Method : other: calculated Canadian Environmental Modeling Centre, Trent 

University, Peterborough, Ontario, Canada. 

Year : 2006 

Result : Tris(hydroxymethyl)aminomethane has high water solubility, a low vapor 

pressure, and low log Kow. The substance has a low potential for 

adsorption to soil or sediments, and a low potential to volatilize from water 

or soil to the atmosphere. If released to air, the substance will react with 

hydroxyl radicals. If released directly to water, the most probable emission 

route based on physical properties and use patterns, most of the substance 

will remain in the water compartment and is expected to be biodegraded. If 

released to soil, the substance is expected to be biodegraded. 

Test condition : Input Parameters for Level I Model: 

Data Temperature (°C) = 25 

Chemical Type = Type 1 indicates chemical can partition into all 

12 / 60 
3. Environmental Fate and Pathways Id 77-86-1 

Date 14.11.2006 

environmental compartments 

Molecular Mass (g/mol) = 121 

Water Solubility (g/m3) = 8.0 x 10^5 

Vapor Pressure @ 25° C (Pa) = 3.0 x 10^-4 

Melting Point (°C) 171.5 

Estimated Henry's Law Constant (H) (Pa m3/mol)= 4.54 x10^-8 

Log Kow Octanol-Water Partition Coefficient = -2.3 

(Estimated value of Log D at pH 7.0 / Estimated value for neutral species) 

Simulated Emission (kg) = 100,000 (Level I Default Value) 

Input parameters to Level III Model: 

Data Temperature (°C)=25 Default environmental temperature 

Chemical Type= Type 1 indicates chemical can partition into all 

environmental compartments 

Molecular Mass (g/mol)= 121 

Water Solubility (g/m3)= 8.0 x 10^5 

Vapor Pressure @ 25°C (Pa)= 3 x 10^-4 

Melting Point (°C)= 171.5 

Henry's Law Constant (Pa*m3/mole)= 4.54 x10^-8 

Log Kow (Octanol-Water Partition Coefficient)= -2.3 

Simulated Emission Rate (kg/hr)= 1,000 

Simulated Environment Level III Default environment 

Reaction Half-lives (hr) Input to Level III Model: 

Air (vapor phase) 4 

*Water (no susp. solids) 3600 

*Soil 7200 

*Sediment 7200 

**Suspended Sediment 1.0 x 10^11 

**Fish 1.0 x 10^11 

**Aerosol 1.0 x 10^11 

*Half-lives extrapolated based on inherent biodegradability classification, 

according to Technical Guidance Document of the European Commission. 

**Default value used in Level III model when reaction is expected to be 

negligible in this compartment. 

Reliability : (2) valid with restrictions 

Accepted calculation method. 

14.11.2006 (15) 

Type : fugacity model level III 

Media : water - air 

Air : 0 % (Fugacity Model Level I)

Water : 100 % (Fugacity Model Level I)

Soil : 0 % (Fugacity Model Level I)

Biota : % (Fugacity Model Level II/III)

Soil : % (Fugacity Model Level II/III)

Method : 

Year : 2002 

Result : This material has very high water solubility, very low vapor pressure, and 

very low log Kow. These properties dictate that the material has low 

potential to volatilize from water or soil to air, or adsorb to soil and 

sediments from the dissolved state. When released to water (the most 

likely emission scenario), the material will remain dissolved in water and is 

expected to be ultimately biodegraded. If released to soil, the material will 

be primarily dissolved, and remain mobile in, soil pore water (groundwater). 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Input Parameters for Level I Model: 

Data Temperature (°C) = 25 

13 / 60 
3. Environmental Fate and Pathways Id 77-86-1 

Date 14.11.2006 

Chemical Type = Type 1 indicates chemical can partition into all 

environmental compartments 

Molecular Mass (g/mol) = 121.14 C 

Water Solubility (g/m3) = 550,000 

Vapor Pressure @ 25° C (Pa) = 3.0 x 10-4 

Melting Point ( C) 171.5 

Estimated Henry's Law Constant (H) (Pa m3/mol) = 6.7 x 10-8 

Log Kow Octanol-Water Partition Coefficient = -2.22 / 1.38 (Estimated 

value of Log D at pH 7.0 / Estimated value for neutral species) 

Simulated Emission (kg) = 100,000 (Level I Default Value) 

Estimated Henry's Law Constant (H) = (Pa m3/mol) 6.7 x 10-8 

Reaction Half-lives (hr.) Input to Level III Model 

Air (vapor phase) 3.8 

Water (no susp. solids) 3600 

Soil 7200 

Sediment 7200 

Suspended Sediment 1.0 x 10^11 

Fish 1.0 x 10^11 

Aerosol 1.0 x 10^11 

Reliability : (2) valid with restrictions 

Acceptable calculation method. 

09.11.2006 (16) 

3.3.2 DISTRIBUTION 

3.4 MODE OF DEGRADATION IN ACTUAL USE 

3.5 BIODEGRADATION 

Type : aerobic 

Inoculum : 

Deg. product : 

Method : OECD Guide-line 301 D "Ready Biodegradability: Closed Bottle Test" 

Year : 1990 

GLP : no data 

Test substance : as prescribed by 1.1 - 1.4 

Conclusion : TRIS AMINO is not readily biodegradable. 

Reliability : (1) valid without restriction 

Meets national standard methods (AFNOR/DIN). 

13.11.2006 (17) 

3.6 BOD5, COD OR BOD5/COD RATIO 

3.7 BIOACCUMULATION 

3.8 ADDITIONAL REMARKS 

14 / 60 
4. Ecotoxicity Id 77-86-1 

Date 14.11.2006 

4.1 ACUTE/PROLONGED TOXICITY TO FISH 

Type

Species 

Exposure period 

Unit 

: 

: 

: 

: 

other: aerated and static were both tested 

other:29 species were tested 

Method : 

Year : 1958 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Fish were exposed to the buffer for 2 days, then placed in untreated water 

and observed for 30 days. Fresh-water species were left in the buffer 

solutions for 9 days. The vessels were tested under static and aerated 

conditions separately. Fish were monitored for signs of toxicity. 

Result : Increases in weight occurred in all species. The pH decline over the 9 day 

fresh-water test was 0.02 pH units. One specimen of chiclid (Aquidens 

portalegrensis) died during the third day, likely die to starvation since none 

were fed until the fourth day. There was no other mortality in any other fish 

throughout the study period. 

The only observations of toxicity noted were to specimens of the opaleye 

(Girella nigricans), which exibited a marked interruption of opercular 

movements after 5 hours in the TRIS buffer. Irregularities appeared in 

solutions ranging from 5-20g TRIS per gallon water. The irregularities were 

characterized by two or three large opercular beats, followed by a pause 

lasting 5-10 seconds. Total beats varied from 8-20 per minute. The upset 

in opercular rhythm did not seem to have an adverse effect upon the fish. 

They appeared normal in all other aspects. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : The following marine species were tested: 

Heterodontus francisci 

Holocentris microstomus 

Myripristis murdjan 

Pseudopeneus bifasciatus 

Amphiprion percula 

Lepidaplois bilunulatus 

Iniistius pavo 

Girella nigricans 

Kuhlia marginatus 

Hippocampus punctulatus 

Hepatus olivaceus 

Hepatus bariene 

Microcanthis strigatus 

Zebrasoma flavescens 

Zanclus canescens 

Heterostichus rostratis 

Leptocottus armatus 

Clinocottus analis 

Balistes vidua 

The following fresh water species were tested: 

Lebistes reticulatus 

Mollienesia sp. 

Aequidens portalegrensis 

Cichlasoma nigrofasciatus 

Conclusion : Tests indicate that 29 species of fish can stand high concentrations of 

buffer (20g / gallon) dissolved in transport water. Light dosages (2-5g / 

gallon) are adequate to stabilize pH during transport of fish, regardless of 

15 / 60 
4. Ecotoxicity Id 77-86-1 

Date 14.11.2006 

the presence of aeration (provided the weight of fish transported does not 

exceed 25-50g / gallon in a closed system). The data indicate that TRIS 

buffer is nontoxic to the 29 species tested under these conditions. 

Buffered solutions are stable for up to three months at normal air 

temperatures. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (18) 

Type

Species 

Exposure period 

Unit 

: 

: 

: 

: 

static 

Brachydanio rerio (Fish, fresh water) 

96 hour(s) 

mg/l 

LC50 : > 10000 measured/nominal 

Method : OECD Guide-line 203 "Fish, Acute Toxicity Test" 

Year : 1997 

GLP : 

Test substance : other TS:AMPD 

Result : Hour LC50 (mg/L) 

24 >10000 

48 >10000 

72 >10000 

96 >10000 

Test substance : AMPD: 2-Amino-2-methyl-1,3-propanediol 

Conclusion : The acute LC50 96-hour for Brachydanio rerio is > 10,000 mg/L for AMPD. 

Reliability : (2) valid with restrictions 

Guideline study with acceptable restrictions. 

14.11.2006 (19) 

Type

Species 

Exposure period 

Unit 

: 

: 

: 

: 

Leuciscus idus (Fish, fresh water) 

96 hour(s) 

mg/l 

LC50 : > 10000 calculated 

Method : 

Year : 1990 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Source : IWL labs 1990 

Conclusion : The 96-h LC50 in golden orfe is >10,000 mg/L. 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data. 

13.11.2006 (20) 

4.2 ACUTE TOXICITY TO AQUATIC INVERTEBRATES 

Type : 

Species : Crangon crangon (Crustacea) 

Exposure period : hour(s) 

Unit : mg/l 

LC50 : = 179 measured/nominal 

Method : 

Year : 1983 

GLP : no data 

Test substance : other TS: AMP 

16 / 60 
4. Ecotoxicity Id 77-86-1 

Date 14.11.2006 

Test substance : AMP-95 (2-Amino-2-methyl-1-propanol) 

Conclusion : The 48- & 96-hour LC50 values for Crangon crangon is 179 mg/L. 

Reliability : (2) valid with restrictions 

13.11.2006 (21)

Type : 

Species : Daphnia magna (Crustacea) 

Exposure period : 48 hour(s) 

Unit : mg/l 

EC50 : = 193 measured/nominal 

Method : 

Year : 1980 

GLP : no data 

Test substance : other TS:AMP

Test substance : AMP95 (2-Amino-2-methyl-1-propanol) 

Conclusion : In Daphnia magna, AMP-95 was reported with a 48-hour EC50 of 193 

mg/L. 

Reliability : (2) valid with restrictions 

13.11.2006 (22) 

4.3 TOXICITY TO AQUATIC PLANTS E.G. ALGAE 

Species : Selenastrum capricornutum (Algae) 

Endpoint : growth rate 

Exposure period : 4 day(s) 

Unit : μg/l 

NOEC : ca. 100 measured/nominal 

Method : 

Year : 1985 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Dilutions of the actively-growing cultures were added to test flasks to give 

an approximate initial count of 1000 cells per mL, and incubated 24 hours. 

An appropriate volume of test material was added to achieve the desired 

concentration, and the culture volume made up to 100mL with particle-free 

deionized water. Cell counts were made every 24 hours. The cell counts 

were used to calculate the growth parameters to establish quantitative toxic 

values. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Stock cultures of Selenastrum were maintained at 22C under constant 

illumination from 2 fluorescent tubes, on slopes of Oxoid agar containing 

Bold's basal medium. About 7 days prior to use, 2 conical flasks of 90mL 

particle-free BBM were aseptically inoculated with Selenastrum from stock 

cultures. The cultures were incubated at 22C, and shaken at 175 rpm 

under constant illumination. Sub-cultures were made into fresh medium 2 

days prior to inoculation of the test flasks, and incubated under identical 

conditions. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (23) 

Species : Selenastrum capricornutum (Algae) 

Endpoint : growth rate 

Exposure period : 96 hour(s) 

Unit : μg/l 

NOEC : ca. 100 measured/nominal 

Method : 

17 / 60 
4. Ecotoxicity Id 77-86-1 

Date 14.11.2006 

Year : 1985 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Dilutions of the actively-growing cultures were added to test flasks to give 

an approximate initial count of 1000 cells per mL, and incubated 24 hours. 

An appropriate volume of test material was added to achieve the desired 

concentration, and the culture volume made up to to 100mL with particlefree deionized water. Cell counts were made every 24 hours. The cell 

counts were used to calculate the growth parameters to establish 

quantitative toxic values. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Stock cultures of Selenastrum were maintained at 22C under constant 

illumination from 2 fluorescent tubes, on slopes of Oxoid agar containing 

Bold's basal medium. About 7 days prior to use, 2 conical flasks of 90mL 

particle-free BBM were aseptically inoculated with Selenastrum from stock 

cultures. The cultures were incubated at 22C, and shaken at 175 rpm 

under constant illumination. Sub-cultures were made into fresh medium 2 

days prior to inoculation of the test flasks, and incubated under identical 

conditions. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (23) 

4.4 TOXICITY TO MICROORGANISMS E.G. BACTERIA 

Type : aquatic 

Species : Pseudomonas putida (Bacteria) 

Exposure period : 

Unit : mg/l 

EC10 : ca. 33447 measured/nominal 

Method : other: Acute Bacteia Cell Multiplication Inhibition Test 

Year : 1990 

GLP : yes 

Test substance : other TS: TRIS AMINO 40% 

Method : A small amount of bacteria from a 7-day old stock culture of Pseudomonas 

putida was inoculated in fluid nutrient medium in Erlenmeyer flasks. The 

preliminary cultures were incubated at 25°C for 16-20 hours. 

Subsequently, the extinction of the monochromatic radiation at 436 nm for 

a 10 mm layer of the bacterial suspension was determined by photoelectric 

measurement. On the basis of the values measured, the final turbidity 

value if the bacterial suspension was adjusted. 

Four parallel dilution series in 300 ml Erlenmeyer flasks stoppered with 

aluminium caps were prepared from the formulated test substance stock 

solution and sterile Milli-Q water. Each flask contained 80 ml of liquid at 

the start. 

Each flask of three dilution seried to be inoculated, was made up to a final 

volume of 100 ml by adding 5 ml of a stock solution I, 5 ml of a stock 

solution II, and 10 ml of the prepared bacterial suspension from the 

preliminary culture having a known adjusted extinction value. 

The flasks of the dilution series that are not inoculated, were made up to 

100 ml by adding 5 ml of stock solution I, 5 ml of stock solution II, and 10 

ml of saline. 

Five culture flasks of the reference series were made up with 80 ml of the 

18 / 60 
4. Ecotoxicity Id 77-86-1 

Date 14.11.2006 

methanol concentration, 5 ml stock solution I, 5 ml stock solution II, and 10 

ml prepared bacterial solution. 

Ten control culture flasks with 80 ml sterile Milli-Q water, 5 ml stock 

solution I, 5 ml stock solution II and 10 ml prepared bacterial solution were 

also included. 

All flasks were left at 25°C for 16-20 hours. Subsequently, cell 

suspensions were homongenized and the extinction of the monochromatic 

radiation at 436 nm in a 10 mm layer in all series were measured. 

Because, after termination of the test period, coloration or turbidity 

occurred in the dilution series for chemical-physical reasons, the analogous 

steps of dilution of the non-inoculated series were used as photometric 

blank values for turbidity fo the inoculated dilutions series. 

Remark : The study procedure was based on the following guideline: 

Umweltbundesamt (UBA) Guidelines: wassergefährdender Stoffe, III 

Bestimmung der akuten Bakterientoxizität, ad-hoc-Arbeidsgruppe I 

(Obmann Dr. Niemitz), LTWS, Nr. 10, September 1979. 

Result : TRIS AMINO 40% was investigated for its ability to inhibit the cell 

multiplication of the bacteria species Pseudomonas putida. Cultures of 

Pseudomonas putida bacteria were exposed to concentrations ranging 

from 432 to 885.6x10^3 TRIS AMINO 40% per litre. Based on the solubility 

of TRIS AMINO 40% in water, a toxicity threshold value of TRIS AMINO 

40% of 33.4x10^3 mg/l for Pseudomonas putida could be determined. 

Conclusion : The Assessment figure or value for bacteria toxicity is 1.5. 

Reliability : (1) valid without restriction 

GLP guideline study. 

13.11.2006 (24) 

Type : aquatic

Species : Pseudomonas putida (Bacteria)

Exposure period : 

Unit : mg/l 

EC10 : = 400 measured/nominal 

EC50 : = 1600 measured/nominal 

Method : DIN 38412, part8 

Year : 1990 

GLP : no data 

Test substance : other TS: TRIS AMINO 40% 

Result : EC50 = 1600 mg/l 

EC10 = 400 mg/l 

Test condition : Concentrations (g/l): 10, 5, 2.5, 1.25, 0.625 and 0.315 

Temperature: 20-22°C 

Reliability : (2) valid with restrictions 

Meets national standard methods with acceptable restrictions. 

13.11.2006 (25) 

4.5.1 CHRONIC TOXICITY TO FISH 

4.5.2 CHRONIC TOXICITY TO AQUATIC INVERTEBRATES 

4.6.1 TOXICITY TO SEDIMENT DWELLING ORGANISMS 

19 / 60 
4. Ecotoxicity Id 

Date 

77-86-1 

14.11.2006 

20 / 60 

4.6.2 TOXICITY TO TERRESTRIAL PLANTS 

4.6.3 TOXICITY TO SOIL DWELLING ORGANISMS 

4.6.4 TOX. TO OTHER NON MAMM. TERR. SPECIES 

4.7 BIOLOGICAL EFFECTS MONITORING 

4.8 BIOTRANSFORMATION AND KINETICS 

4.9 ADDITIONAL REMARKS 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

5.0 TOXICOKINETICS, METABOLISM AND DISTRIBUTION 

5.1.1 ACUTE ORAL TOXICITY 

Type

Value 

: 

: 

LD50 

ca. 5000 ml/kg bw 

Species 

Strain 

: 

: 

mouse 

no data 

Sex : no data 

Number of animals : 10 

Vehicle : 

Doses : 10000, 7000, 5000, 3500 and 2000 mg/kg bw 

Method : 

Year : 1955 

GLP : no 

Test substance : as prescribed by 1.1 - 1.4 

Method : Ten mice per dose were administered TRIS AMINO solutions via gavage at 

a constant volume of 0.05 ml/gm bw. 

Conclusion : The oral LD50 in mice is 5500 mg/kg. 

Reliability : (2) valid with restrictions 

Meets national standard methods with acceptable restrictions. 

13.11.2006 (26) 

Type

Value 

: 

: 

LD50 

> 3000 mg/kg bw 

Species 

Strain 

: 

: 

other: rat and mice 

other:Wistar and Swiss 

Sex : 

Number of animals : 

Vehicle : 

Doses : 1000, 2000, and 3000 mg/kg as a solution 

Method : 

Year : 1962 

GLP : no data 

Test substance : as prescribed by 1.1 - 1.4 

Method : Solutions of 20% and 5% of TRIS AMINO were given via gastric intubation 

to rats and mice respectively at doses of 1000, 2000, and 3000 mg/kg. 

Result : There was no toxicity noted in either species at the top dose levels, 

although abundant urine output was noted for some animals 

Conclusion : The LD50 for rats and mice are estimated to be >3000 mg/kg in solution. 

Reliability

13.11.2006 

: (2) valid with restrictions 

(27) 

Type

Value 

: 

: 

LD50 

ca. 3350 mg/kg bw 

Species 

Strain 

: 

: 

mouse 

no data 

Sex : no data 

Number of animals : 

Vehicle : 

Doses : 7000, 5000, 3530, 2500, and 2000 mg/kg bw 

Method : 

Year : 1955 

GLP : no 

Test substance : other TS:AMPD 

21 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Test substance : AMPD: 2-Amino-2-methyl-1-propanol 

Reliability : (2) valid with restrictions 

Meets national standard methods with acceptable restrictions. 

13.11.2006 (26) 

5.1.2 ACUTE INHALATION TOXICITY 

5.1.3 ACUTE DERMAL TOXICITY 

Type : LD50

Value : > 1000 mg/kg bw 

Species : rat 

Strain : 

Sex : 

Number of animals : 5 

Vehicle : 

Doses : 500 mg/kg (delivered via 5% solution) 

Method : 

Year : 1962 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Five rats were injected with 500 or 1000 mg/kg (via 5% solution) of THAM. 

Result : 500 mg/kg caused irritation at the injection site. 

1000 mg/kg caused the formation of lesions. 

There were no other observations noted. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (27) 

Type : LD50

Value : > 1000 mg/kg bw 

Species : mouse 

Strain : 

Sex : 

Number of animals : 5 

Vehicle : 

Doses : 

Method : 

Year : 1962 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Mice were injected with 500 or 1000 mg/kg THAM (via 5% solution). 

Result : 500 mg/kg caused irritation at the injection site. 

1000 mg/kg caused skin lesions at the site. 

There were no other observations of toxicity noted. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

22 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

09.11.2006 (27) 

Type

Value 

: 

: 

LD50 

> 2000 mg/kg bw 

Species 

Strain 

: 

: 

rabbit 

no data 

Sex : male/female 

Number of animals : 12 

Vehicle : other: no vehicle 

Doses : 1000, 1500, and 2000 mg/kg 

Method : other: Pharmacology Lab Protocol 

Year : 1980 

GLP : yes 

Test substance : other TS:AMP 

Method : Each group of rabbits was treated with 1000, 1500, or 2000 mg of test 

material per kg body weight (mg/kg). The desired dose was spread over 

the prepared abdominal skin area (abraded or smooth as designated). The 

skin was covered with a gauze and a sheet of impervious rubberized cloth 

to prevent any loss of the test material. The trunk was further enclosed 

with a flexible wire screen held in place by tape. The animals were 

returned to individual cages. 

After 24 hours dermally exposed, the bindings and patches were removed, 

the exposed areas gently cleaned, and observed for skin irritancy. The 

animals were observed for another 14 days for any gross symptoms of 

toxicity. At the end of the 14 day observation period, the animals were 

weiged, sacrificed, and the organs examined for gross pathology. 

Result : At the end of the 24 hour exposure period, the intact and abraded treated 

skin sites were severely irritated and black in color. The sites became 

necrotic within two to three days and remained necrotic for the 14 days. 

The treated sites had severe eschar formation by the 14th day. The rabbits 

in the three treatment groups lost body weight over the 14 day observation 

period. The animals in all treated groups showed no signs of toxicity or 

abnormal pharmacological behavior. At necropsy, all organs in all rabbits 

were grossly normal. The treated skin sites in all rabbits were necrotic. 

Test condition : 12 Rabbits weighing 3.0 +/- 0.5 kg were divided into 3 groups of 4 each, 

and their abdomens were shaved free of hair. The skin of 2 rabbits were 

further prepared by abrasions. The abrasions were made 2-3 cm apart 

over the area of exposure with a blunt hypodermic needle without bleeding. 

Test substance : AMP:2-Amino-2-methyl-1-propanol; CAS# 124-68-5; molecular formula 

C4H11NO; molecular weight 89.14 

Conclusion : The acute dermal LD50 for P-1826 for the rabbit was >2000 mg/kg. The 

test material was dermally nontoxic, but was a severe skin irritant. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable assessment. 

13.11.2006 (28) 

5.1.4 ACUTE TOXICITY, OTHER ROUTES 

Type : LD50 

Value : ca. 3350 ml/kg bw 

Species : mouse 

Strain : no data 

Sex : no data 

Number of animals : 

Vehicle : 

Doses : 4000, 3600, 3250, 2500 and 2000 mg/kg bw 

Route of admin. : i.p. 

23 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Exposure time 

Method

: 

: 

96 hour(s) 

Year : 1955 

GLP : no 

Test substance : as prescribed by 1.1 - 1.4 

Method : Ten mice per dose were administered TRIS AMINO solutions via 

intraperitonal at a constant volume of 0.015 ml/gm bw. 

Conclusion : The acute LD50 i.p. of TRIS AMINO is 3350 mg/kg bw. 

Reliability : (2) valid with restrictions 

Meets national standard methods with acceptable restrictions. 

13.11.2006 (26) 

Type

Value 

: 

: 

LD50 

ca. 16.5 other: mM TRIS/kg 

Species 

Strain 

: 

: 

mouse 

Sex : 

Number of animals : 10 

Vehicle : no data 

Doses : 

Route of admin. : i.v. 

Exposure time 

Method

: 

: 

.5 minute(s) 

Year : 1961 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : IV injections of Tris over 30 seconds using un-neutralized and neutralized 

solutions of 0.3M Tris. 

Result : The LD50 = 16.5 mM Tris / kg 

Mice that were given a lethal dose convulsed immediately before death. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Ten mice for each dose, injected IV. Mice were observed for 24 hours and 

LD50 calculated from the per cent of mice that died. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (29) 

Type

Value 

: 

: 

LC50 

 3.28 - 4.04 other:g/kg 

Species 

Strain 

: 

: 

rat 

Sprague-Dawley 

Sex : male/female 

Number of animals : 6 

Vehicle : physiol. saline 

Doses 

Route of admin. 

: 

: 

2.0, 2.5, 3.0, 3.5 g/kg of 0.6M THAM, 4.0 and 4.5 g/kg of 0.9M THAM. 

i.v. 

Exposure time 

Method

: 

: 

1 minute(s) 

Year : 1965 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Group 1 

Males and females (3 rats each sex) were administered various doses of 

THAM via the tail vein. The dose levels of THAM administered were 2.0, 

2.5, 3.0, 3.5 g/kg of 0.6M THAM, 4.0 and 4.5 g/kg of 0.9M THAM. 

Group 2 

A replication of experiments conducted with Group 1. Instead of 

administering a single given dose level of THAM, to all rats in one unit in 

24 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

one day, the different dosage levels were given at one sitting to pairs of 

rats, and repeated, on subsequent days, until all 36 animals in this group 

had been used. Ultimately, 3 male and 3 female rats from Group 2 

received THAM at each of the dosage levels shown for Group 1. 

Group 3 

As a partial control (to rule out adverse effects of rapid infusions of large 

volumes of fluid), 4 pairs of male and female rats received IV infusions, via 

the tail vein, of physiological saline (0.9g NaCl per 100mL). The infusion 

rates and volumes of saline were similar to the fluid infusion rates and 

volumes required for each dose level of THAM. 

In all cases, the rate of administration of the test solutions was established 

individually based each rat's body weight. Each animal received the test 

material such that they receive 0.45g THAM per kg body weight would be 

administered in one minute. Sterile equipment was used throughout the 

study, and each animal was treated with a separate syringe and needle. 

Animals that survived the infusions were held and observed for 2 hours 

post-infusion and were sacrificed and necropsied. Necropsies were 

likewise performed on animals dying spontaneously following treatment. 

Specimens from all organs and tissues were preserved, embedded, and 

stained. All histopathologic and histochemical methods were performed 

according to established methods. 

Result : In most cases, rats that did not survive the post-infusion period died during 

the infusion or very soon afterward. Those animals that survived longer 

than 10 minutes following treatment survived the entire post-infusion period 

and recovered with no grossly-observable ill effects. All 8 control animals 

survived the infusion. 

There were no significant gross lesions noted at necropsy for any of the 

animals, with the exception of the liver and kidneys. Peracute toxic 

nephrosis was noted consistently in the kidneys up to 2 hours postinfusion. The lesion varied in that it was limited to a moderate degree to 

pyknosis of the nuclei of isolated segments of the renal tubular epithelium 

in rats infused with 2 and 2.5 g/kg THAM doses, and increased in severity 

with the dose. In higher dose levels, the lesions were characterized by 

severe pyknosis of the nuclei of swollen renal tubular epithelial cells of 

carried segments of the cortex. The cytoplasm of the affected cells was 

coagulated, distinctly granular, and intensely eosinophilic. Lumens of the 

affected tubules were distended with eosinophilic, amorphous tissue debris 

and secretions. Affected tubules were observed adjacent to apparently 

normal tubules. The incidence of lesions increased with increasing dose 

levels, and were noted in a similar dose-response pattern in animals dying 

spontaneously or at scheduled sacrifice. 

Lethargy was noted sporadically in rats at 3 -4 g/kg dose levels. There 

were all noted with lesions of acute toxic hepatitis. The lesion was 

characterized by pyknosis of the nuclei of the hepatocytes and cloudy 

swelling of the cytoplasm of hepatocytes. Although the lesions are thought 

to be related to THAM administration, they did not constitute a consistent 

characteristic lesion as did the peracute toxic nephrosis. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Eighty, 200-300g Sprague-Dawley rats (males & females) were observed 

for 14 days prior to study start for health evaluation. They were segregated 

into 3 groups: 2 experimental groups of 36 animals each (18 males and 18 

females), and one control group (4 males and 4 females). 

Conclusion : The actual LD50 of THAM given intravenously was calculated to be 3.5 

g/kg +- 0.1 for Group 1, and 3.6 g/kg +- 0.2 for Group 2. Statistical 

evaluation calculated a maximum likelihood estimate of 3.55 and 3.64 g/kg 

of body weight respectively, with a fiducial probability of 95%. The value of 

LD50 in groups 1 and 2 were expected to be 3.28-3.83 g/kg and 3.28-4.04 

g/kg, respectively. 

A NOAEL was not observed. Observations, treatment-related, were noted 

25 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

at the lowest dose level tested. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (30) 

Type

Value 

: 

: 

LC50 

ca. 6000 mg/kg bw 

Species 

Strain 

: 

: 

rat 

Sex : 

Number of animals : 10 

Vehicle : 

Doses : 100, 200, 400, 500, 1000, 3000, 5000, 6000, 7000 mg/kg (1 & 20% 

solutions) 

Route of admin. : i.v. 

Exposure time 

Method

: 

: 

Year : 1962 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Result : There were no notations of any toxicity at doses lower than 3000 mg/kg. At 

5000 mg/kg, 30% mortality was noted, at 6000 mg/kg, 60% mortality was 

noted, and at 7000 mg/kg, 70% mortality was noted. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (27) 

Type

Value 

: 

: 

LC50 

ca. 6100 mg/kg bw 

Species 

Strain 

: 

: 

mouse 

Sex : 

Number of animals : 10 

Vehicle : 

Doses : 100, 200, 400, 500, 1000, 2000, 3000, 5000, 6000, 7000 mg/kg (1% 

solution) 

Route of admin. : i.v. 

Exposure time 

Method

: 

: 

Year : 1962 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Result : There was no mortality noted at doses less than 5000 mg/kg. At 6000 

mg/kg, 40% mortality was noted, and at 7000 mg/lg, 100% mortality was 

recorded. Animals experienced muscle weakness accompanied by 

respiratory difficulty prior to death. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (27) 

Type

Value 

: 

: 

LC50 

Species 

Strain 

: 

: 

rabbit 

Sex : 

26 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Number of animals : 5 

Vehicle : 

Doses : 250, 500 mg/kg (5% solution) 

Route of admin. : i.v. 

Exposure time 

Method

: 

: 

Year : 1962 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Marginal vein in the ear was used. 

Result : There was no treatment-related mortality. Changes in respiratory rate and 

amplitude were the only observations noted. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (27) 

Type

Value 

: 

: 

LC50 

> 125 ml/kg bw 

Species 

Strain 

: 

: 

dog 

Sex : 

Number of animals : 5 

Vehicle : 

Doses : 125 mg/kg (5% solution) 

Route of admin. : i.v. 

Exposure time 

Method

: 

: 

Year : 1962 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Saphenous vein was used. 

Result : Alterations in respiratory rate and amplitude were the only observations 

noted. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (27) 

Type

Value 

: 

: 

LD50 

> 3000 mg/kg bw 

Species 

Strain 

: 

: 

rat 

Wistar 

Sex : 

Number of animals : 10 

Vehicle : 

Doses : 

Route of admin. : other: gastric tube 

Exposure time 

Method

: 

: 

Year : 1962 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Doses of 1000 and 3000 mg/kg were administered by gastric tube in a 20% 

solution. 

Result : There were no signs of acute toxicity noted. 

27 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Abundant urine output was recorded for some animals. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (27) 

Type

Value 

: 

: 

LD50 

> 3000 mg/kg bw 

Species 

Strain 

: 

: 

mouse 

Swiss 

Sex : 

Number of animals : 10 

Vehicle : 

Doses : 

Route of admin. : other: gastric tube 

Exposure time 

Method

: 

: 

Year : 1962 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Doses of 1000, 2000, and 3000 mg/kg were delivered by gastric tube in a 

5% solution. 

Result : There was no significant toxicity noted, other than increased urine output. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (27) 

5.2.1 SKIN IRRITATION 

Species 

Concentration 

: 

: 

rabbit 

Exposure 

Exposure time 

Number of animals 

: 

: 

: 

Vehicle : 

PDII : 

Result : moderately irritating 

Classification : 

Method : Draize Test 

Year : 1961 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : A saturated solution (pH 10.8), 25% solution, and the crystalline product 

were tested on intact and abraded skin of rabbits. 

Result : The saturated solution and the crystalline product produced comparable 

primary irritation scores. There was no noticeable irritation produced by 

any of the test concentrations on unabraded skin. All signs of irritation 

were completely resolved in 48 hours. 

Solution Intact Abraded Total 

crystals 0 0.83 0.4 

saturated 0.16 0.83 0.5 

25% soln 0 0.16 0.08 

The test material is considered a mild irritant to the skin. 

28 / 60 
5. Toxicity Id 

Date 

77-86-1 

14.11.2006 

Source 

Reliability

09.11.2006 

: 

: 

Dow Chemical, TERC Midland, MI 

(4) not assignable 

Documentation insufficient for assessment. 

(31) 

Species 

Concentration 

Exposure 

Exposure time 

Number of animals 

Vehicle 

PDII 

Result

Classification 

Method

Year 

GLP 

Test substance 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

rabbit 

highly irritating 

irritating 

Draize Test 

1975 

no 

other TS:AMP 

Source 

Test substance 

Reliability

13.11.2006 

: 

: 

: 

ANGUS Chemie GmbH Ibbenburen 

European Commission - European Chemicals Bureau Ispra (VA). 

AMP: 2-Amino-2-methyl-1-propanol; Molecular formula C4H11NO; 

Molecular weight 89.14 

(4) not assignable 

Documentation insufficient for assessment. 

(32) 

5.2.2 EYE IRRITATION 

Species 

Concentration 

Dose 

Exposure time 

Comment

Number of animals 

Vehicle 

Result

Classification 

Method

Year 

GLP 

Test substance 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

rabbit 

undiluted 

6 

none 

not irritating 

not irritating 

1975 

as prescribed by 1.1 - 1.4 

Result : Combined Average Score = 0/110 

Source 

Reliability

13.11.2006 

: 

: 

Classification = Non-irritating 

Dow Chemical, TERC Midland, MI 

(4) not assignable 

Documentation insufficient for assessment. 

(33) 

Species 

Concentration 

Dose 

Exposure time 

Comment

Number of animals 

Vehicle 

Result

Classification 

: 

: 

: 

: 

: 

: 

: 

: 

: 

rabbit 

40 % 

6 

water 

not irritating 

not irritating 

29 / 60 
5. Toxicity Id 

Date 

77-86-1 

14.11.2006 

Method

Year 

GLP 

Test substance 

: 

: 

: 

: 

1992 

as prescribed by 1.1 - 1.4 

Source 

Reliability

13.11.2006 

: 

: 

L. Troester (2006). Personal communication. 

(2) valid with restrictions 

Data from handbook or collection of data. 

(34) 

5.3 SENSITIZATION 

Type

Species 

Concentration 

Number of animals 

Vehicle 

Result

Classification 

Method

Year 

GLP 

Test substance 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

Intracutaneus test 

guinea pig 

1st: Induction .1 % 

2nd: Challenge .05 % 

3rd: Challenge .01 % 

30 

water 

not sensitizing 

not sensitizing 

1982 

other TS:AMP 

Method : One group was treated with 0.05mL of 1% P-1826 solution, a negative 

control group was treated with saline, and a positive control group was 

treated with dinitrochlorobenzene (DNCB solubilized in alcohol and made 

to volume with saline). After 24 hours, sites were cleaned and scored for 

erythema and edema according to Draize (Draize, JH, "Appraisal of the 

Safety of Chemicals in Foods, Drugs, and Cosmetics". Assoc. of Food and 

Drug Officials of the United States, p. 48, 1957). At 48 hours, the 

application was repeated with each group, and continued 2-3 times per 

week until 10 applications were made. Animals were allowed a 2 week 

recovery period, and then challenged at a virgin site. The test and negative 

control animals were challenged with 0.1mL of 0.05% and 0.01% solutions 

of P-1826. Positive and negative control animals were also challenged 

with 0.3% and 0.03% DNCB solution. After 24 hours, they were depilated, 

and three hours later scored for erythema and edema. Sites were scored 

again at 48 hours. 

Result : 

Test material is considered a sensitizer if the challenge elicits skin 

reactions in a large number of test animals when compared to the negative 

control. 

During the induction phase, the first injection at 1% and second injection at 

0.5% P-1826 induced necrotic lesions, so the remaining 8 injections were 

made with 0.1% solutions. The 0.3% DNCB sites were necrotic for the 

entire 10 injections. 

At challenge with 0.05% and 0.01% P-1826, one animal in the test group 

showed mild reactions with 0.05%, but none of the negative controls 

challenged with P-1826 showed any reactions at 24 or 48 hours. In the 

repeat challenge, none of the animals in the test group showed any 

reactions with P-1826, but of the negative control group, 4 animals at 

0.05% and 1 animal at 0.01% showed skin reactions at 24 hours. 

A challenge with the positive control induced skin reactions in the positive 

control group. The 0.03% solution did not elicit any skin reaction at 48 

hours. 

30 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Test condition : Thirty male guinea pigs (250-300g each) were divided into 3 groups of 10 

each. The animals' backs and flanks were shaved free of hair. The guinea 

pigs were intradermally-injected with the solutions. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

14.11.2006 (35) 

Type

Species 

Concentration 

: 

: 

: 

Patch-Test 

guinea pig 

1st: Induction 5 % 

2nd: Challenge 2.5 % 

3rd: Challenge 5 % 

Number of animals : 30 

Vehicle : water 

Result : not sensitizing 

Classification : not sensitizing 

Method : other: Buehler 

Year : 1982 

GLP : 

Test substance : other TS: AMP 

Method : : One group was treated with 0.5mL of 10% P-1826 solution, a 

negative control group was treated with saline, and a positive control group 

was treated with dinitrochlorobenzene (DNCB solubilized in alcohol and 

made to volume with saline). After 24 hours, the patches were removed, 

and sites were cleaned and scored at 24 and 48 hours for erythema and 

edema according to Draize (Draize, JH, "Appraisal of the Safety of 

Chemicals in Foods, Drugs, and Cosmetics". Assoc. of Food and Drig 

Officials of the United States, p. 48, 1957). At 48 hours, the application 

was repeated with each group, and continued 2-3 times per week until 10 

applications were made. Animals were allowed a 2 week recovery period, 

and then challenged at a virgin site. The test and negative control animals 

were challenged with 0.5mL of 2.5% and 5% solutions of P-1826. Positive 

and negative control animals were also challenged with 0.03% DNCB 

solution. After 24 hours, the test material was cleaned away, depilated, 

and three hours later scored for erythema and edema. Sites were scored 

again at 48 hours. 

Test material is considered a sensitizer if the challenge elicits skin 

reactions in a large number of test animals when compared to the negative 

control. 

Result : During the induction, the 10% P-1826 solution was found to be mildly 

irritating to all animals in the test group, so the remaining 8 doses during 

the induction were made with a 5% solution. The positive control, DCNB, 

elicited a mild to strong reaction during the 10 applications. There was one 

death in the positive control group, but was deemed not treatment-related 

via necropsy. 

At challenge with 2.5% and 5% solutions of P-1826, none of the animals in 

the test or positive control groups showed any skin reactions at 24 hours, 

but the positive control animals showed mild skin reactions at 48 hours. 

Nine of ten positive controls when challenged with DNCB at 24 hours 

showed skin reactions, and 7/10 showed reactions at 48 hours. Only 4/10 

negative controls showed reactions when challenged with DNCB at 24 

hours, and none at 48 hours. 

Test condition : Thirty male guinea pigs (250-300g each) were divided into 3 groups of 10 

each. The animals' backs and flanks were shaved free of hair. The guinea 

pigs were topically treated with the solutions applied under an occlusive 

patch. 

Conclusion : 2-Amino-2-methyl-1-propanol was a non-sensitizer in the topical 

31 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

sensitization test in guinea pigs, under these test conditions. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

14.11.2006 (36) 

Type

Species 

Number of animals 

: 

: 

: 

other 

human 

Vehicle : 

Result : 

Classification : 

Method : 

Year : 

GLP : no data 

Test substance : other TS: AMPD and AMP 

Result : In patch tests with humans, cosmetic formulations containing either 0.22% 

AMP or 0.5% AMPD or 0.075% AMPD were negative for dermal 

sensitization. 

Test condition : AMP 

The skin irritation potential of a cosmetic formulation containing 0.22% 

AMP-95 was examined using a single insult occlusive patch test on 15 

panelists. One panelist formulation containing 0.22% AMP-95 had a 

negligible primary skin irritation potential. 

AMPD 

A cosmetic formulation containing 0.073% AMPD was tested for 

sensitization potential in a group of 30 human test subjects using a 

repeated insult open patch test. The material was applied to the arm daily 

4 days/week for 2 weeks, alternating arms daily. In addition, an occlusive 

patch was was applied on the first day of the test. After the 2-week 

application period, there was a 2-week nontreatment period. After this 2­

week period, the test subjects received a reapplication of the formulation of 

the formulation to the test site along with an occlusive patch at an adjacent 

site. The original patch, challenge patch, and open challenge test sites 

were read at 24, 48, and 96 hour. No reactions were observed in any of 

the test subjects. The formulation containing 0.073% AMPD was neither a 

primary irritant, nor a fatiguing agent, nor a sensitizer, and the formulation 

was safe under the conditions of the study. 

A modified repeated insult patch test of a cosmetic formulation containing 

0.5% AMPD was performed on a panel of 39 women and 20 men. The test 

material, 0.5 ml, was applied to a semiopen patch on the arm of each 

panelist every Monday, Tuesday, Wednesday, and Thursday for two 

weeks. The patch sites were graded approximately 24 h after application. 

In addition, a closed patch was applied to each panelist on the first day fo 

the study and on the day of challenge. No patches were applied for 2 

weeks after the induction phase. On Monday following the nontreatment 

period, challenge patches were applied to the original test site and an 

adjacent site; the second closed patch patch was also applied at this time. 

The challenge sites were graded 1, 2, and 4 days after application. Slight 

erythema was noted at one adjacent applicatin site at each of the grading 

times, but it was clear whether these reactions occurred in the panelist. 

The formulation containing 0.5% AMPD was not a sensitizer under the 

conditions fo the test. 

Reliability : (2) valid with restrictions 

Data from handbook or collection of data 

14.11.2006 (37) (38) 

32 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

5.4 REPEATED DOSE TOXICITY 

Type : Sub-chronic 

Species : rabbit 

Sex : 

Strain : 

Route of admin. : i.v. 

Exposure period : 1-99 days 

Frequency of treatm. : once daily 

Post exposure period : 

Doses : 5-100 mL of 0.3M Tris per kg bodyweight, given at pH 7.4 and at pH 5.5 

Control group : 

Result : Treatment-related mortality was first noted a few days after start of 

treatment. Results of the study indicate that neutralized Tris is less toxic. 

Toxic symptoms noted included anorexia, bloody urine, hindleg paralysis, 

and irregular respiration. Gross observations at necropsy included 

abnormally red lungs, necrosis at the point of infusion, bleached liver, 

darkened spleen, bloated stomach, and lesions on the heart and kidney. 

Histological examinations of the organs were negative. 

Blood sampling following treatments with TRIS indicated that the levels 

increased upon successive treatments, and remained high the following 

day. Results indicate an accumulation of Tris at 25mL/kg (0.3M), the top 

dose evaluated for this parameter, but not at doses lower. 

Blood sampling following treatment with Tris (0.3M neutralized and nonneutralized) could not establish a direct relationship between Tris 

concentrations and glucose concentrations in the blood due to lost 

sampling data. The glucose concentrations, however, dropped significantly 

during the infusions, but returned to normal or above normal following the 

end of the infusions (Tris-induced hypoglycemia persisted longer than the 

Tris-neutralized). Tris and Tris-Neutralized both caused transient 

hypoglycemia. Blood analysis on extracted blood (Tris added to blood 

droplets at varying levels) also determined that there was no deleterious 

effect on erythrocytes. Urinalysis (urine collected via Foley catheter 

measured every hour for 7 hours following start of infusion) revealed that 

the amount of Tris excreted in the urine reached a maximum at the end of 

infusion, and dropped rapidly after infusion stopped. Only a small quantity 

of chloride was excreted. With Tris pH 5.5, a larger amount of chloride 

than with Tris was excreted. At the end of the 7 hours, 44% of the infused 

Tris was found in the urine, while with Tris pH 5.5, 77% was found. 

Causes of local necrosis around the infusion site were investigated using 

Tris pH 5.5 and 7.4. Using injected Trypan dye, the irritation caused by the 

solutions was evaluated by observing the amount of extravasated dye. 

Neutralization of the Tris reduced the irritation, suggesting that the pH of 

the Tris is the probable cause of the dermal irritation. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Two or three rabbits for group, injected IV over 3-6 hours for 1-99 

consecutive days (depending on the endpoint being measured) at a doses 

ranging 5-100 mL of 0.3M Tris per kg bodyweight. The doses were given 

at pH 7.4 and at pH 5.5 to investigate differences related strictly to pH. 

Conclusion : 1. Acute IV toxicity of 0.3M Tris is 55mL/kg. Neither neutralization of 

addition of glucose or NaCl decreases the toxicity. 

2. Maximum subchronic non-lethal dose of 0.3M Tris in rabbits is 75­

90mL/kg over 5 hours. Neutralization appears to decrease the toxicity. 

3. If high doses of Tris are given frequently, Tris will accumulate. 

4. Injection of Tris causes hypoglycemia during infusion and afterward. 

Tris neutralized causes hypoglycemia only during infusion. There is no 

direct relationship between Tris and glucose concentrations in the blood. 

33 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

5. Dermal irritation is likely caused by pH, and not toxicity per se of 

Tris. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (29) 

Type

Species 

Sex 

: 

: 

: 

Sub-acute 

rabbit 

Strain : 

Route of admin. : infusion 

Exposure period 

Frequency of treatm. 

Post exposure period 

Doses 

: 

: 

: 

: 

10 days 

once daily 

Control group 

Method

: 

: 

Year : 1961 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Result : No treatment-related mortality was noted in either species. There were no 

toxic symptoms, and a histological study of the organs was negative. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Three of each species for each dose, injected IV over 30 seconds for 10 

consecutive days at a dosage of 50 mL and 10 mL of 0.155M Tris per kg 

bodyweight. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (29) 

Type

Species 

Sex 

: 

: 

: 

Sub-chronic 

rat 

male/female 

Strain : Sprague-Dawley 

Route of admin. : oral feed 

Exposure period 

Frequency of treatm. 

Post exposure period 

Doses 

: 

: 

: 

: 

3 months 

0, 25, 150, 250, 2500 ppm in feed 

Control group 

LOAEL 

: 

: 

yes, concurrent vehicle 

= 2500 ppm 

Method : 

Year : 1981 

GLP : 

Test substance : other TS:AMP 

Remark : Results & methods sections referenced appendix data, which is not 

provided in Dow's copy of the report. As such, test material intake 

(mg/kg/day) could not be estimated. 

Test substance : AMP-95/HCl 66.1ai (Lot 109-1) 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

13.11.2006 (39) 

Type

Species 

Sex 

: 

: 

: 

Sub-acute 

rat 

Strain : Sprague-Dawley 

34 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Route of admin. : infusion 

Exposure period 

Frequency of treatm. 

Post exposure period 

Doses 

: 

: 

: 

: 

20 days 

1 infusion daily 

24 hour or 7 day recovery period without infusions prior to necropsy 

0.3M THAM (0.5, 1.5g/kg THAM: 10 or 20 infusions) 

Control group 

NOAEL 

: 

: 

yes, concurrent vehicle 

ca. 500 mg/kg 

Method : 

Year : 1965 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : Group 1 

Twelve rats (6 each sex) were given 20 daily infusions via the tail vein of 

0.3M THAM at 0.5 g/kg administered at 0.45g/kg/min. 

Group 2 

Twelve rats (6 each sex) were given 20 daily infusions via the tail vein of 

0.3M THAM at 1.5 g/kg administered as a single injection in a 1-2 minute 

period. 

Group 3 

Twelve rats (6 each sex) were given 10 daily infusions via the tail vein of 

0.3M THAM at 0.5 g/kg administered at 0.45g/kg/min. On the 11th day, the 

infusions were discontinued and IP injections were commenced at the 

same dose level. The IP injections were given daily for 10 days as a single 

injection in a 1-2 minute period. 

Group 4 

As controls, 4 rats (2 each sex) received 20 daily IV infusions, via the tail 

vein, of a solution containing 9g NaCl and 0.37g KCl per liter of water. The 

rate of injection was 1mL/kg/min. 

Group 5 

As controls, 4 rats (2 each sex) received 20 daily IP injections of a solution 

containing 9g NaCl and 0.37g KCl per liter of water. The rate of injection 

was 1mL/kg/min. 

Half of the surviving rats of Group 1 & 2 and of the rats of the remaining 

groups were observed for 24 hours after the 20th infusion and were 

sacrificed and necropsied. The remaining rats of groups 1 & 2 were 

observed an additional 7 days post-infusion before a scheduled necropsy. 

At necropsy, tissue and organ specimens were taken, preserved, 

processed, and evaluated according to established histopathologic and 

histochemical methods. 

Result : There were no findings noted in any animal in Group 1. Group 1 &3 

animals experienced dry gangrene at the sites of the tail injections. 

Approximately half of the rats in Group 2 & 3 were noted with a mild 

inflammation of various parts of the visceral peritoneum, or fat necrosis and 

hemorrhage of the serosa of various parts of the stomach, intestine, and 

peritoneum. No gross lesions were noted in any control animal. 

Microscopic examination of tissues revealed a chronic cellulites at the 

injection sites, and peracute toxic nephrosis of the kidneys (5/6 rats of 

Group 1 necropsied 24 hours after injection, but not seen in animals 

allowed the 7 day recovery period). In group 2, all rats necropsied at 24 

hours and 5/6 rats in the 7-day recovery group presented similarly. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Sprague-Dawley, 200-300g, rats (19 males & 19 females) were observed 

for 14 days prior to study start for health evaluation. They were segregated 

into 5 groups. 

Conclusion : NOAEL = 0.5g/kg of 0.3M THAM 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (30) 

35 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Type

Species 

Sex 

: 

: 

: 

Sub-acute 

mouse 

Strain : 

Route of admin. : infusion 

Exposure period 

Frequency of treatm. 

Post exposure period 

Doses 

: 

: 

: 

: 

10 days 

once daily 

Control group 

Method

: 

: 

Year : 1961 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Result : No treatment-related mortality was noted in either species. There were no 

toxic symptoms, and a histological study of the organs was negative. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Three animals for each dose, injected IV over 30 seconds for 10 

consecutive days at a dosage of 50 mL and 10 mL of 0.155M Tris per kg 

bodyweight. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (29) 

Type

Species 

Sex 

: 

: 

: 

Sub-acute 

rabbit 

male/female 

Strain : New Zealand white 

Route of admin. : i.v. 

Exposure period 

Frequency of treatm. 

Post exposure period 

Doses 

: 

: 

: 

: 

4 weeks, 5 days per week 

once daily 

24 hours or 20 day recovery periods 

0.3M THAM at 0.5g/kg at a rate of 0.5 mL/min. 

Control group : yes, concurrent vehicle 

Method : Group 1 

Each animal in the first group was given 20 daily infusions (5 days per 

week for 4 weeks) of 0.3M THAM at 0.5g/kg at a rate of 0.5 mL/min. 

Group 2 

Animals were given 20 daily IV infusions of normal saline to which 5 m Eq 

of KCl were added per liter. The dosage and rate of administration were 

equal in volume and time, on a kg bodyweight basis, to the first group. 

Two males and 2 females from each group were sacrificed and necropsied 

within 24 hours of the completion of the last treatment. The remaining 

animals in each group were held for an additional 20 days post-infusion 

prior to necropsy. Bodyweight, food and water intake, and urine output 

were recorded daily, urinalysis weekly. Rectal temperature was recorded 

twice daily during the pre- and post-infusion periods, and immediately 

before and hourly until temperatures returned to normal after all infusions 

given over the 20 day treatment period. Urinalysis (pH, albumin, glucose, 

benzidine test for hemoglobin on centrifuged sediment and supernate, and 

microscopic examination for red and white blood cells and casts) was 

performed on the first urine voided after infusions during the 20 day 

treatment period on the first day of infusions, and twice a week for the 

remaining 3 weeks. Two days a week during the infusion period, a postinfusion urinary THAM excretion was measured on 2 males and 2 females 

in each group. Heart blood specimens were collected for BSP retention 

tests once during the pre- and post-infusion weeks and during the second 

week of the infusion period. Blood specimens were collected from an ear 

36 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

vein for the following tests, once during the pre- and post-infusion periods 

and twice a week during the infusions: total serum proteins, A/G ratios, 

serum bilirubin, cephalin flocculation, and serum transaminase. Also, 

blood specimens were collected at the same time for hemoglobin and 

hematocrit determinations, and for white blood cell, red blood cell, 

differential, and platelet counts. 

At necropsy, specimens from all organs and tissues were extracted, 

preserved, and examined grossly and microscopically. Histochemical 

examinations were performed on liver and kidney specimens fixed in 

formalin-calcium for the following: alkaline phosphatase, acid phosphatase, 

esterase, peptidase, DPN diaphorase, and PPN diaphorase. 

Result : Food and water consumption and body temperature was not effected by 

treatment in any group, nor was water diuresis produced. Body weight 

fluctuated throughout study in all animals, including control, but not in any 

treatment-related pattern. Seven of 8 rabbits receiving THAM had 

inflammatory lesions of the external ear. The lesions carried from swelling 

and redness to dry gangrene and erosion. 

Weekly analyses on blood samples were normal for the following 

parameters: total serum proteins, A/G ratio, serum bilirubin, cephalin 

flocculation, serum transaminase, RBC, differential counts, hemoglobin, 

microhematocrit, and platelet counts. White blood cell counts in excess of 

13,000 were seen in 5/8 rabbits receiving THAM. In all cases, elevated 

WBC coincided with the observations of dry gangrene in the external ear. 

No significant findings were noted in any of the parameters tested during 

urinalysis. 

No gross lesions were noted in control animals at necropsy, however 2/4 

test rabbits necropsied 20 days post-infusion presented grossly visible 

infarcts in the kidneys. No gross lesions were noted in any other organ or 

tissue in any other animal. 

In 7/8 test animals in which there were gross lesions of the ear, there were 

microscopic lesions of chronic cellulites and necrosis at sites of injection in 

the subcutaneous tissues of the ear. The gross kidney lesions in the 2 

animals were confirmed microscopically. They were also found to have 

chronic interstitial nephritis. Infiltrations of lymphocytes were seen in tissue 

sections of the liver and kidney of 3 additional test rabbits. The infiltrations 

were seen in animals that were allowed to recover 20 days post-infusion, 

as well as those sacrificed immediately following the treatment series. 

Peracute toxic nephrosis was observed in 1 rabbit, which also presented 

urolithiasis. Lesions of peracute toxic nephrosis were not observed in any 

of the other 7 rabbits receiving THAM. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : New Zealand rabbits (16 adult, 3-4kg) were used. After a 2 week 

observation period, the animals were segregated into 2 groups composed 

of 4 male and 4 female animals per group. 

Conclusion : Other than the necrotizing effects at the injection site, and transient body 

temperature changes, the IV administration of up to 20 daily doses of 

0.5g/kg of 0.3M THAM produces no readily detected deleterious effects in 

mature rabbits. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (30) 

Type

Species 

Sex 

: 

: 

: 

Chronic 

dog 

male/female 

Strain : Beagle 

Route of admin. : oral feed 

Exposure period 

Frequency of treatm. 

Post exposure period 

Doses 

: 

: 

: 

: 

1 year 

Continuous 

0, 1.1, 11, 110 ppm 

37 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Control group 

NOAEL 

Method

: 

: 

: 

yes, concurrent vehicle 

> 110 ppm 

Year : 1990 

GLP : 

Test substance : other TS: AMP-HCl (47.1% AMP) 

Remark : Test materia

consumption. 

l intake is estimated based on week 36 body weights and food 

Males 

Control 

esti (mg/kg/day) 

0 

mated 

1.1ppm 

11ppm 

110ppm 

.031 

0.31 

2.98 

Females 

 estimated (mg/kg/day) 

Control 0 

1.1ppm .029 

11ppm 0.31 

110ppm 2.55 

Test substance : 2-amino-2-methyl-1-propanol supplied by Angus Chemical Co, Northbrook, 

IL. Supplied as an aqueous solution of AMP-HCl. Concentration of AMP in 

the solution was 47.1%. 

Conclusion : Based on the findings under these study conditions, there is no effect at 

any dose level on general appearance, behavior, body weight, food 

consumption, ophthalmoscopic exams, clinical chemistry, hematology, 

organ weights, or tissue histopathology. Based on the absence of 

statistically and biologically significant findings in dose-response patterns, 

the No-Observed Effect Level for AMP in the diets of Beagle dogs in 

greater than 110 ppm. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

13.11.2006 (40) 

5.5 GENETIC TOXICITY ‘IN VITRO‘ 

Type : Gene mutation in Saccharomyces cerevisiae 

System of testing : 

Test concentration : 

Cycotoxic concentr. : 

Metabolic activation : 

Result : negative 

Method : 

Year : 1990 

GLP : 

Test substance : other TS 

Result : No evidence of ketorolac tromethamine-induce mutagenesis in in vitro 

Saccharomyces cerevisiae [Syntex Laboratories, Inc. Toradol IM (ketorolac 

tromethamine) prescribing information, product monograph and formulary 

facts. Palo Alto, CA; 1990] 

Source : Dow Chemical, TERC Midland, MI 

Test substance : Ketorolac is commerically available as the tromethamine salt. Ketorolac 

tromethamine is commercially available as a racemic mixture. 

38 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Reliability : (4) not assignable 

Documentation insufficient for assessment. 

13.11.2006 (41) 

Type

System of testing 

Test concentration 

: 

: 

: 

Bacterial gene mutation assay 

E.coli 

Cycotoxic concentr. 

Metabolic activation 

: 

: 

Result : negative 

Method : 

Year : 1990 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Result : No evidence of ketorolac tromethamine-induce mutagenesis in in vitro 

Escherichia coli [Syntex Laboratories, Inc. Toradol IM (ketorolac 

tromethamine) prescribing information, product monograph and formulary 

facts. Palo Alto, CA; 1990] 

Source : Dow Chemical, TERC Midland, MI 

Test substance : Ketorolac is commerically available as the tromethamine salt. Ketorolac 

tromethamine is commercially available as a racemic mixture. 

Reliability : (4) not assignable 

Documentation insufficient for assessment. 

13.11.2006 (41) 

Type

System of testing 

Test concentration 

: 

: 

: 

other: Mechanism of nucleolysis in DMA 

Streptomyces lividans 

Cycotoxic concentr. 

Metabolic activation 

: 

: 

Result : positive 

Method : 

Year : 1992 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Method : The authors investigated reactivity using a test system of electrophoretic 

activation of electrophoresis buffer conponents and a combination of the 

activated samples with S.lividans plasmid DNA. After termination of the 

reaction, DNA samples were assayed for double-strand cleavage. The 

assay involved gel electrophoresis of the DNA samples in HEPES buffer, 

components of which are non-reactive with the DNA modifications, 

Southern transfer, and hybridization. 

Result : The authors conclude that two finctional groups of TRIS are involved in 

strand scission. Initial electrophoretic activation at the anode is absolutely 

required for the formation of a TRIS derivative, a presumptive oxygencentered radical species which can be scavenged by thiourea. This 

species reacts with the DNA modifications in the first instance. As a result, 

the lesions are then susceptible to further attack, resulting in strand 

cleavage. The authors infer that it is the amine group in particular which 

confers on TRIS its nucleolytic activity. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (42) 

Type

System of testing 

Test concentration 

: 

: 

: 

Salmonella typhimurium reverse mutation assay 

Cycotoxic concentr. : 

39 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Metabolic activation : 

Result : negative 

Method : 

Year : 1990 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Result : No evidence of ketorolac tromethamine-induce mutagenesis in in vitro 

Salmonella typhimurium [Syntex Laboratories, Inc. Toradol IM (ketorolac 

tromethamine) prescribing information, product monograph and formulary 

facts. Palo Alto, CA; 1990] 

Source : Dow Chemical, TERC Midland, MI 

Test substance : Ketorolac is commerically available as the tromethamine salt. Ketorolac 

tromethamine is commercially available as a racemic mixture. 

Reliability : (4) not assignable 

Documentation insufficient for assessment. 

13.11.2006 (41) 

5.6 GENETIC TOXICITY ‘IN VIVO‘ 

Type : Micronucleus assay 

Species : mouse 

Sex : 

Strain : 

Route of admin. : 

Exposure period : 

Doses : 

Result : negative 

Method : 

Year : 1990 

GLP : 

Test substance : as prescribed by 1.1 - 1.4 

Result : There was no evidence of mutagenicity when the micronucleus assay was 

used to test for chromosome breaks in vivo mice that had received 

ketorolac tromethamine [Syntex Laboratories, Inc. Toradol IM (ketorolac 

tromethamine) prescribing information. Palo Alto, CA; 1990] 

Source : Dow Chemical, TERC Midland, MI 

Test substance : Ketorolac is commerically available as the tromethamine salt. Ketorolac 

tromethamine is commercially available as a racemic mixture. 

Reliability : (4) not assignable 

Documentation insufficient for assessment. 

13.11.2006 (41) 

5.7 CARCINOGENICITY 

Species : dog 

Sex : male/female 

Strain : Beagle 

Route of admin. : oral feed 

Exposure period : 1 year 

Frequency of treatm. : continuous 

Post exposure period : 

Doses : 0, 1.1, 11, 110 ppm 

Result : negative 

Control group : yes, concurrent vehicle 

Method : 

Year : 1990 

40 / 60 
5. Toxicity Id 

Date 

77-86-1 

14.11.2006 

GLP 

Test substance 

: 

: other TS: AMP-HCl (47.1% AMP) 

Remark : Test material intake is estimated based on week 36 body weights and food 

consumption. 

Males 

Control 

1.1ppm 

11ppm 

110ppm 

estimated (mg/kg/day) 

0 

.031 

0.31 

2.98 

Females 

Test substance 

Conclusion 

Reliability

13.11.2006 

: 

: 

: 

 estimated (mg/kg/day) 

Control 0 

1.1ppm .029 

11ppm 0.31 

110ppm 2.55 

2-amino-2-methyl-1-propanol supplied by Angus Chemical Co, Northbrook, 

IL. Supplied as an aqueous solution of AMP-HCl. Concentration of AMP in 

the solution was 47.1%. 

Based on the findings under these study conditions, there is no effect at 

any dose level on general appearance, behavior, body weight, food 

consumption, ophthalmoscopic exams, clinical chemistry, hematology, 

organ weights, or tissue histopathology. Based on the absence of 

statistically and biologically significant findings in dose-response patterns, 

the No-Observed Effect Level for AMP in the diets of Beagle dogs in 

greater than 110 ppm. 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(40) 

Species 

Sex 

Strain 

Route of admin. 

Exposure period 

Frequency of treatm. 

Post exposure period 

Doses 

Result

Control group 

Method

Year 

GLP 

Test substance 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

: 

Syrian hamster 

male 

other: intratracheal 

negative 

yes, concurrent vehicle 

1979 

no data 

other TS: TRIS AMINO and 0.9% NaCl 

Method : Thirty 8-week old male Syrian golden hamsters were used in the control 

group. The animals received a pelleted diet and water ad libitium. Weekly 

intratracheal instillations of a 0.2 ml mixture of TRIS buffer and 0.9% NaCl 

were performed for the life of the hamster. 

Result : 

Animals were observed for life or sacrificed when moribund. Body weights, 

average survival time and tumor incidence for the respiratory tract (trachea, 

larynx and lungs) were analyzed. Complete necropsies were performed 

and the organs fixed in a 10% buffered formalin. 

TRIS AMINO did not induce tumors when tested in male Syrian golden 

hamsters. 

41 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

13.11.2006 (43) 

5.8.1 TOXICITY TO FERTILITY 

Type : other 

Species : rat 

Sex : male/female 

Strain : other:CD 

Route of admin. : oral feed 

Exposure period : Males were exposed for at least two weeks prior to breeding & throughout 

breeding for 37 days. Females were exposed for 2 weeks prior to 

breeding, continuing through breeding (up to 2 weeks), gestation (3 

weeks), & lactation (4 days). 

Frequency of treatm. : 

Premating exposure period 

Male : At least two weeks prior to breeding. 

Female : Two weeks prior to breeding 

Duration of test : 

No. of generation : 

studies

Doses : 100, 300, or 1000 mg/kg/day 

Control group : yes, concurrent no treatment 

Method : OECD Guide-line 421 

Year : 2005 

GLP : yes

Test substance : other TS:AMP

Method : Male and female CD rats were fed diets supplying 0 (control), 100, 300, or 

1000 mg/kg/day of AMP-HCL. Males were exposed for at least two weeks 

prior to breeding and continuing throughout breeding for 37 days. The 

females were exposed for two weeks prior to breeding, continuing through 

breeding (up to two weeks), gestation (three weeks), and lactation (four 

days). Effects on gonadal function, mating behavior, conception, 

development of the conceptus, parturition, litter size, pup survival, sex, pup 

body weight, pup gross external morphological alterations, and pathology 

of adult gonads were assessed. 

Result : Increases in absolute and relative liver weights, accompanied by a very 

slight degree of microvacuolization of periportal hepatocytes, with or 

without vacuolization of hepatocytes were noted in males. Females in all 

treatment groups exhibited similar histopathological changes in the liver, 

but in the absence of an organ weight change. AMP had no effect on 

mating performance or conception, but caused marked, dose-related 

increases in post-implantation loss (embryo resorption). At the high dose 

level, all 12 pregnant females showed evidence of complete litter resorption 

(100% post-implantation loss), while at 300 mg/kg/day, post-implantation 

loss was 70% (vs. 10% in controls). Effects associated with, or secondary 

to the post-implantation loss increase at 300 mg/kg/day included 

decreased litter size, increased pup body weight, and decreased gestation 

body weight and body weight gain. There were no treatment related 

effects on reproductive performance in the 100 mg/kg/day group. 

Test substance : Chemical Name: 2-Amino-2-methyl propanol hydrochloride salt 

Molecular Formula: C4H11NO 

Molecular Weight: 89.14 

Synonyms: AMP, AMP-HCL 

Conclusion : The NOEL for general toxicity in males was 300 mg/kg/day, while the 

general toxicity for females could not be determined, based on the 

presence of very slight microscopic liver effects. The NOEL for 

reproductive effects was considered to be 100 mg/kg/day. 

Reliability : (1) valid without restriction

GLP guideline study 

42 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

13.11.2006 (44) 

5.8.2 DEVELOPMENTAL TOXICITY/TERATOGENICITY 

Species : rat 

Sex : female 

Strain : 

Route of admin. : dermal 

Exposure period : 6 hours daily day from gestation days (GD) 6-20 

Frequency of treatm. : daily 

Duration of test : from gestation days (GD) 6-20 

Doses : 30, 100, or 300 mg AMP/kg/day 

Control group : yes

NOAEL maternal tox. : = 100 mg/kg bw 

other: NOEL for : = 300 mg/kg bw 

developmental Tox. 

Result : There was no evidence of test article related systemic maternal or

developmental toxicity at any dose level tested. 

Method : OECD Guide-line 414 "Teratogenicity" 

Year : 2006 

GLP : yes

Test substance : other TS:AMP

Method : Female rats were exposed 6 hours daily dermally to 0, 30, 100, or 300 mg 

AMP/kg/day from gestation days (GD) 6-20 (Carney and Thorsrud, 2006). 

Rats were sacrificed on GD 21, and subjected to a pathological 

examination including examination of the external tissues and all orifices, 

stomach, liver, kidneys, and uterine findings. The first four presumed 

pregnant females from each dose group were selected for blood collection 

to evaluate systemic exposure following dermal administration of AMP on 

the last day of dosing (GD 20). 

Result : Dermal administration of 300 mg/kg/day of AMP produced significant 

effects at the test site, as evidenced by scabbing and moderate to severe 

scaling. The dermal finding of slight scaling at 30 and 100 mg/kg/day was 

not considered adverse, as the observation was transient in nature and 

relatively low in incidence. There was no evidence of test article related 

systemic maternal or developmental toxicity at any dose level tested. 

Analyses of blood samples confirmed systemic exposure to AMP in a doseresponsive manner, although the study was not designed to quantify 

percent absorption. 

Test substance : CAS Number: 124-68-5 

IUPAC Name: 2-Amino-2-methyl-1-propanol 

Molecular Formula: C4H11NO 

Molecular Weight: 89.14 

Synonyms: AMP, AMP-95 

Conclusion : Under the conditions of this study, the NOAEL for maternal toxicity based 

on dermal effects was 100 mg/kg/day. The NOEL for developmental 

toxicity was 300 mg/kg/day, the highest dose level tested. 

Reliability : (1) valid without restriction 

GLP study. 

13.11.2006 (45) 

5.8.3 TOXICITY TO REPRODUCTION, OTHER STUDIES 

5.9 SPECIFIC INVESTIGATIONS 

Endpoint : other: Dermal Absorbtion 

43 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Study descr. in chapter 

Reference 

: 

: Wepierre, J. and Noel-Hudson, M.S. 

Type

Species 

Sex 

: 

: 

: 

other: human skin 

Strain : 

Route of admin. : 100 uL applications to the skin. 

No. of animals : 

Vehicle : 

Exposure period 

Frequency of treatm. 

Doses 

: 

: 

: 

24 hour(s) 

once 

0.1% and 10% solutions 

Control group 

Observation period 

Result

: 

: 

: less than 1% of applied dose is absorbed into the skin. 

Method : 

Year : 1993 

GLP : 

Test substance : other TS: C-14 labeled Tromethamine hydrochloride 

Method : In vitro percutaneous absorption was studied using dermatomized human 

skin (obtained from plastic surgery biopsies of the abdomen and frozen 

until use) placed in Franz diffusion cells to permit contact of the dermis with 

a preservation liquid of sodium chloride and bovine serum albumin. The 

skin was thawed, defatted, and cut to 0.3mm thickness. A cutaneous 

biopsy is maintained horizontally between the dermis and epidermis. The 

system is surrounded with a warm water jacket to maintain the temperature 

at 37C. The air and liquid in the system are circulated continuously to 

insure consistent temperature. 

The test material, C-14- labeled tromethamine hydrochloride, was 

furnished by L'Oreal under the same S1 (0.1%) and S2 (10%). The test 

material (100 uL) was applied to 0.635 cm^2 skin. At regular time intervals 

(2, 4, 6, 8, 10 hours), the totality of the liquid contained in the dermal 

compartment is taken by lateral adjustment and replaced by new liquid. At 

t=24 hours, the preservation liquid is removed and the surface of the 

biopsy is washed with 100 uL of different solvents: 

1st wash- Cetavlon / doubly-distilled water 

2nd wash- doubly-distilled water 

3rd wash- Cetavlon / doubly-distilled water 

4th wash- doubly-distilled water 

5th wash- doubly-distilled water 

The application zone was wiped with cotton rolls, the dermis and epidermis 

were separated mechanically with a scalpel, and digested in Soluene TM 

for 24 hours at 37C. 

The detection of remaining radioactivity was determined via liquid 

scintillation counter. The preservation liquid removed, cotton rolls, and 

glass cylinder are also counted for radioactivity. Counting values were 

corrected by the method of external standard to obtain the dpm. 

Result : Absorption of the test material is low and variable from one skin sample to 

another. At the end of 24 hours, 0.506 +- 0.765 for the 0.1% solution and 

0.797 +- 0.691 for the 10% solution were determined. There is no 

significant difference between the percentages, showing that the increase 

in test material concentraion does not alter cutaneous permeability under 

these test conditions. 

The fluxes in the 2 cases reaches a maximum value after 4 hours and 

remain constant during the rest of the experiment. After washing, the 

retention of tromethamine hydrochloride in the dermis and epidermis is low 

(0.13-0.14% for the 2 solutions in the epidermis and 0.69- 0.22% in the 

dermis). The test material is not retained in the horny layer. The washing 

waters contained more than 90% of the applied dose. 

Source : Dow Chemical, TERC Midland, MI 

44 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Conclusion : Percutaneous absorption through human skin in vitro is low, on average 

less than 1% of the applied dose remains at the end of 24 hours, and the 

finding is independent of the concentration of tromethamine hydrochloride 

applied. 

The test material is almost totally eliminated by washing the skin after 24 

hours. 

The test material is not retained in the horny layer. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (46) 

5.10 EXPOSURE EXPERIENCE 

Type of experience : Direct observation, clinical cases 

Method : THAM (36g in 5% dextrose water) was infused in 4 of the subjects over a 

period of 30 minutes to 24 hours. One patient received 9g THAM over 30 

minutes. 

Result : In all cases, there was a substantial rise in the blood pH and a significant 

increase in the total CO2 content of the blood. However, none of the 

patients showed any clinical improvement. The increase in blood pH and 

total CO2 content appeared to persist for >48 hours in most of the patients 

and continued to remain elevated for a period of several days in 2 of the 

patients. Three of five patients showed 2 major complications following 

THAM administration: hyperkalemia and oliguria. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Five patients manifesting 3 types of renal disease: postpartum bilateral 

renal cortical necrosis, acute and chronic glomerulonephritis, and diabetic 

intracapillary glomerulonephrosclerosis. All subjects had severe 

impairment of renal functions as manifested clinically by oliguria, elevated 

blood urea nitrogen, and abnormal urinary findings. Two were anuric and 2 

others were oliguric. 

Conclusion : In 2 of the cases of complications, the subjects were acutely ill and 

manifested a severe renal failure that could have resulted in the 

hyperkalemia and oliguria. However, the third patient, who received the 

THAM administration more rapidly than the other 4 patients, presented 

initially with normal urine output and normal serum potassium, and within 

12 hours of THAM administration showed marked oliguria and 

hyperkalemia and an elevation of blood urea nitrogen level, although the 

mechanism of such complications was not known at the time of publication. 

THAM is an effective agent in the prompt correction of metabolic acidosis. 

In comparison with sodium bicarbonate or lactate, it may also offer the 

advantage of being able to buffer the intracellular hydrogen ion. THAM 

may therefore be a more suitable agent to correct acidosis when sodium 

intake is a concern. The authors suggest a maximum dose of 500mg/kg 

(0.3M THAM in dextrose) given over 24 hours with careful monitoring of 

urinary output, serum potassium, and blood urea nitrogen for 48 hours 

following THAM administration. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

23.03.2004 (47) 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Samiy, et al., 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

45 / 60 
5. Toxicity Id 

Date 

77-86-1 

14.11.2006 

acidosis. The following reference supports the general findings of the 

authors of this article. 

Source 

Reliability

23.03.2004 

: 

: 

Authors support THAM's use as treatment of metabolic acidosis, noting 

generally positive outcomes and no adverse effects associated with THAM. 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(48) 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Samiy, et al., 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

acidosis. The following reference supports the general findings of the 

authors of this article. 

Source 

Reliability

23.03.2004 

: 

: 

The authors support THAM as treatment of respiratory acidosis, and 

additionally noting a slight decrease in respiration rate following treatment. 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(49) 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Samiy, et al., 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

acidosis. The following reference supports the general findings of the 

authors of this article. 

Source 

Reliability

09.11.2006 

: 

: 

For treatment of acidosis during cardiac bypass procedures and during 

total circulatory arrest, these authors additionally note that THAM is even 

more effective when CO2 is allowed a means to leave the blood (via 

respiration, etc), and can be used when sodium bicarbonate cannot be 

(when a patient is on total cardiopulmonary bypass). THAM has not been 

associated with any toxic effects and is rapidly excreted in the urine. It has 

however, been noted to have transient effects on blood sugar, serum 

potassium, increased urinary (water) loss, and depressed respiratory rates. 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(50) 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Samiy, et al., 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

acidosis. The following reference supports the general findings of the 

authors of this article. 

Authors note that Tromethamine NF is an effective blood buffer for 

Source 

Reliability

23.03.2004 

: 

: 

metabolic and respiratory acidosis. They suggest administering sufficient 

amounts of water with treatment may prevent hyperosmolarity and avoid 

tissue dehydration, and that caution should be used to avoid hyperkalemia, 

hypoglycemia, and depression of the respiratory center. 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(51) 

46 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Samiy, et al., 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

acidosis. The following reference supports the general findings of the 

authors of this article. 

Authors recommend THAM for treatment of diabetic acidosis, when 

patients are unable to tolerate sodium bicarbonate or lactate therapy due to 

severe cardiac and/or sodium-retaining renal failure. The authors suggest 

that THAM may reduce the insulin requirements for management of 

diabetic comas. The patients in this article, while responding favorably to 

THAM treatment, eventually succumbed to other complications of their 

conditions, and upon post-mortem examinations there were no findings that 

suggested THAM contributed to the causes of death. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

23.03.2004 (52) 

Type of experience : Direct observation, clinical cases 

Method : The patient breathes oxygen in a nonbreathing system to remove nitrogen 

from the lungs, after which a barbiturate is used to render the patient 

unconscious during the procedure. THAM is administered IV (0.33M 

solution in 0.2% NaCl) to investigate the buffering effect of THAM. 

Succinylcholine is injected and the bronchoscope introduced when the 

patient is completely paralyzed. Oxygen is continuously administered to 

the patients to ensure complete apneic oxygenation of the blood during the 

6-minute procedure. Likewise, no carbon dioxide is allowed to exit the 

lungs. Arterial blood samples were drawn before and immediately 

following the 6-minute apneic period, and at 5 minutes and 2 hours postprocedure. All patients were maintained on ventilation until recovery of 

normal spontaneous respiration. Blood was analyzed for pH (one 

anaerobically and two at known CO2 tensions) and pCO2. Actual HCO3- 

was calculated according to Henderson-Hasselbalch fornula, and pO2 was 

determined with a modified Clark electrode. Brachial arterial blood 

pressure was measured using an inflatable cuff and mercury manometer. 

Result : During the 6 minute procedure, the PaCO2 increased from 38 to 66 mmHg, 

with a fall in pH from 7.41 to 7.24 and a slight increase in actual 

bicarbonate from 24 to 28 mEq/L. When THAM was administered, the 

arterial pH was kept nearly constant, with a rise of almost identical 

proportions in H2CO3 and HCO3- in all cases. The PaCO2 rose from 37 to 

42 mmHg and the HCO3- from 24 to 28 mEq/L. In all subjects, the arterial 

blood was completely saturated with oxygen throughout the procedure. 

The two subjects in poor condition prior to the procedure were cyanotic 

when breathing air, however breathing pure O2 for 5 minutes relieved the 

cyanosis. Analysis of arterial blood in both subjects showed an almost-fully 

compensated respiratory acidosis. PaO2 during breathing suggested a 

shunting of nonoxygenated blood in the lungs. Six minutes of controlled 

ventilation pre-procedure increased the PaO2 slightly and caused a drop in 

PaCO2 to normal values with a marked alkaline shift in pH. Both faired 

similarly to the subjects in better initial health during the apneic period. 

Both showed improved respiratory status upon removal of secretions from 

the airways. 

In patients not receiving THAM, there was a consistent rise in diastolic 

blood pressure, not seen when the respiratory acidosis was buffered with 

THAM. No patient receiving THAM reported any complaints or 

47 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

complications that could be attributed to the buffer or the apnea. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Twelve adult subjects were treated with THAM in the study. The changes 

in acid-base status were compared with those occurring in 6 subjects not 

receiving THAM. Ten of the subjects had lung tumors or small tuberculous 

cavities and underwent bronchoscopy as a routine preoperative procedure. 

They were all in good general condition without respiratory distress. Two 

subjects, dealt with separately, were in poor condition with ventilatory 

insufficiency prior to the bronchoscopy. 

Conclusion : Because all CO2 produced by the body remained in the body during the 

apneic period, a nearly-perfect stoichometric relationship was revealed 

between CO2 produced and the THAM needed to buffer it. The buffer was 

found to not only reduce the increase in arterial blood pressure, but also 

reduce the typical increase in cerebrospinal fluid pressure seen in 

respiratory acidosis. THAM was not found to cause any hypoglycemia, nor 

were any toxic manifestations noted following THAM treatment. 

THAM is considered by the author to be helpful in counteracting respiratory 

acidosis especially in patients where a blood pressure rise or CSF pressure 

rise is not desired, during procedures where adequate ventilation cannot be 

maintained at all times. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

23.03.2004 (53) 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Holmdahl, 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

acidosis. The following references support the general findings of the 

authors of this article. 

For treatment of respiratory acidosis caused by chronic alveolar 

hypoventilation, the following authors caution use of THAM, because, even 

though an effective buffer, they noted it caused in some patients an 

accentuation of anoxemia that became very severe, and suggested that 

THAM should not be used to treat such cases unless other means of 

oxygenation are supplied (mechanical aid). The authors do not support 

general use of THAM as a treatment for respiratory acidosis caused by 

chronic alveolar hypoventilation. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

23.03.2004 (54) 

Type of experience : Direct observation, clinical cases 

Result : Results of this study (Holmdahl, 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

acidosis. The following reference supports the general findings of the 

authors of this article. 

For treatment of respiratory acidosis, the authors likewise caution the use 

of THAM to buffer the blood unless supplemental oxygen is given due to a 

resulting decrease in minute ventilation rate. The authors advance the 

theory that the decrease in minute ventilation rate is due to the increase in 

pH of the blood and not due to a reduction of CO2 tension per se. They 

report spurious findings of kidney (swelling and hydropic degeneration of 

the lining of proximal tubules) and/or liver (hydropic degeneration of the 

cells) changes in 2 patients receiving THAM, however the authors are 

reluctant to attribute the findings directly to THAM based on others in their 

48 / 60 
5. Toxicity Id 

Date 

77-86-1 

14.11.2006 

Source 

Reliability

23.03.2004 

: 

: 

sampling that do not present such signs. 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(55) 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Holmdahl, 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

acidosis. The following reference supports the general findings of the 

authors of this article. 

Source 

Reliability

23.03.2004 

: 

: 

For treatment of respiratory acidosis, the authors find THAM an effective 

blood buffer, noting also a decrease in ventilation rate, and additionally a 

consistent rise in arterial blood pH and a considerable increase in urinary 

pH with an associated increase in urinary excretion of bicarbonate. They 

noted no adverse effects attributed to THAM treatment, and did not note 

hypoglycemia as other researches have, likely due to lower dose levels. 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(56) 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Holmdahl, 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

acidosis. The following reference supports the general findings of the 

authors of this article. 

Source 

Reliability

23.03.2004 

: 

: 

For treatment of respiratory acidosis, the authors find THAM an effective 

blood buffer, noting also a decrease in ventilation rate, and additionally a 

consistent rise in arterial blood pH and a considerable increase in urinary 

pH with an associated increase in urinary excretion of bicarbonate. They 

noted no adverse effects attributed to THAM treatment, and did not note 

hypoglycemia as other researches have, likely due to lower dose levels. 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(57) 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Holmdahl, 1961) are typical of many publications 

evaluating clinical treatment of ill patients with THAM as a buffer for 

acidosis. The following reference supports the general findings of the 

authors of this article. 

Source 

Reliability

: 

: 

In the treatment of artificially-induced respiratory acidosis (in patients 

recovering from pulmonary tuberculosis with a normally sensitive 

respiratory center), THAM is found to be an effective buffer that prevents 

hyperventilation while breathing CO2. No toxicity has been noted, and 

respiratory toxicity was suggested by the authors to be unlikely due to 

rapidly-reversible effects on ventilation rates. 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

49 / 60 
5. Toxicity Id 

Date 

77-86-1 

14.11.2006 

09.11.2006 (58) 

Type of experience : Direct observation, clinical cases 

Remark : Tromethamine occurs in Ketorolac Tromethamine at approximately 32% of 

the formulation to improve solubility. While it is not possible to differentiate 

the side effects of the active drug from Tromethane, there were no 

clinically-significant findings that would suggest it is inherently toxic. 

Result : 

Results of this study are typical of many publications evaluating clinical 

treatment of post-operative patients with Ketorolac Tromethamine. 

Ketorolac Tromethamine is a non-steroidal anti-inflammatory drug (NSAID) 

indicated for the treatment of acute pain, recently approved by the FDA 

(U.S. Food and Drug Administration) for IM (intramuscular) administration. 

It is a pyrrolo-pyrrole compound related to tolmetin and zomepirac. The 

tromethamine salt in Ketorolac enhances its solubility; there are 6.8mg 

ketorolac in 10mg ketorolac tromethamine. 

Clinical trials of Ketorolac Tromethamine have produced positive analgesic 

effects in post-operative patients with quick onset of relief lasting longer 

than comparable doses of morphine. In addition, Ketorolac Tromethamine 

treatment provides a non dependency-forming alternative to opiates. 

Authors noted that some patients experienced a decreased platelet count 

and bleeding time that was statistically, but not clinically, significant, 

although it is not recommended for treatment of patients with existing 

bleeding disorders. It has, like most NSAIDS, the potential to cause gastric 

mucosal injury. Diarrhea, dizziness, sweating, and pain at the injection site 

were noted in 1-3% of patients. There have been no drug interactions 

noted. Although animal studies have shown no evidence of mutagenesis, 

carcinogenesis, or fertility impairment, it is not recommended for pregnant 

or lactating women. Respiratory depression has not been noted in patients 

using the drug. 

Source 

Conclusion 

Reliability

23.03.2004 

: 

: 

: 

While IM administration has been approved by the USFDA, intravenous 

administration was not approved when the article was published. 

Dow Chemical, TERC Midland, MI 

Ketorolac Tromethamine has been evaluated by the USFDA to be a viable 

alternative to opiates for pain relief. While side-effects have been noted 

similar to other NSAIDS, it can be safely used as a non-habit forming drug 

to relieve pain in most patients. 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(59) 

Type of experience : Direct observation, clinical cases 

Remark : Results of this study (Resman-Targoff, 1990) are typical of many 

publications evaluating clinical treatment of post-operative patients with 

Ketorolac Tromethamine. The following reference supports the general 

findings of the authors of this article. 

Source 

Reliability

23.03.2004 

: 

: 

Noting an increase in liver function test results, the following authors have 

additionally noted that the drug may not be ideal for use in patients with 

prior liver damage. 

Dow Chemical, TERC Midland, MI 

(2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

(60) 

Type of experience : Direct observation, clinical cases 

50 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

Remark : Results of this study (Resman-Targoff, 1990) are typical of many 

publications evaluating clinical treatment of post-operative patients with 

Ketorolac Tromethamine. The following reference supports the general 

findings of the authors of this article. 

A transient renal insufficiency was noted by the following authors, directly 

attributed to Ketorolac Tromethamine treatment. Decreased urine output 

and an increased serum creatinine concentration were measured. There 

was no hyperkalemia noted. These observations, however, are in discord 

with observations of hyperkalemia and increased urine output noted with 

THAM infusion (minus Ketorolac) in other patients, suggesting that the 

observations noted by these authors could be primarily attributed to the 

Ketorolac. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

23.03.2004 (61) 

Type of experience : Direct observation, clinical cases 

Method : Four healthy adults received THAM via IV over 30-60 minutes in 0.03M 

NaCL / 0.005M KCl during 2.3 or 3.4% CO2 breathing. 

Result : 64% of THAM administered was eliminated in the urine over 2 days, and 

77% over 3 days. 

Major side effects noted in the subject given 8.8 mM/kg bodyweight 

included: hypotension, hypoxia, hunger, sweating, periodic breathing, 

weakness, somnolence, diarrhea, intense wretching and vomiting, 

sensations of heat, swelling and numbness of face. In all other subjects, 

water diuresis was noted with decrease blood serum glucose 

concentrations. Urine pH and CO2 content rose as the THAM was 

eliminated. 

Source : Dow Chemical, TERC Midland, MI 

Reliability : (4) not assignable 

Documentation insufficient for assessment. 

24.03.2004 (62) 

Type of experience : Direct observation, clinical cases 

Method : Venous blood samples were taken from the other arm 10, 20, and 30 

minutes after starting the infusion, and 5, 10, 20, and 40 minutes at 1, 2, 4, 

8, 12, 20, and 24 hours after it had ended. 

Urine was collected from the beginning of the infusion until 30 minutes after 

its end, from 30 min to 4 hours, from 4 to 8 hours, and from 8 to 24 hours. 

Five patients required haemodialysis or haemofiltration as a result of acute 

anuria. In two patients, gastric juices were drained continuously via a 

plastic tube and were collected for 48 hours and analyzed for TRIS. In one 

patient, a drain had been implanted in the common bile duct diring 

choledocholithotomy and the bile was collected over two 24 hour periods. 

All samples were analyzed for TRIS concentration via gas chromatography. 

Result : In three patients, unidentified peaks were seen with the same retention 

times as TRIS due to additional medication. The haemofiltrates of these 

patients was subsequently not analyzed for TRIS concentrations. 

The results from the 6 healthy subject were pooled. At the end of infusion, 

the TRIS plasma concentration averaged 565 ug/mL. There was a 

biexponential decline of plasma TRIS levels and after 24 hours, the level 

51 / 60 
5. Toxicity Id 77-86-1 

Date 14.11.2006 

was only 3.8 ug/mL. The half-life of the terminal phase was 5.6 hours. 

TRIS concentrations in erythrocytes rose more slowly, reaching a 

maximum 20 minutes after the end of infusions. After 2 hours, drug levels 

in erythrocytes were about 1.5 times greater than those in plasma, and 

they remained well above the corresponding plasma levels during the rest 

of the observation period. 

Pharmacokinetic parameters were calculated from the individual 

concentration-time curves using a two-compartment model with elimination 

from the central compartment. 

TRIS is mainly excreted by the kidney. Already 30 minutes after the end of 

infusion, 25% of the TRIS was found in the urine, and after 24 hours, 82% 

of the TRIS had been eliminated in that way. 

Infusion of the strongly alkaline solution (pH 10.9) was well tolerated by all 

patients without adverse reactions. 

The half-life of TRIS in normuric patients (including some with poor renal 

function) was longer than in healthy patients (16-45 hours), and the 

volumes of distribution were much larger. Up to 72% of the TRIS was 

eliminated in the urine after 24 hours, and an additional 2-5% excreted 

during the next 24 hours. 

The half-life of TRIS in anuric patients ranged 15-58 hours. 25-66% of the 

infused TRIS left the plasma in the first 24 hours, and the clearance 

averaged 16.7 mL/kg/hr. Periods of haemodialysis or haemofiltration did 

not affect plasma TRIS level. The amount of TRIS eliminated via these 

procedures could not be measured as the fluid could not be collected for 

analysis. 

Less than 0.2% of the infused dose of TRIS was found during 24 hours in 

gastric juice or bile. 

Source : Dow Chemical, TERC Midland, MI 

Test condition : Six healthy volunteers (5 males, 1 female, ages 27-37, weighing 50-90 kg) 

and 20 patients in a surgical intensive care unit (diagnoses ranged from 

traumatic lesions, intestinal bleeding, perforated appendicitis, and 

pancreatitis to rectal and gastric cancer, and aortic aneurysm) were infused 

with 121 mg/kg TRIS of 0.3 mol/L solution at a pH of 7.4 over 30 minutes in 

an antebrachial vein. 

Conclusion : TRIS is primarily eliminated via the kidneys in the urine. There were no 

adverse effects related to TRIS treatment in any subject. 

Accumulation of TRIS may occur in the body if patients with impaired renal 

funtion are repeatedly given TRIS treatment. 

Reliability : (2) valid with restrictions 

Meets generally accepted scientific standards, well-documented and 

acceptable for assessment. 

09.11.2006 (63) 

5.11 ADDITIONAL REMARKS

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6. Analyt. Meth. for Detection and Identification Id 77-86-1 

Date 14.11.2006 

6.1 ANALYTICAL METHODS 

6.2 DETECTION AND IDENTIFICATION 

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7. Eff. Against Target Org. and Intended Uses Id 

Date 

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7.1 FUNCTION 

7.2 EFFECTS ON ORGANISMS TO BE CONTROLLED 

7.3 ORGANISMS TO BE PROTECTED 

7.4 USER 

7.5 RESISTANCE 
8. Meas. Nec. to Prot. Man, Animals, Environment Id 

Date 

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14.11.2006 

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8.1 METHODS HANDLING AND STORING 

8.2 FIRE GUIDANCE 

8.3 EMERGENCY MEASURES 

8.4 POSSIB. OF RENDERING SUBST. HARMLESS 

8.5 WASTE MANAGEMENT 

8.6 SIDE-EFFECTS DETECTION 

8.7 SUBSTANCE REGISTERED AS DANGEROUS FOR GROUND WATER 

8.8 REACTIVITY TOWARDS CONTAINER MATERIAL 
9. References Id 77-86-1 

Date 14.11.2006 

(1) Frauson, L. (2004) Personal e-mail to C. Houtman dated March 19, 2004. 

(2) The Merck Index (Eleventh Edition). Merck & Co., INC. Rahway, NJ, USA. 1989. 

(3) ANGUS Material Safety Data Sheet. 

(4) Eilerman, D. and Rudman, R. (1980) Polymorphism of crystalline poly(hydroxymethyl) 

compounds. III. The Structures of crystalline and plastic 

tris(hydroxymethyl)aminomethane. J. Chem. Phys. 72(10): 5656-5666. 15 May 1980. 

(5) The Merck Index (Ninth Edition). Merck & Co., Inc. Rahway, NJ, USA. 1976. 

(6) Nahas, G. (1962) The Pharmacology of Tris(hydroxymethyl)aminomethane (THAM). 

Pharmacology Review, 14:447-472. 

(7) Gabriel, C.L. (1940) The Nitroparaffins: New Synthetics for Synthesis. Ind. Eng. Chem. 

32:887-892. 

(8) U.S. EPA. (2000) EPIWIN software, version v3.11. United States Environmental 

Protection Agency, Office of Pollution Prevention and Toxics, Washington, D. C. Available 

at: http://www.epa.gov/oppt/exposure/docs/episuitedl.htm 

(9) Lhotak, H. (1996) Partition Coefficient of Various Products (AMPD APD). ANGUS Chemie 

GmbH. Report of The Dow Chemical Company. 

(10) Lhotak, H. (1997) Partition Coefficient of Various Products (AMPD APD). ANGUS Chemie 

GmbH. Determination of Partition Coefficient Pow (n-octanol/water) of AMPD, APD and 

Corrguard B-90 according to OECD method 107. Report of The Dow Chemical Company. 

(11) West, R.J. (2004) A report of The Dow Chemical Company, Using ACD Log D Suite 

software, version 5.0 (2001). Advanced Chemistry Development Inc., Toronto, Ontario. 

(12) Troester, L. (2006) ANGUS Technical data sheet. Personal communication. 

(13) Bates, R.J. and Pinching, G. (1949) Dissociation of weak bases from electromotive force 

measurements of solutions of partially hydrolyzed salts. J. Res. nat. Bur. Stand. 43:519­

526. 

(14) Troester, L. (2006) Personal communication. 

(15) Gonsior, S. (2006). Prediction of the Environmental Distribution and Transport Between 

Environmental Compartments for Tris(hydroxymethyl)aminomethane Using Level I and 

Level III Fugacity Models. Draft Report of the Dow Chemical Company. 

(16) West, R.J. (2004) A report of The Dow Chemical Company using Level I model version 

2.11, Obtained from the Canadian Environmental Modeling Centre, Trent University, 

Peterborough, Ontario, Canada. 

(17) IWL (1990) Institut für gewerbliche Wasserwirtschaft und Leftreinhaltung e. V. IWL -

Auftragsnummer: Lab 594. 

(18) McFarland, W.N. and Norris, K.S. (1958) The Control of pH by Buffers in Fish Transport. 

California Fish and Game. 291-310. 

(19) Akute Toxizität für Fische OECD Guideline 203, 96 h, statisch (1997). AMPD für ANGUS 

Chemie GMBH. Steinbeis-Transferzentrum Angewandte und Umwelt-Chemie. 

(20) ANGUS MSDS # AT58, dated 9/13/2001. 

56 / 60 
9. References Id 77-86-1 

Date 14.11.2006 

(21) Young, B.E. and Tapp, J.F. (1983) The Toxicity of AMP 95 to the brown shrimp (Crangon 

crangon) and plaice (Pleuronectes platessa). Report K349/B for the Central Electricity 

Generating Board, Manchester, UK by Imperial Chemical Industries, PLC. 

(22) Parekh, C. (1980) AMP-95 Acute Toxicity Effects on Daphnia, 48 Hr LC50. Report #25561 

for the International Minerals & Chemical Corporation, Pharmacology Laboratories, Animal 

Science Research by Analytical Bio Chemistry Laboratories, Columbus, MO, USA. 

(23) Adams, N., Goulding, K.H., and Dobbs, A.J. (1985) Toxicity of Eight Water-Soluble 

Organic Chemicals to Selenastrum capricornutum: A Study of Methods for Calculating 

Toxic Values Using Different Growth Parameters. Arch. Environ. Contam. Toxicol. 14:333­

345. 

(24) Coenen, T. M. M. (1990) Acute Bacteria Cell Multiplication Inhibition Test with TRIS AMINO 

40%. Report of the RCC NOTOX B.V. RCC NOTOX Project 038328. The Netherlands. 

(25) Bakterientest (Zellvermehrungshemmtest) von TRIS AMINO 40% (1990) IWLInstitut für 

gewerbliche Wasserwirtschaft und Leftreinhaltung e. V. IWL - Auftragsnummer: IB/35/90. 

(26) Acute Toxicities of Amines. (1955) Hill Top Research Intitute Inc., Miamiville, OH, USA. 

(27) Giroux, J. and Beaulaton, I. (1962) Recherches Pharmacologiques Sur Le THAM. Societe 

Pharmacie Montpellier. 21:206-217. 

(28) Parekh, C. (1980) Dermal Toxicity of P-1826 (AMP). Report PLR-113 of Pharmacology 

Laboratories Animal Science Research, Terre Haute, IN. 

(29) Roberts, M. and Linn, S. (1961) Acute and Subchronic Toxicity of 2-Amino-2­

hydroxymethyl-1,3-propanediol. In Vitro and In Vivo Effects of Amine Buffers, Annals of the 

New York Academy of Sciences. V 92:724-734. 

(30) Thompson, S.W., Allen, M.R., and McDowell, M.E. (1965) Toxicity Studies with Tris 

(hydroxymethyl) aminomethane. U.S. Army Medical Research and Nutrition Laboratory, 

Fitzsimons General Hospital, Denver, CO, USA. 1 March 1965. 

(31) Baldwin, R. (1961) Tris(hydroxymethyl)aminomethane Primary Skin Irritation Studies. 

Internal correspondence of The Dow Chemical Company. May 19, 1961. 

(32) Machle, W., Scott, E. W. and Treon, J. F. (1940) The Physiological Response of Animals 

to Some Simple Mononitroparaffins and to Certain Derivatives of These Compounds. 

Journal of Industrial Hygiene and Toxicology V22, No.8 (315-332). 

(33) Power, C. (1975) Eye Irritation, Bioassay Report #26775. Pharmacology Laboratories 

Research and Development, Commercial Solvents Corporation. May 21, 1975. 

(34) Toxicology data summary on TRIS AMINO, 1992. In DR-0017-3524-019 and Toxicological 

Profile on Tris Amino. In DR-0017-3524-019. The Dow Chemical Company. 

(35) Parekh, C. (1982) Intradermal Sensitization Potential of AMP (P-1826). Report No. PLR265 of Bio/dynamics Inc, East Millstone, NJ. Sponsored by the International Minerals & 

Chemical Corporation, Terre Haute, IN. 

(36) Parekh, C. (1982) Topical Sensitization Potential of AMP (P-1826). Report No. PLR-266 

of Bio/dynamics Inc, East Millstone, NJ. Sponsored by the International Minerals & 

Chemical Corporation, Terre Haute, IN. 

(37) CIR: Cosmetic Ingredient Review Board (1990). A Final Report on the Safety Assessment 

of Aminomethylpropanol and Aminomethylpropanediol. J. Am. Coll. of Toxicol. 9:203-228 

57 / 60 
9. References Id 77-86-1 

Date 14.11.2006 

(38) Kociba, R. (2003). Assessment of the Potential for Skin Sensitization of StructurallyRelated Analogs Represented by 2-Amino-2-(Hydroxymethyl)-1,3-Propanediol, 2-Amino-2­

Methyl-1-Propanol, and 2-Amino-2-Methyl-1,3-Propanediol. Written communication. 

(39) Parekh, C. (1981) A Three Month In Diet Toxicity Study of 2-Amino-2-methyl-1-propanol in 

Rats. Study 80-2503 of Bio/dynamics Inc, East Millstone, NJ. Sponsored by the 

International Minerals & Chemical Corporation, Terre Haute, IN. 

(40) Griffin, T. (1990) A One-Year Oral Toxicity Study of AMP in Dogs. Coulston Research 

Incorporated, White Sands Research Center, Alamogordo, NM. Amended by the original 

author on April 20, 1993. 

(41) Livtak, K.M. and McEvoy, G.K. (1990) Ketorolac, an injectable nonnarcotic analgesic. 

Clinical Pharmacy. 9:921-935. 

(42) Ray, T. and Dyson, P. Tris as a bifunctional cleaving agent of Streptomyces lividans DNA. 

(1992) Mutagenesis: 7(5):384. 

(43) Ketkar, M. , Green, U., Schneider, P., and Mohr, U. (1979) Investigation on the 

carcinogenic burden by air pollution in man. Intratracheal instillation studies with 

benzo[a]pyrene in a mixture of Tris buffer and saline in Syrian golden hamsters. Cancer 

Letters, 6 279-284. 

(44) Carney, E.W., Quast, J.F., and Zablotny, C.L. (2005) 2-Methyl-2-Aminopropanol 

Hydrochloride: A Reproductive / Developmental Toxicity Screening Test in CD Rats. 

Report DR-0038-3186-001 of the Dow Chemical Company. 

(45) Carney, E.W. and Thorsrud, B. (2006) AMP: Dermal Developmental Toxicity Study in 

CRL:CD(SD) Rats. The Dow Chemical Company Report No: DR-0399-3940-001 

(46) Wepierre, J. and Noel-Hudson, M.S. Percutaneous Absorption of Tromethamone 

Hydrochloride: Study on Human Skin in In Vitro Diffusion Cells (1993) University of ParisSud, Faculty of Pharmacy. August 9, 1993. 

(47) Samiy, A.H., Ramsay, A.G., Rees, S.B., and Merrill, J.P. (1961) The Use of 2-Amino-2­

hydroxymethyl-1,3-propanediol in the Management of Renal Acidosis. In Vitro and In Vivo 

Effects of Amine Buffers, Annals of the New York Academy of Sciences. V 92:802-812. 

(48) Conant, J.S. and Hughes, R.E. (1961) The Usefulness of THAM in Metabolic Acidosis. In 

Vitro and In Vivo Effects of Amine Buffers, Annals of the New York Academy of Sciences. 

V 92:751-754. 

(49) Sieker, H.O., Merwarth, C.R., and Saltzman, H.A. (1961) The Use of 2-Amino-2­

hydroxymethyl-1,3-propanediol in Severe Carbon Dioxide Intoxication. In Vitro and In Vivo 

Effects of Amine Buffers, Annals of the New York Academy of Sciences. V 92:783-793. 

(50) Peirce, E.C. (1961) Effects of 2-Amino-2-hydroxymethyl-1,3-propanediol (TRIS) During 

Cardiac Bypass Procedures. In Vitro and In Vivo Effects of Amine Buffers, Annals of the 

New York Academy of Sciences. V 92:765-782. 

(51) Hoover, J.E. (1975) Remington's Pharmaceutical Sciences, 15th Edition. Mack Publishing 

Company, Easton, Pennsylvania, USA. 

(52) Rees, S.B., Younger, M.D., and Freedlender, A.E. (1961) Some In Vivo and In Vitro 

Observations on the Effects of Tris(hydroxymethyl)aminomethane in Diabetic Acidosis. In 

Vitro and In Vivo Effects of Amine Buffers, Annals of the New York Academy of Sciences. 

V 92:755-764. 

(53) Holmdahl, M.H. (1961) The Use of Tris(hydroxymethyl)aminomethane During Short 

Periods of Apneic Oxygenation in Man. In Vitro and In Vivo Effects of Amine Buffers, 

Annals of the New York Academy of Sciences. V 92:794-801. 

58 / 60 
9. References Id 77-86-1 

Date 14.11.2006 

(54) Luchsinger, P.C. (1961) The Use of 2-Amino-2-hydroxymethyl-1,3-propanediol in the 

Management of Respiratory Acidosis. In Vitro and In Vivo Effects of Amine Buffers, Annals 

of the New York Academy of Sciences. V 92:743-750. 

(55) Brinkman, G.L., Brunswick, F.W., and Whitehouse, F.W. (1961) The Use of 2-Amino-2­

hydroxymethyl-1,3-propanediol in the Correction of Metabolic and Respiratory Acidosis. In 

Vitro and In Vivo Effects of Amine Buffers, Annals of the New York Academy of Sciences. 

V 92:735-742. 

(56) Brinkman, G.L., Remp, D.G., Coates, E.O., and McCall Priest, E. (1960) The Treatment of 

Respiratory Acidosis with THAM. Am. J. Med. Sci. 239:341-346. 

(57) Brown, E.S., Bennett, T.E., Bunnell, I.L., Elam, J.O., Evers, J.L., Greene, D.G., Janney, 

C.D., Lowe, H.J., Nahas, G.G., and Tarail, R. (1959) Effects of THAM During CO2 

Breathing in Man: Ventilation and CO2 Exchange. The Physiologist. 2:18-19. 

(58) Brinkman, G.L. (1960) The Use of THAM to Prevent Hyperventilation and Acidosis While 

Breathing Carbon Dioxide. Am. J. Med. Sci. 239:728-731. 

(59) Resman-Targoff, B.H. (1990) Keterolac: A Parenteral Nonsteroidal Antiinflammatory Drug. 

DICP, The Annals of Pharmacotherapy. 24:1098-1104. 

(60) Dipalma, J.R. (1991) Ketorolac: An Injectable NSAID. American Family Physician. 

43(1):207-210. 

(61) Corelli, R.L. and Gericke, K.R. (1993) Renal Insufficiency Associated with Intramiscular 

Administration of Ketorolac Tromethamine. The Annals of Pharmacotherapy. 27:1055­

1057. 

(62) Tarail, R., Bennett, T.E., Brown, E.S., Bunnell, I.L., Elam, J.O., Evers, J.L., Greene, D.G., 

Janney, C.D., Lowe, H.J., and Nahas, G.G. (1959) Effects of THAM During CO2 Breathing 

in Man: Metabolic and Toxic Effects. The Physiologist, 2:114. 

(63) Brasch, H., Thies, E., and Iven, H. (1982) Pharmacokinetics of TRIS (hydroxymethyl­

)aminomethane in Healthy Subjects and in Patients with Metabolic Acidosis. European 

Journal of Clinical Pharmacology 22:257-264. 

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10. Summary and Evaluation Id 

Date 

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14.11.2006 

10.1 END POINT SUMMARY 

10.2 HAZARD SUMMARY 

10.3 RISK ASSESSMENT 

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