To order NIOSH publications or to receive information about occupational safety and health problems, call 1-800-35-NIOSH (1-800-356-4674)No. 95-100 PREFACE A memorandum o f understanding has been signed by two government agencies in the United States and Sweden-the Division of Standards Development and Technology Transfer, National Institute for Occupational Safety and Health (DSDTT/NIOSH), U.S. Department of Health and Human Services; and the Criteria Group o f Occupational Standards Setting, Swedish National Institute of Occupational Health (NIOH). The purpose of the memorandum is to exchange information and expertise in the area o f occupational safety and health. One product o f this agreement is the development of documents to provide the scientific basis for establishing occupational exposure limits. These limits will be developed separately by the two countries according to their different national policies. This document on the health effects of occupational exposure to 2-ethyl-2-hydroxymethyl-1,3propanediol (trimethylolpropane) is the sixth product of that agreement. The document was written by Dr.#
5.2 at a concentration of 250 g/1.
Trimethylolpropane is a white, crystalline substance that is mildly aromatic. In crystalline form, trimethylolpropane shows no decomposition at room temperature, but the substance has a strong hygroscopic property. Trimethylolpropane is totally soluble in water and has a half-life in solution of more than one year at pH 4.7 and 9.0, at 25C (14).
The industrial product contains no additives. Major impurities are trimethylolpropanemonomethylether and trimethylol-methylformal. According to one source the purity of trimethylolpropane as an industrial product is more than 99% (wt) (14).
In solid form trimethylolpropane is inflammable but a mixture o f dust and air is explosive at concentrations o f 2 % to 11.8 % by volume. At high temperature the substance vaporizes and forms a vapor/air mixture that is heavier than air and explosive in contact with hot surfaces, sparks, or flames. No published data on world production rates o f trimethylolpropane have been found. An estimation o f the world production, and the Swedish production, was given by U. Rich (personal communication) at the Swedish Products Register at the National Chemical Inspectorate. His estimation o f the world production level was approximately 100,000 metric tons per year, and there is one producer in Sweden, Perstorp AB, with a production of 20,000 metric tons per year.

# USES AND OCCURRENCE

# Production and Uses
According to the Japanese OECD report (14) the production level in Japan in 1991 was about 10,000 tons (not specified if it is metric tons) per year. In 1991 about 2,000 tons o f trimethylolpropane were imported to Japan. The major part was used for paint resin (7,500 tons), urethane resin (1,500 tons), setting resin by UV-ray (1,400 tons), synthetic lubricant oil (800 tons), and others (1,200 tons). Hoechst-Celanese Chemical Company is the only United States producer of trimethylolpropane with a plant at Bishop, Texas (10).

# Occupational Exposure and Analytical Methods for Air Monitoring
No data were available on the present occupational exposure levels or techniques for sampling and analysis o f trimethylolpropane in ambient air.

# Present Occupational Standards

# TOXICOKINETICS
There are no data on human uptake, distribution, biotransformation, or elimination o f trimethylolpropane. In experimental animals no quantitative data were found on toxicokinetics.

# Uptake
In animals trimethylolpropane is absorbed via dermal, oral, and respiratory routes o f exposure. Systemic effects after dermal absorption have been observed. In an unpublished report, cited in BIBRA (3), trimethylolpropane was applied to closely clipped intact abdominal rabbit skin. After 24 hours there was residual substance at all dosage levels (2.15, 4.64, and 10.0 g/kg of b.wt.), except at the lowest (1.00 g/kg of b.wt.). Although no analysis was made on the amount of residual substance on the skin, the nonresidual part was assumed to have been absorbed by the skin. No systemic effects apart from kidney changes were observed.
No systemic effects were seen in mice after immersion o f their tails in 50% solution (w/w or w/v not specified) of trimethylolpropane for 4 hours according to a Soviet study (16). In the same paper a test is described where 0.5 ml of 50% solution (the dose/kg - day was not specified) of trimethylolpropane was applied daily to the skin of rabbits for

# Distribution, Biotransformation, and Elimination
N o data are available.

# GENERAL TOXICITY
No data on the general toxicity in humans have been found. In the literature available on trimethylolpropane, only toxic mechanisms causing a narcotic effect have been discussed (12).

# Acute Toxicity
In laboratory animals the acute toxicity o f trimethylolpropane is extremely low after oral administration, inhalation, and dermal exposure. The LC/LDso-values found in the literature on trimethylolpropane are listed in Table 1.
Test conditions o f the different studies are described in Section 6, except for the following:
The first is an unpublished study cited in reference 14. Five male and five female Wistar rats received a single oral dose of 5 g/kg b.wt. of trimethylolpropane. The animals were observed for 14 days and no changes of body weights or clinical signs o f toxicity were observed. The No chronic toxicity studies were found.

# I a

# ORGAN EFFECTS

# Skin and Mucous Membranes
The

# Chronic Toxicity

# I
The BIBRA document (3) also presents brief information about eye irritancy, but the original studies are not published. According to one study, 50 mg trimethylolpropane was not irritating to the rabbit eye when observed for up to 7 days. The number of animals tested or other test conditions were not described in this short citation. There were indications o f mild transient irritation (particularly in two animals) when 0.1 cm3 powder was introduced into the eye o f nine rabbits. Four days after application there were no signs of irritation.
No inflammation of the skin or the mucous membrane of the eye was observed according to an unpublished study cited by an OECD document (14). A dose of 0.5 g of trimethylolpropane was put into the ear o f two rabbits for 24 hours and 50 mg of trimethylolpropane was put into the conjunctival sac o f the eye o f two rabbits.

# Nervous System
Trimethylolpropane belongs chemically to a group o f alcohols that are organic chemicals associated with narcotic-type toxicity. Human data are missing, but CNS depressive symptoms have been observed in experimental animals after exposure to trimethylolpropane. No data have been found on the toxicity to the peripheral nervous system.
A Soviet paper presents subchronic inhalation toxicity data for trimethylolpropane (16). This study is cited in a BIBRA document (3), which gives a description o f this study as "obscure and poorly reported."
Twenty albino rats (gender or strain not specified) were divided into two groups (size not given). The animals were exposed to either a concentration o f 100-700 mg/m3 (mean 130 mg/m3) or a concentration of 700-1,800 mg/m3 (mean 1,100 mg/m3). Exposure time was 4 hours per day in chambers during a period o f 3.5 months (it was not specified if it was for 7 or 5 days per week). The air supplied to the chambers passed through a tube, with the preparation placed in a boiling water bath, so as to resemble the technological process, where temperatures o f up to 100 C are used. A dysfunction of the nervous system was described, measured by the threshold of neuromuscular excitability after electric stimuli. A raised threshold could be noticed after 8 w eeks o f exposure to trimethylolpropane at a concentration o f 1.1 mg/1 air (1,100 mg/m3). A concentration o f 0.13 mg/1 (130 m g/m 3) caused "recorded sh ifts" beginning with the 12th week. According to a BIBRA document (3), the results o f this experiment remain obscure and can therefore not be evaluated. The effect o f raised neuromuscular excitability was noticed earlier in the control animals than in the animals exposed to trimethylolpropane, according to the figures presented in the report.
A short-term experiment was also performed using the concentrations mentioned above (700 -2 ,0 0 0 mg/m3), where an unspecified number o f animals were exposed for 4 hours. No antemortem signs of toxicity were noticed but terminal histopathology revealed a "swelling of the cells" in some organs including the brain.
The report also describes signs of poisoning o f the nervous system o f rats after oral administra tion of trimethylolpropane. The symptoms were sluggishness, decreased respiration rate, and clonic-tonic spasms. Test conditions are poorly described. The number o f animals tested was not given, and it was not mentioned if controls were used. Even data about actual doses at which these effects occurred are missing.
Inhibition o f the central nervous system was observed in an unpublished study cited in BIBRA (3). Twenty-five male albino rats (strain not defined), divided into five groups, received trimethylolpropane orally at doses o f 1 .0 ,2 .1 5 ,4 .6 4 ,1 0 .0 , and 21.5 g/kg b.wt. No animals were used as controls. Within 1 to 2 hours after a single dose o f 2.15 g/kg or more, the animals appeared depressed and exhibited lacrimation, slow and labored respiration, ataxia, and splaying of the legs. The animals at the 21.5 g/kg level all died and the premortal signs o f intoxication were depressed or absent reflexes o f pain, righting, and placement. Symptoms remained for 24 hours; but at 43 hours following dosage, the surviving animals exhibited normal appearance and behavior.

# Toxic Effects in Other Internal Organs

# I
Biochemical analysis of blood revealed a significant decrease of hepatic enzymes (SGPT and SAP) at a dosage level o f 200 mg/kg - day and above for male rats. Corresponding changes were also seen in female rats at a dosage level of 667 mg/kg - day. SGOT levels remained unchanged.
After the administration of hepatotoxic substances there is usually an increase of liver enzymes in blood (e.g., SGPT and SGOT). Therefore no safe conclusions can be based on these results.
At a dose o f 667 mg/kg - day there was a significant increase in the relative weight of the liver, kidneys, spleen, thyroid (female), adrenals (male), ovary, and brain (female) when compared with a nonexposed control group. There was no significant difference in terminal body weights between the various groups, including controls.
Morphological changes o f liver and spleen were observed. Lymphocyte infiltration and nor moblasts were observed in the sinusoids of the liver at the highest dosage level (667 mg/kg). In female rats there were enlarged Kuppfer cells containing pigment granules at the highest dose level. Treatment-related changes in the spleen were also reported (hyperplasia of phagocytically active reticuloendothelial cells).
The subchronic oral toxicity of trimethylolpropane was investigated in sis strain Sprague-Dawley rats as presented in an unpublished report cited in OECD (14). The animals received doses of 0 to 800 mg/kg - day in distilled water. Before mating, the administration period was 42 days for male rats and 14 days for female rats. Dosing of females continued after mating until day 3 of lactation. It is not specified in this short citation if it was for a consecutive number of days or 5 days per week. No deaths occurred among the 60 animals and no clinical signs attributable to the treatment were observed. Body weights of both male and female animals receiving 800 mg/day were lower than those of the control group. Liver weight (absolute and relative) was significantly elevated in rats of both sexes receiving 800 mg/kg - day. Histopathological examination revealed renal changes (slight tubular basophilic change of tubular epithelial cells) in male rats of all groups and in some of the females, but no dose-related morphological lesions of the liver or the kidneys were noticed.
Another unpublished study cited in OECD ( 14) showed significantly increased liver and kidney weights (absolute and relative) of rats (40 male and 40 female Wistar rats) after an oral dose of 2,000 mg/kg - day for 28 days. The animals were divided into four groups, each consisting of ten animals, with intake levels from their food of 0,0.33,1.00, and 3.00 % (which corresponds to 0 ,2 2 0 ,6 6 7 , and 2,000 mg/kg . day).
Treatm ent-related m orphological changes (enlarged hepatocytes and pericholangitis) of the liv er w ere seen at a dose o f 667 m g/kg - day or m ore. Renal changes (m inim al tubular nephrosis and deposits of a proteinaceous material in Bowmans space) were observed at a dose o f 2,000 m g/kg . day.
Kidney changes (a hyperemic zone at the periphery of the medulla) were observed according to an unpublished report, cited in BIBRA (3). Twenty-five male albino rats (age and strain not specified) were given trimethylolpropane at doses of 1.0, 2.15, 4.64, 10.0, and 21.5 g/kg b.wt. as a single oral dose. No animals were used as controls. The kidney changes were observed at autopsy in all animals receiving 4.64 g/kg or more.
All animals given the highest dose died within 24 hours after administration, and autopsy showed hyperemic or hemorrhagic lungs, irritation of the pyloric portion of the stomach, small intestine, and peritoneum , as well as congested kidneys and adrenals. The acute oral LD5 0 o f trimethylolpropane was estimated to be 14.7 g/kg b.wt. (male albino rats).

# ALLERGENIC PROPERTIES
Patch tests performed on 200 human subjects indicated that trimethylolpropane was not a skin sensitizer, according to a short citation in a chemical encyclopedia (10). The original report on this study could not be found and evaluated.
No other studies or case reports on the allergenic properties of trimethylolpropane were available.

# GENOTOXICITY
Available data on the genotoxic effects of trimethylolpropane have not revealed any evidence of genotoxicity. All published information about genotoxicity in this section (exclusively in vitro tests for gene mutations) originates from one single secondary source of information, the OECD document (14).
Four different strains of Salmonella typhimurium (TA100, TA1535, TA98, TA1537) were tested, with and without an exogenous metabolic activation system (the S-9 mix from rat liver). Doses up to 5 mg of trimethylolpropane (99.51 % purity) per plate did not cause any bacteriotoxic effects or any evidence of mutagenic activity, in comparison with the negative controls.
A second study on the genotoxicity of trimethylolpropane was also negative (14). The short citation provided no information about the test method or genotoxic end-point. Test species were Salmonella typhimurium (strain TA98, TA100, TA1535, TA1537 and TA1538) and Escherichia coli (strain wp2 and uvrA).
The OECD document ( 14) also cites a third unpublished study which was negative. The short citation provides no information about test method. Test species were Salmonella typhimurium (strain TA98, TA100, TA1535, TA1537) and Escherichia coli (strain wp2 and uvrA). Mutagenicity was tested both with and without metabolic activation.
In a fourth unpublished study, cited in OECD ( 14), a nonbacterial in vitro test was performed on cultured Chinese hamster CHL cells. This short citation provides no information about test method or genotoxic end-point. The lowest concentration producing cell toxicity, both with and without metabolic activation, was 1.5 mg/ml. No genotoxic effect was observed.

# CARCINOGENICITY
No information is available.

# I 10 REPRODUCTIVE TOXICITY AND TERATOGENICITY
One citation of an unpublished report on the reproductive toxicity and teratogenicity of trim ethylolpropane was available (14). Sprague-Dawley rats (strain sic) were given trimethylolpropane, in distilled water, by gavage. The administration period was 42 days prior to mating for male rats and from 14 days before mating to day 3 of lactation for female rats. A total number of 60 animals received doses from 0 to 800 mg/kg - day.
No significant toxic effects of test substance were observed on copulation, fertility, and oestrus cycles of rats. There was no increase in the incidence of abnormal pups and no effect on dams during the lactation period. Stillborn pups and pups killed at day 4 of the lactation period showed no gross abnormalities due to the treatment with trimethylolpropane.

# DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS
The acute toxic effects found in the literature on trimethylolpropane are summarized in Table 2 and the toxic effects of repeated exposure are summarized in Table 3.

# RESEARCH NEEDS
There is a striking shortage of published material on trimethylolpropane. Most information originates from unpublished reports. Consequently, there is a need for peer-reviewed, published, experimental toxicological studies. Additional inhalation studies are especially needed to quantitatively estimate safe airborne exposures.
There is also an information gap concerning toxicological effects in humans. Only one source of information about toxicological effects in humans was found. No epidemiological studies on health status of workers chronically exposed to trimethylolpropane were available. Information about dermal, narcotic, hepatotoxic, and renal effects would be of great value.
Quantitative data on the toxicokinetics of the substance are absent. Studies on toxicokinetics, both on humans and animals, would be valuable to assess uptake, distribution, metabolism, and excretion.

# DISCUSSION AND EVALUATION
Limited documentation exists of the toxic effects of trimethylolpropane in experimental animals. Many data originate from unpublished reports cited in reviews. Only two papers contained original information from toxicological studies on trimethylolpropane. One of these two reports gives a brief presentation of trimethylolpropane among 109 industrial chemicals, and the other is a Soviet paper (translated into English) that omits many data on test conditions and results.
In an evaluation by BIBRA, this paper was described as obscure and poorly reported.
a

# Reference 16
No acute inhalation toxicity studies on experimental animals have shown any antemortem signs of poisoning. However, according to one study with concentrations ranging from 700 to 2,000 mg/m3, terminal histopathology revealed moderate congestion, a slight disturbance in the permeability of the vessel walls, and swelling of the cells of parenchymatous organs, including the brain. It is uncertain if these changes were significant since relevant data about test conditions were missing. To what extent trimethylolpropane actually is absorbed via the lungs was not investigated since no quantitative toxicokinetic measurements were performed.
In one study, rats were exposed to an aerosol of trimethylolpropane at 100 to 1,800 mg/m3 for 3.5 months. Subsequent autopsies showed significantly increased relative weight of the adrenals. Histological changes of other internal organs were also noticed but it is uncertain if they were significant, because relevant data concerning test conditions were missing. Conse quently, there are no good-quality inhalation data on which to base any safe occupational exposure limit.
The acute oral toxicity of trimethylolpropane in experimental animals is extremely low. The lowest oral LD5 0 value found was 13.7 g/kg b.wt. in mice. In rats the lowest oral LD5 0 value was 14.1 g/kg b.wt. Signs of acute poisoning were noted in the nervous system and some internal organs. The CNS effects were mainly of the narcotic type (e.g., drowsiness, decreased respiration rate, and ataxia). These effects were never seen at oral doses lower than 2.25 g/kg in rats. A physiological narcotic-type reaction could be theoretically anticipated, since this is a well-known effect of other alcohols.
Autopsy of animals that died after they were given high oral doses of trimethylolpropane showed irritation of the gastrointestinal tract, and congested lungs and kidneys. The lowest single oral dose given to animals where morphological changes of internal organs were demonstrated was 4.6 g/kg b.wt. (significant changes in kidney structure of rats).
An oral dose of 667 mg/kg - day to rats for 3 months caused significant enlargement of the liver, kidneys, and spleen. Rats fed trimethylolpropane for 28 days had pericholangitis and enlarged hepatocytes at a dose of 667 mg/kg - day or more and tubular nephrosis at a dose of 2 g/kg - day (significant effects).
Although trimethylolpropane belongs chemically to the group of alcohols of which many are considered toxicologically nonreactive, theoretically some suspicion could be raised about irritative effects of trimethylolpropane. Trihydric alcohols are used for their reactive properties and are used as reagents in the production of plastics such as polyurethanes and multifunctional acrylates. Furthermore, a dissolution effect could reduce the protective fatty layer of the skin. Experimental data on the other hand indicate a mild acute dermal irritative effect in animals.
Actually only one study (on rabbits) showed any irritative effect at all and the results of this study can be questioned since irritation of the skin occurred at all dosage levels and no animals were used as controls. Patch tests performed on humans did not reveal any irritative or allergenic effects of trimethylolpropane.
The observed effects following acute exposure to very high doses of trimethylolpropane are damage to internal organs (kidney changes and irritation of the gastrointestinal tract) and signs of CNS depression. Long-term effects are changes of internal organs such as enlargement of the lungs, liver, kidneys, and spleen as well as some histological changes in these organs, but no conclusion about a critical effect can be made because of insufficient data.

# SUMMARY
R Walinder: NIOH and NIOSH Basis for an Occupational Health Standard: 2-Ethyl-2hydroxymethyl-1,3-propanediol. Arbete och Halsa 1994:10
This document is a survey of the literature on 2-ethyl-2-hydroxymethyl-1,3-propanediol, also called 1,1,1-trimethylolpropane, as well as an evaluation of data that is relevant for establishing occupational exposure limits.
In experimental animals, 1,1,1-trimethylolpropane seems to be of low toxicity. The toxic effects in experimental animals, following both acute and repeated exposures, are depression of the central nervous system together with hepatic and renal changes. No conclusion about the critical effect or dose can be made because of insufficient data.
Limited studies have revealed mild irritative dermal effects in animals but no convincing evidence of irritation in exposed humans. Epidemiological studies or case reports on workers occupationally exposed to 1,1,1-trimethylolpropane have not been found. Limited in vitro tests did not show any signs of genotoxicity. No studies on carcinogenicity were available. 18 references.
Key-words: 2-ethyl-2-hydroxymethyl-1,3-propanediol; 1,1,1-trimethylolpropane; occupational exposure limits; CNS-effects; hepatotoxicity; renal toxicity.

# SAMMANFATTNING
R Walinder: NIOH and NIOSH Basis for an Occupational Health Standard: 2-Ethyl-2hydroxymethyl-1,3-propanediol. Arbete och Halsa 1994:10.
I detta dokum ent redovisas en sammanstallning av tillganglig litteratur om 2-etyl-2hydroxymetyl-l,3-propandiol, aven kallad 1,1,1-trimetylolpropan, och en utvardering av de datauppgifter som bedoms vara relevanta for faststallande av ett hygieniskt gransvarde for yrkesmassig exponering.
Toxiciteten hos 1,1,1-trimetylolpropan forefaller att vara lag hos forsoksdjur. De toxiska effektema hos forsoksdjur, efter bade akut och upprepad tillforsel, ar paverkan pa centrala nervsystemet tillsammans med lever och njurforandringar. En slutsats om kritisk effekt eller dos gar inte att dra pga otillrackligt dataunderlag.
Data fran ett begransat antal studier har visat en latt hudirritativ effekt hos djur men inga overtygande bevis om hudirritativa effekter hos manniskor. Epidemiologiska studier eller fallrapporter om arbetare som exponeras for 1,1,1-trimetylolpropan i yrket har ej hittats. Enligt a ett begransat antal in vitro tester kunde genotoxiska effekter ej pavisas. Inga studier om kancerframkallande egenskaper var tillgangliga. 18 referenser.
Nyckelord: 2-etyl-2-hydroxym etyl-l,3-propandiol; 1,1,1-trim etylolpropan; hygieniska gransvarden; centralnervosa effekter; levertoxicitet; njurtoxicitet.