Dimethylamine. 1 Toxic Effects and Modes of Action. 1.1 Nitrosamine formation. Classification/MAK value: 4mg/m 3. MAK value dates from: 1993

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1 Dimethylamine Classification/MAK value: MAK value dates from: 1993 Chemical name (CAS): 2 ml/m 3 (ppm) 4mg/m 3 CAS number: N-methylmethanamine Structural formula: H 3 C NH CH 3 Molecular formula: C 2 H 7 N Molecular weight: Melting point: 93 C Boiling point: C 1 ml/m 3 (ppm) = 1.87 mg/m 3 1mg/m 3 = ml/m 3 (ppm) 1 Toxic Effects and Modes of Action Dimethylamine is a colourless inflammable gas with a strongly ammoniacal odour. It is readily soluble in water and more basic than ammonia. Because of its good solubility in lipids, dimethylamine is readily and rapidly absorbed in the gastrointestinal and respiratory tracts. Concentrated dimethylamine vapour is highly irritating to mucous membranes. Absorbed dimethylamine is a central nervous system depressant; the mechanism of this action has not been studied in detail. A long-term inhalation study with rats and mice produced no evidence of a carcinogenic potential. Numerous mutagenicity studies in which the substance was tested without added nitrite yielded negative results. One teratogenicity study has been carried out in mice; the results were negative. Liquid dimethylamine readily penetrates the skin; the skin penetration of the vapour has not been studied. Sensitizations caused by dimethylamine in man have not been reported to date. 1.1 Nitrosamine formation In the presence of nitrite or nitrous gases, dimethylamine is converted to dimethylnitrosamine. Since dimethylamine is highly basic, the yield of nitrosamine is low. The ph optimum for the reaction is about 3.0; this suggests that nitrosation could take place in the stomach after simultaneous intake of amine and nitrite. Nitrosamine formation in

2 76 Dimethylamine Volume 7 vivo has been demonstrated in mice given oral doses of dimethylamine and nitrite (Iqbal et al. 1981) and after intubation with dimethylamine followed by inhalation of NO 2 (Iqbal 1986). In studies in which rats or mice were given oral doses of dimethylamine (1 mg/kg body weight) and sodium nitrite (50 mg/kg body weight), about 0.8 % of the dimethylamine dose was nitrosated. Simultaneous administration of 50 mg vitamin C or 50 mg vitamin E reduced the nitrosation by 80 % and 50 %, respectively (Meier-Bratschi et al. 1983). It may be assumed that similar nitrosation conditions are found in man but that because the nitrite levels in the human stomach are normally low, only low levels of nitrosamine are formed. The significance of endogenous nitrosation is still unclear. Dimethylnitrosamine is also formed in reactions between dimethylamine and nitrogen oxides in the gas phase. The nitrosamine, which is stable in the dark and behind window glass, is formed in yields of 1 % to 3 % (Glasson 1979, Pitts et al. 1978). In sunlight it is decomposed with a half-life of 0.5 hours. The main decomposition products include dimethylnitramine, dimethylformamide, formaldehyde and carbon monoxide (Tuazon et al. 1978). The nitrosation of dimethylamine has been described in detail elsewhere (Henschler 1984). Dimethylnitrosamine is found regularly as an impurity ( mg/kg) in samples of liquid dimethylamine (Spiegelhalder et al. 1978). 1.2 Pharmacokinetics Dimethylamine is a biogenic amine and can be detected in the urine of man and other mammals; it is produced in the metabolism of choline and choline-containing phosphatides (Asatoor and Simenhoff 1965, Asatoor et al. 1967, Blau 1961). Orally administered dimethylamine is excreted largely unchanged (Dargel 1966). Analysis of air and urine was carried out during a period of 24 hours in a factory processing dimethylamine; the workplace air contained not only dimethylamine and methyl-amine but also highly variable amounts of ethylamine, methylisobutylamine and methylisopropylamine which never amounted to more than one twentieth of the average dimethylamine concentration. At the workplaces in this factory the dimethylamine concentrations varied between 1.2 and 34 mg/m 3 and the methyl-amine between 0.7 and 37 mg/m 3. Before the beginning of the shift the levels of urinary amines were the same in the exposed and the control groups. Whereas the urine values in the control group remained practically unchanged during the course of the day, in the exposed persons there was a marked increase, especially in the excretion of dimethylamine which rose after only a short period of exposure from about 18 mg/l to 65 mg/l. The urine levels did not return to the pre-exposure values within 24 hours. The authors considered these findings to be of significance because of the danger of cumulative effects and the possibility of nitrosamine formation during simultaneous exposure to nitrogen oxides (Bittersohl and Heberer 1980). Thus the metabolism of dimethylamine differs markedly from that of methyl-amine and trimethylamine. In the animal, methylamine is broken down almost completely (Rechenberger 1940); trimethylamine is mostly N-oxidized and excreted as trimethylamine oxide (Lintzel 1934).

3 Volume 7 Dimethylamine 77 After intravenous injection of 250 µg radioactively labelled dimethylamine into rats, half of the radioactivity had vanished from the blood after 12.5 minutes; after 15 minutes, secretion of dimethylamine from the blood into the intestines was observed. The reabsorption from the intestine led to a second dimethylamine peak in the blood 25 minutes after the injection; the second half-life in plasma was 15.2 minutes (Ishiwata et al. 1984). After exposure of F344 rats for 6 hours to chromatographically purified 14 C- dimethylamine at a concentration of 10 or 175 ml/m 3, the plasma radioactivity was seen to decrease biphasically. The half-times were given as αt 1 2 = 1 2 hours and βt = hours. Immediately after the exposure, the level of radioactivity in the mucous membranes of the upper respiratory tract was two orders of magnitude larger than that in any other tissue; 72 hours after the end of exposure most of the radioactivity (90.5 %) was found in urine and faeces as unchanged dimethylamine, and the tissues contained 7%to8%.Onlyaverysmallfractionofthedose(1.5%)wasexhaledasCO 2 (McNulty and Heck 1983). After ingestion of dimethylamine (23.6 ppm in the diet) by Wistar rats, the substance was shown to be poorly absorbed in the stomach and readily absorbed in the intestinal tract (U stomach 198 minutes, t 1 2 intestines minutes) (Ishiwata et al. 1984). The metabolism of dimethylamine in the respiratory and olfactory epithelia of rats was studied in vitro in microsomal preparations and in vivo in animals which had inhaled 10 or 175 ml/m 3 for 6 hours; the production of 14 C-formaldehyde and the subsequent 14 C-incorporation into macromolecules could be demonstrated. The rate of metabolism was significantly higher in the olfactory epithelium than in the respiratory epithelium (McNulty et al. 1983). It was calculated that about 8 % of the dimethylamine dose was metabolized to formaldehyde (McNulty and Heck 1983). In vitro in rat liver cells and in mouse macrophages, dimethylamine is taken up and stored by acidic vacuoles such as lysosomes; this results in osmotic enlargement of the vacuoles and inhibition of the normal lysosomic protein degradation processes (Okhuma and Poole 1981, Seglen and Gordon 1980). It is not known whether this effect is of significance in vivo. 2 Effects in Man 2.1 Acute toxicity The odour thresholds which have been published for dimethylamine are shown in Table 1. A test person ingested 8 g dimethylamine hydrochloride and tolerated it well. One day later, 91.5 % of the dose had been excreted in the urine (Rechenberger 1940). 2.2 Effects on skin and mucous membranes In data sheets for dimethylamine, the producers warn that the substance is highly caustic, even dilute solutions causing "chemical burns". In addition to penetrating the skin so readily, liquid short-chain secondary monoamines are able to alter the skin structure so

4 78 Dimethylamine Volume 7 Table 1. Published odour thresholds for dimethylamine Odour threshold (ml/m 3 ) Medium References air Oelert and Florian air Leonardos et al air Amoore and Hautala air Oelert and Florian water Amoore and Forrester water Dzhanashvili 1967 that it becomes permeable to substances which can normally not be absorbed (NIOSH 1981). It is not known whether or to what extent gaseous dimethylamine can penetrate the skin. Therefore the substance is not designated with an "H". Several authors have reported without any other details that amine production workers suffer from hazy vision (glaucopsy). Such reversible visual disorders are said to be induced by dimethylamine vapour (Mellerio and Weale 1966, Munn 1967). Other authors (Friemann and Overhoff 1956, Graf 1961) describe a consistent set of symptoms of eye damage in persons exposed briefly or for longer periods to vapours of dimethylamine or trimethylamine or occasionally to aerosols: conjunctival irritation, red and swollen eyelids, swelling and later clouding of the cornea, keratitis. The damage can persist for days or months, depending on its severity, and is associated not only with pronounced visual impairment but also with severe pain. Long-term exposure of workers to low concentrations of dimethylamine vapour resulted not only in conjunctivitis but also in dermatitis (Air Products and Chemicals Inc. 1978). 2.3 Subchronic and chronic toxicity In a series of inhalation studies, five test persons aged between 25 and 35 years were exposed in a pressure chamber at 308 mm Hg, 20 ± 2 C and 40 % to 60 % humidity during a cycle of 40 minutes work and 20 minutes rest with an energy output of 400 kcal/hour. In the first series (control) the persons inhaled pure oxygen, in the second and third series a mixture of oxygen with dimethylamine at concentrations of 1 or 3 mg/m 3 (0.5 or 1.5 ml/m 3 ). The exposures were carried out on five consecutive days each week for up to 6 hours daily for a period of 15 days. At the high dimethylamine concentration, pulse rates increased during both the work and rest periods from exposure day 2; there was a tendency to lower systolic blood pressure which persisted for the whole 15 day period. The ECG data for this group of test persons were comparable with the control data. The parameter "vigilance of the visual analyser" proved to be labile in the exposed persons. Repeated inhalation of dimethylamine concentrations of 3 mg/m 3 frequently resulted in tremor. At this concentration both reduction and increase in blood catalase activity, a considerable increase in blood serum cholinesterase activity and a decrease in the ascorbic acid level in blood were found. Inhalation of 1 mg/m 3 had no effect on the tested parameters (Sedov et al. 1980). This publication is very difficult to assess for the following reasons: the methods used are not described in detail nor made available by literature

5 Volume 7 Dimethylamine 79 references. The experimental data are not given. The parameters which are affected are almost all unspecific and cannot form the basis of a specific toxicological assessment. There are no studies on allergenic effects of dimethylamine. Carcinogenicity studies with the substance have not been carried out. 3EffectsonAnimals 3.1 Acute toxicity Inhalation For rats which had inhaled dimethylamine for 4 or 6 hours, LC 50 values of 4700 and 4540 ml/m 3, respectively, were obtained; for mice which inhaled dimethylamine for 2hours, the LC 50 value was 7650 ml/m 3 (see Table 2). After as little as one hour exposure, laboured breathing, restlessness or apathy and convulsions were seen. Particularly marked were signs of irritation of the exposed mucous membranes of the mouth, nose and eyes. In addition to mucosal haemorrhage, marked salivation, nasal secretion, mucosal erythema, lacrimation and spasmodic closing of the eyes were observed. The average survival period was 4.7 days. Symptoms of broncho-pneumonia persisted for 8 to 14 days and were clearly dose-dependent (Koch et al. 1980). Pathological examination of 43 rats which died 2 to 18 days after exposure revealed most frequently emaciation and inflammatory changes in the lungs in the form of bronchitis and bronchopneumonia (74 % of animals). In addition, various degrees of fatty degeneration of the peripheral lobules of the liver were found, slight degeneration of the liver parenchyma, kidney changes in the form of lower nephron nephrosis and slight granular degeneration of the heart muscle fibres. In 41 rats which survived the dimethylamine intoxication and were killed by decapitation 41 to 48 days post expositionem, no pathological anatomical changes could be found (Johannsen et al. 1980). The irritant effects of dimethylamine on the respiratory epithelium caused reflex respiratory depression; the RD 50 values (concentration producing a 50 % reduction in respiration rate) after exposure of rats and mice for 10 minutes were determined as 573 ml/m 3 and 511 ml/m 3, respectively (Buckley et al. 1984, Steinhagen et al. 1982). In another study the RD 50 value for mice exposed for 15 minutes was given as 70 ml/m 3 (Gagnaire et al. 1989) lngestion The oral LD 50 for dimethylamine in rats was found to be about 700 mg/kg body weight, in mice about 320 mg/kg and in guinea pigs and rabbits 240 mg/kg. In neutralized form (ph 8.0) the substance was less toxic, having LD 50 values of 8100 mg/kg body weight in rats, 1070 mg/kg in guinea pigs and 1600 mg/kg in rabbits (Table 2).

6 80 Dimethylamine Volume 7 Table 2. Acute toxicity of dimethylamine Species Administration route LD 50 mg/kg bw LC 50 ml/m 3 References rat inhalation (4 h) 4700 ( ) Koch et al rat inhalation (6 h) 4540 Steinhagen et al mouse inhalation (2 h) 7650 Steinhagen et al rat oral (base) (ph 8) Dzhanashvili 1967 mouse oral 316 (base) Dzhanashvili 1967 guinea pig oral rabbit oral bw body weight (base) (ph 8) (base) (ph 8) Dzhanashvili 1967 Dzhanashvili 1967 The effects of ingested dimethylamine included excitement and subsequent lethargy, lateral position and coordination disorders. Severe irritation of the mucous membranes was seen as well as extensive bleeding of the stomach walls and in the intestines of animals which died (Dzhanashvili 1967) Effects on skin and mucous membranes Erythema, swelling and finally ulceration of rabbit skin developed after contact with 3 % to 6 % aqueous solutions of dimethylamine (single applications). Treatment of mouse skin (tip of the tail dipped for 2 hours into a 6 % solution), on the other hand, led to a sharply defined hyperaemic area with subsequent tissue necrosis (gangrene) (Kremneva and Sanina 1961). Direct contact with dimethylamine vapour or with aqueous solutions results in concentration-dependent damage to skin and mucous membranes; the damage can be particularly severe in the eyes. Solutions containing as little as 1 % dimethylamine applied to the rabbit eye caused photophobia, blepharospasm, conjunctivitis, conjunctival oedema, keratitis and clouding of the cornea after a latent period of up to 6 days. Solutions of 5 % dimethylamine or more caused severe damage (vascularization and clouding of the cornea) which persisted for up to 28 days (Friemann and Overhoff 1956). Higher concentrations applied to the rabbit eye caused whitish-blue discolouration and translucence of the cornea after only a few seconds (Mellerio 1966).

7 Volume 7 Dimethylamine Subchronic and chronic toxicity Inhalation Exposure of F344 rats to a dimethylamine concentration of 175 ml/m 3, 6 hours daily for 1, 2, 4 or 9 days, led after one day to impairment of mucociliary clearance in the respiratory tract, to changes in the direction of mucous flow (reversal, whirlpool-like patterns), ciliostasis and mucostasis. The mucostasis was not always accompanied by histologically detectable tissue damage. Histological changes were most pronounced in the anterior region of the nose. Focal inflammation and necrosis of the squamous epithelium was accompanied by accumulation of neutrophils in the underlying connective tissue. In the olfactory epithelium after one and two days of exposure, severe vacuolation was seen in the olfactory sensory cells of the dorsal nasal passages and after 4 and 9 days exposure loss of olfactory cells and olfactory nerve bundles (Gross et al. 1987). Exposure of mice to 511 ml/m 3, 6 hours daily for 5 days, resulted in mild metaplasia of the squamous respiratory epithelium, moderately severe degeneration of the olfactory nerves and severe exfoliation, erosion, ulceration and necrosis of the respiratory and olfactory epithelia (Buckley et al. 1984). In rats which inhaled dimethylamine vapour in concentrations of 10, 30 or 100 ml/m 3, 6 hours daily, 5 days per week for 90 days, food consumption, body weight, mortality, clinical symptoms, haematological, clinical-chemical and urinary parameters, and pathological changes were investigated. Slight statistically significant changes in haematological and clinical chemical parameters were not considered to be caused by the exposures. Pathological examination of 44 types of tissue including brain, lungs and nasal conchae revealed no exposure-related damage (Mitchell et al. 1982). A group of 15 rats, 15 guinea pigs, 3 rabbits, 2 dogs and 3 monkeys were all exposed together in a large chamber for a period of 90 days to a dimethylamine concentration of 9±1mg/m 3 (5 ml/m 3 ). The continuous exposure was discontinued only very briefly (< 2.2 % of the time) to feed the animals and clean the cages. None of the exposed animals died. There were no symptoms of toxicity. The haematological and clinicalchemical parameters were normal (urea, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase). Histological examination revealed inflammatory changes in the pulmonary interstitial tissue in all species, bronchus dilation in 3 rabbits and 2 of the 3 monkeys but no substance-specific histopathological changes (Coon et al. 1970). In an unpublished study carried out in 1964, a group of 10 rats, 6 guinea pigs and 2 rabbits (male and female), 5 mice (female) and one monkey (male) was exposed to dimethylamine concentrations of 97 ml/m 3 (180 mg/m 3 ) or 183 ml/m 3 (340 mg/m 3 ), 7 hours daily, 5 days per week for 18 to 20 weeks. After 9 days, corneal damage developed in guinea pigs and rabbits. In all species apart from the monkeys, centrilobular fatty degeneration of the hepatocytes and necrosis of liver parenchyma cells were observed. Degeneration of the testis tubules was seen in the high dose group rabbits and the low dose group monkeys (Hollingsworth and Rowe 1964).

8 82 Dimethylamine Volume lngestion After administration of dimethylamine hydrochloride doses of 110 or 220 mg/kg body weight alone and in combination with NaNO 2 doses of 110 mg/kg to groups of 8 male Wistar rats, daily for 30 days, no signs of liver or kidney toxicity were found. Only in the highest dose group (NaNO mg/kg plus dimethylamine hydrochloride 220 mg/kg) was ascites found in 3 animals and mild liver damage in one (Garcia-Roché et al. 1983). In 5 male rats given dimethylamine in the drinking water for 72 days in daily doses of about 94 mg/kg body weight, microscopic examination revealed focal macrophage aggregations in the lungs and, in 2 animals, slight metaplasia of the bronchial squamous epithelium (Kimbrough and Sedlak 1968). Dimethylamine hydrochloride was administered orally to guinea pigs in doses of 0.035, 0.35 and 3.5 mg/kg body weight and to rats in doses of 0.007, and 0.35 mg/kg body weight (daily? details not clear) for a period of 8 months. In the high dose group guinea pigs, the coproporphyrin excretion in the urine, the blood urea level and the relative liver weights were increased and the vitamin C level in the adrenal cortex decreased. There were no effects on blood haemoglobin or methaemoglobin levels, erythrocyte or leukocyte counts, blood cholinesterase activity or phagocytotic activity of the leukocytes. Histological examination of the animals at the end of the study revealed no substance-related effects. In the rats, the 0.35 and mg/kg body weight doses caused changes in the conditioned reflexes. Administration of 0.35 mg/kg reduced the phagocytotic activity of the rat leukocytes and increased the relative liver weights. No effects were seen in the low dose group (Dzhanashvili 1967). These changes are not considered to reflect adverse effects of the substance on health Intraperitoneal injection Intraperitoneal administration of dimethylamine doses of 250 mg/kg body weight, daily for 4 days, reduced the cytochrome P450 levels in the liver microsomes of mice and reduced the rate of dimethylamine N-dealkylation without affecting the N-oxidation of dimethylamine. Histological examination of the liver revealed fatty infiltration and single cell necrosis. None of these effects was observed after doses of 25, 50 or 125 mg/kg body weight administered daily for 4 days (Wirth and Thorgeirsson 1978). The authors considered that the cytochrome P450-dependent N-dealkylating monooxygenase of the mouse liver is more sensitive to the hepatotoxic effects of dimethylamine than is the N-oxidizing monooxygenase. 3.3 Allergenic effects In a test for sensitization with groups of 11 guinea pigs (patch test of Magnusson and Kligman), induction with a 0.5 M solution (50 mg dimethylamine) and provocation after 72 hours with a 0.5 M or 0.05 M dimethylamine solution produced positive reactions in all animals and in 9 of the 11, respectively (Kantoh et al. 1985).

9 Volume 7 Dimethylamine 83 Since the data base is inadequate and since no sensitization of humans handling dimethylamine has been observed to date, it does not seem to be justified to designate the substance with an "S". 4 Reproductive and Developmental Toxicity After intraperitoneal injection of dimethylamine doses of 13.7, 45.9 or mg/kg body weight into groups of 12 pregnant Swiss mice on day 8 post conceptionem, gross pathological examination (implantation losses, foetal weight, litter size, placental weight, body weights of the dams) on day 18 post conceptionem revealed no toxic effects on dams or foetuses (Varma et al. 1990). 5 Genotoxicity The results which have been obtained in studies of the genotoxic effects of dimethylamine are summarized in Table 3. In the absence of nitrite, dimethylamine was not mutagenic in a number of in vitro tests in Salmonella typhimurium, Escherichia coli or Saccharomyces cerevisiae with or without metabolic activation nor in the HPRT test in CHO cells. An exception was the Ames Salmonella-microsome test with strain TA1530 in which dimethylamine was a weak mutagen after metabolic activation. The authors considered that this finding requires further investigation. In hamster lung fibroblasts (CHL cells) in vitro, neither chromosomal aberrations nor sister chromatid exchange was observed with or without metabolic activation. An in vivo test for structural chromosomal aberrations in bone marrow cells (metaphase) of rats exposed for 3 months to dimethylamine concentrations of 0.5 or 1 mg/m 3 also yielded negative results. The authors' statement that the incidence of aneuploidy was significantly increased after 90 days in both concentration groups must be accepted with caution because of the methods employed (Isakova et al. 1971) and should be confirmed in a study which would allow reliable assessment of such effects. An in vitro UDS test in rat hepatocytes yielded negative results, but positive results after addition of nitrite. In host-mediated assays in rats and mice with S. typhimurium (G46, TA1534, TA1950, TA1951, TA1952), dimethylamine proved to be not mutagenic at the doses tested (for rat and mouse maximum dose 440 mg/kg body weight, oral) except when nitrite (c 150 mg/kg body weight) was administered simultaneously. The effect of nitrite isputdowntotheformationofnitrosodimethylamineinthestomachoftheexperimental animals. Nitrosodimethylamine is mutagenic in the mouse at doses of 0.2 mg/kg body weight or more and in the rat at doses of 0.6 mg/kg or more (Whong et al. 1979). Positive results were also obtained in another host-mediated assay with Schizosaccharomyces pombe in the mouse after oral nitrosodimethylamine doses of mg/kg body weight (Barale et al. 1981).

10 Table 3. Genotoxicity studies with dimethylamine 84 Test system Indicator organism Results References with S9 tests for gene mutation in vitro Ames test Salmonella typhimurium TA TA1531, TA1532, TA1964 Ames test S. typhimurium TA100, TA1535, TA1537, TA98 without S9 Green and Savage 1978 Zeiger et al Ames test S. typhimurium TA100, TA98 Kawachi et al reversion Escherichia coli Sd-4-73 Szybalski 1958 recombination Bacillus subtilis Kawachi et al petite mutants Saccharomyces cerevisiae canavanine resistance D B with Udenfriend's hydroxylation system Mayer 1971 HPRT test CHO cells Hsie et al tests for gene mutation in vivo host mediated assay host mediated assay mouse (800 mg/kg bw i.m.); S. typhimurium TA1534, TA1950, TA1951, TA1952; mutants determined in bacteria recovered by intraperitoneal lavage mouse, rat (440 mg/kg bw oral); mouse (66, 220, 440 mg DMA/kg bw or 160 mg NaNO 2 /kg bw); +* rat (220, 440 mg DMA/kg bw or 160 mg NaNO 2 /kg bw); S. typhimurium G46, mutants determined +* in bacteria recovered from liver tissue Green and Savage 1978 Whong et al Dimethylamine Volume 7

11 Table 3. (continued) Test system host mediated assay mouse (2000 mg DMA/kg bw mg NaNO 2 /kg bw, oral); S. typhimurium G46; mutants determined in bacteria recovered by intraperitoneal lavage +* Couch and Friedman 1975 tests for chromosomal damage in vitro chromosomal aberrations CHL cells Kawachietal.1980 chromosomal aberrations tests for chromosomal damage in vivo chromosomal aberrations tests for other end points CHL cells Ishidate and Odashima 1977 rat (3 months; 0.5, 1 mg/m 3 inhalation) examined 15 and 90 days after end of exposure Isakova et al UDS rat hepatocytes +* Martelli et al sister chromatid CHL cells Kawachietal.1980 exchange * in the presence of nitrite bw body weight Indicator organism Results with S9 without S9 References Volume 7 Dimethylamine 85

12 86 Dimethylamine Volume 7 6 Carcinogenicity Male and female F344 rats and B6C3F 1 mice were exposed to dimethylamine vapour at concentrations of 10, 50 or 175ml/m 3, 6 hours daily, 5 days per week for 24 months. From the second week of exposure to 175 ml/m 3, body weight gains were reduced significantly in the rats and less markedly in the mice. The only exposure-related changes were progressive, concentration-dependent nasal lesions in rats and mice of both sexes. Two regions were affected: the respiratory epithelium near the vestibule and along the dorsal edges of the nasal conchae and the olfactory epithelium in the dorsal nasal passages and sometimes in the more distal region of the nose. Local destruction of the anterior nasoturbinate and the nasal septum, local inflammation and squamous metaplasia of the respiratory epithelium were found in rats and mice, and goblet cell hyperplasia in the rat. In the olfactory epithelium there was a clear reduction in the number of sensory cells and olfactory nerves with enlargement of the Bowman glands and accumulation of eosinophilic material in the ducts of other adjacent glands. In the 175 ml/m 3 groups, these lesions were more marked in rats than in mice. Progression of the lesions between the 6-month and 12-month killings was minimal; however, in the 10 ml/m 3 group, there were slight changes in the olfactory epithelium in 7 of 30 animals after 12 months which had not been present after 6 months. The mucosal damage in the two species at the end of the study was described as focal and mild at 10 ml/m 3, moderate at 50 ml/m 3 and severe at 175 ml/m 3. No treatment-related increase in the incidence of neoplasms was seen (Swenberg 1990). 7 Manifesto (MAK value, classification) TheMAKvalueof10ml/m 3 (18 mg/m 3 ) which was valid until 1993 was established in line with the American threshold limit value to exclude mucosal irritation. However, two studies in which various animal species were exposed by inhalation demonstrate that pathological changes are to be expected at a dimethylamine concentration of 10 ml/m 3. Continuous exposure of animals of 5 species to a dimethylamine concentration of 9 mg/m 3 (5 ml/m 3 ) for 90 days did not produce symptoms of toxicity (Coon et al. 1970). Inhalation of 10, 30 or 100 ml/m 3, 6 hours daily, 5 days per week for 90 days did not produce exposure-related lesions in rats (Mitchell et al. 1982). After exposure of rats and mice to dimethylamine concentrations of 10, 50 or 175 ml/m 3, 6 hours daily, 5 days per week for 2 years, concentration-dependent lesions of the nasal epithelium developed. Lesions were not apparent after 6 months exposure at 10 ml/m 3 but were observed after 12 months exposure (Swenberg 1990). Since concentrations below 10 ml/m 3 have not yet been tested in a 2-year study and 10 ml/m 3 has been shown to produce mild mucosal damage, at least in rats, the MAK value was reduced in 1993 to 2 ml/m 3. It requires substantiation from experience of human exposures. As a substance with an intensive odour, dimethylamine is classified in category V for the limitation of exposure peaks (short term exposure level twice the MAK value, maximum duration 10 minutes, maximum frequency 4 times per shift).

13 Volume 7 Dimethylamine 87 Because of the inadequate data base, dimethylamine cannot be classified in one of the pregnancy risk groups and is listed in Section IIc. It should be remembered that dimethylamine can react with nitrogen oxides and nitrite to form mutagenic and carcinogenic nitrosamines and that the amine can contain the nitrosamine as an impurity. 8 References Air Products and Chemicals Inc.: Material Safety Data Sheet Dimethylamine, Allentown, PA, USA, 1978 Amoore, J. E., L. J. Forrester: "Specific anosmia to trimethylamine. The fishy primary odor", J.Chem. Ecol. 2, 49 (1976) Amoore, J. E., E. Hautala: "Odor as an aid to chemical safety: odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution", J.Appl. Toxicol. 3, 212 (1983) Asatoor, A.M., M. J. Chamberlain, B. T. Emmerson, J. R. Johnson, A. J. Levi, M. D. Milne: "Metabolic effects of oral neomycin", Clin.Sci.33,111 (1967) Asatoor, A. M., M. L. Simenhoff: "The origin of urinary dimethylamine", Biochim. Biophys. Acta. (Amst) 111, 384 (1965) Barale, R., D. Zucconi, N. Loprieno: "A mutagenicity methodology for assessing the formation of N-dimethylnitrosamine in vivo", Mutat. Res. 85, 57 (1981) Bittersohl, G., H. Heberer: "Ergebnisse von Arbeitsplatz- und Urinanalysen bei Expositionen mit aliphatischen Aminen", Z. ges. Hyg. 26, 258 (1980) Blau, K.: "Chromatographic methods for the study of amines from biological material", Biochem. J. 80, 193 (1961) Buckley,L.A.,X.Z.Jiang,R.A.James,K.T.Morgan,C.S.Barrow:"Respiratorytractlesions induced by sensory irritants at the RD50 concentration", Toxicol. Appl. Pharmacol. 74,417 (1984) Coon, R. A., R. A. Jones, L. J. Jenkins jr., J. Siegel: "Animal inhalation studies on ammonia, ethylene glycol, formaldehyde, dimethylamine, and ethanol", Toxicol. Appl. Pharmacol. 16, 646(1970) Couch, D. B., M. A. Friedman: "Interactive mutagenicity of sodium nitrite, dimethylamine, methyl-urea and ethylurea", Mutat. Res. 31, 109 (1975) Dargel, R.: "Ausscheidung von Dimethylamin unter Zufuhr methylierter Stickstoffverbindungen", Acta Biol. Med. Germ. 16, 474 (1966) Dzhanashvili, G. D.: [Hygienic substantiation of the maximum permissible content of dimethylamine in water bodies], Gig. i Sanit. No. 6, 16 (1967) (translation) Friemann, W., W. Overhoff: "Keratitis als Berufserkrankung in der Ölheringsfischerei", Klin. Monatsbl. Augenheilk. 128, 425 (1956) Gagnaire, F., S. Azim, P. Bonnet, P. Simon, J. P. Guenier, J. de Ceaurriz: "Nasal irritation and pulmonary toxicity of aliphatic amines in mice", J. Appl. Toxicol. 9, 301 (1989) Garcia-Roché, M., T. Ballentilla, A. Castillo, V. Silva, Y. Cabrera: "The toxicity of the daily intake of nitrite and dimethylamine", Die Nahrung 27, 837 (1983) Glasson, W. A.: "An experimental evaluation of atmospheric nitrosamine formation", Environm. Sci. Technol. 13, 1145 (1979) Graf, K.: "Experimented Untersuchungen über die Schädlichkeit von Rotbarschgewebsflüssigkeit für das Kaninchenauge", Dtsch. Gesundh.-Wes. 16, 70 (1961) Green, N. R., J. R. Savage: "Screening of safrole, eugenol, their ninhydrin positive metabolites and selected secondary amines for potential mutagenicity", Mutat. Res. 57, 115 (1978) Gross, E. A., D. L. Patterson, K. T. Morgan: "Effects of acute and chronic dimethylamine exposure on the nasal mucociliary apparatus of F-344 rats", Toxicol. Appl. Pharmacol. 90, 359 (1987)

14 88 Dimethylamine Volume 7 Henschler, D. (Ed.): "Die Nitrosierung flüchtiger Amine am Arbeitsplatz", Gesundheitsschädliche Arbeitsstoffe. Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten, VCH Verlagsgesellschaft, Weinheim, 1984, also available in English in the present series in Occupational Toxicants Volume 1 Hollingsworth, R. L., V. K. Rowe: Chronic inhalation toxicity of dimethylamine for laboratory animals, Dow Chemical Company, Midland, MI, USA, 1964, cited in Swenberg (1990) Hsie, A. W, J. P. O'Neill, S. Sebastian: "Quantitative mutagenesis and mutagen screening with Chinese hamster ovary cells", Appl. Methods Oncol. 3, 89 (1980) Iqbal, Z. M., S. S. Epstein, I. S. Krull, U. Goff, K. Mills, D. H. Fine: "Kinetics of nitrosamine formation in mice following oral administration of trace-level precursors", IARC Sci. Publ.:No. 31, 169(1981) Iqbal, Z. M.: "DNA binding in organs of mice exposed to dimethylamine (DMA) by gavage and nitrogen dioxide (NO 2 ) by inhalation", Proc. Am. Assoc. Cancer Res. 27, 85 (1986) Isakova, G. K., B. Y. Ekshtat, Y. Y Kerkis: [The study of the mutagenic action of chemical substances in substantiation of hygienic standards], Gig. i Sanit. No. 11, 9 (1971) (translation) Ishidate, M., S. Odashima: "Chromosome tests with 134 compounds on Chinese hamster cells in vitro a screening for chemical carcinogens", Mutat. Res. 48, 337 (1977) Ishiwata, H., R. Iwata, A. Tanimura: "Absorption, secretion and excretion of dimethylamine in rats", IARC Sci. Publ. No. 57, 255 (1984) Johannsen, U., G. Mehlhorn, R. Kliche, R. Lang: "Untersuchungen zur Pathomorphologie der akuten aerogenen Dimethylaminintoxikation bei Ratten", Wiss. Z. Karl-Marx-Univ., Leipzig, Math.-Naturwiss. Reihe 29, 475 (1980) Kantoh, H., M. Ishihara, M. Itoh, K. Hosono, M. Nishimura: "Allergens in rubber products", Hifu 27, 501 (1985) Kawachi, T., T. Yahagi, T. Kada, Y. Tazima, M. Ishidate, M. Sasaki, T. Sugiyama: "Cooperative programme on short-term assays for carcinogenicity in Japan", IARC Sci. Publ. No. 27, 323 (1980) Kimbrough, R. D., V. A. Sedlak: "Lung morphology in rats treated with hexamethylphosphoramide", Toxicol. Appl. Pharmacol. 12, 60 (1968) Koch, R, G. Mehlhorn, R. Kliche, R. Lang: "Untersuchungen zur aerogenen Intoxikation bei Ratten durch Methylamine", Wiss. Z. Karl-Marx-Univ., Leipzig, Math.-Naturwiss. Reihe 29, 463 (1980) Kremneva, S. N., Y P. Sanina: "Toxicology of dimethylamine", Toksikol. Novykh. Prom. Khim. Veshchesv. 1, 41 (1961), cited in NIOSH (1981) Leonardos, G., D. Kendall, N. Barnard: "Odor threshold determinations of 53 odorant chemicals", J. Air Pollut. Contr. Ass. 19, 91 (1969) Lintzel, W: "Untersuchungen über Trimethylammoniumbasen. III. Mitteilung: Trimethylammoniumbasen im menschlichen Harn". Biochem. Z. 273, 243 (1934) Martelli, A., E. Fugassa, A. Voci, G. Brambilla: "Unscheduled DNA synthesis induced by nitrosated ranitidine in primary cultures of rat hepatocytes", Mutat. Res. 122, 373 (1983) Mayer, V. W: "Mutagenicity of dimethylnitrosamine and diethylnitrosamine for Saccharomyces in an in vitro hydroxylation system", Molec. Gen. Genet. 112, 289 (1971) McNulty, M. J., H. D. Heck: "Disposition and pharmacokinetics of inhaled dimethylamine in the Fischer 344 rat", Drug Metab. Dispos. 11, 417 (1983) McNulty, M. J., M. Casanova-Schmitz, H. D. Heck: "Metabolism of dimethylamine in the nasal mucosa of the Fischer 344 rat", Drug Metab. Dispos. 11, 421 (1983) Meier-Bratschi, A., W. K. Lutz, C. Schlatter: "Methylation of liver DNA of rat and mouse by N- nitrosodimethylamine formed in vivo from dimethylamine and nitrite", Food chem. Toxicol. 21, 285 (1983) Mellerio, J., R. A. Weale: "Hazy vision in amine plant operatives", Br.J.Ind.Med.23,153 (1966) Mitchell, R. I., K. L. Pavkov, W. D. Kerns, M. M. Connell: A 90-day inhalation toxicology study in rats exposed to dimethylamine, Chemical Industry Institute of Toxicology (CIIT) Docket No. 215N2, Research Triangle Park, NC, USA, 1982 Munn, A.: "Health hazard in the chemical industry", Trans. Soc. Occup. Med. 17, 8 (1967)

15 Volume 7 Dimethylamine 89 NIOSH (National Institute of Occupational Safety and Health): Secondary and tertiary aliphatic monoamines, Report No. 7, Contract No , Silver Spring, MA, USA, 1981 Oelert, H. H., T. Florian: "Erfassung und Bewertung der Geruchsbelästigung durch Abgase von Dieselmotoren", Staub-Reinhalt. Luft 32, 400 (1972) Okhuma, S., B. Poole: "Cytoplasmic vacuolation of mouse peritoneal macrophages and the uptake into lysosomes of weakly basic substances", J. Cell Biol. 90, 656 (1981) Pitts, J. N., D. Grosjean, K. van Cauwenberghe, J. P. Schmidt, D. R. Fitz: "Photooxidation of aliphatic amines under simulated atmospheric conditions: formation of nitrosamines, nitramines, amides, and photochemical oxidant", Environm. Sci. Technol. 12, 946 (1978) Rechenberger, J.: "Über die flüchtigen Alkylamine im menschlichen Stoffwechsel. II. Mitteilung: Ausscheidung im Harn nach oraler Zufuhr", Hoppe-Seylers Z. Physiol. Chem. 265, 275 (1940) Sedov, A. V., N. A. Surovtsev, G. E. Mazneva, O. N. Shevkun: [Materials for use in establishment of a maximum allowable concentration for dimethylamine in the gaseous medium of insulating means of individual protection], Gig. i Sanit. No. 2, 81 (1980) (translation) Seglen, P. O., P. B. Gordon: "Effects of lysosomotropic monoamines, diamines, amino alcohols, and other amino compounds on protein degradation and protein synthesis in isolated rat hepatocytes", Mol. Pharmacol. 18, 468 (1980) Spiegelhalder, B., G. Eisenbrand, R. Preussmann: "Verunreinigung von Aminen mit N-Nitrosaminen", Angew. Chem. 90, 379 (1978) Steinhagen, W. H., J. A. Swenberg, C. S. Barrow: "Acute inhalation toxicity and sensory irritation of dimethylamine", Am. Ind. Hyg. Assoc. J. 43, 411 (1982) Swenberg,J.A.:Twenty four month final report inhalation toxicity of dimethylamine in F344 rats and B6C3F1 mice, Chemical Industry Institute of Toxicology (CIIT) Docket No , Research Triangle Park, NC, USA, 1990 Szybalski, W.: "Special microbiological systems. II. Observations on chemical mutagenesis in microorganisms", Ann. N. Y. Acad. Sci. 76, 475 (1958) Tuazon, E. C., A. M. Winer, R. A. Graham, J. P. Schmidt, J. N. Pitts: "Fourier transform infrared detection of nitramines in irradiated amine-nox systems", Environm. Sci. Technol. 12, 954 (1978) Varma, D. R., I. Guest, S. Smith, S. Mulay: "Dissociation between maternal and fetal toxicity of methyl isocyanate in mice and rats", J. Toxicol. Environm. Health 30, 1 (1990) Whong, W.-Z., N. D. Speciner, G. S. Edwards: "Mutagenicity detection of in vivo nitrosation of dimethylamine by nitrite", Environm. Mutag. 1, 277 (1979) Wirth, P. J., S. S. Thorgeirsson: "Amine oxidase in mice sex differences and developmental aspects", Biochem. Pharmacol. 27, 601 (1978) Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, K. Mortelmans, W. Speck: "Salmonella mutagenicity tests: III. results from the testing of 255 chemicals", Environ. Mutagen. 9, Suppl. 9, 1 (1987) completed