Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 200-679-5 | CAS number: 68-12-2
Repeated dose toxicity oral: BASF AG, 1977, Repeated dose 28-day oral gavage study in rats, 238, 475, 950, 1900 mg/kg in water, comparable to the OECD TG 407. NOAEL = 238 mg/kg bw (both sexes). Repeated dose toxicity dermal: data can be waived from oral or inhalation studies; Repeated dose toxicity inhalation: Malley et al., 1994. Chronic toxicity/oncogenicity of dimethylformamide in rats and mice following inhalation exposure; according to the OECD TG 451, NOAEC = 80 mg/m³
The repeated application of dimethylformamide in doses from 950 mg/kg onwards leads to distinct acute haemorrhagic liver dystrophy with necrosis. Females were in general more tolerant to dimethylformamide.
This non-GLP in vivo study was conducted similar to OECD TG 407 (Repeated Dose 28-Day Oral Toxicity in Rodents). In the present study, Sprague-Dawley rats received 250, 500, 1000 and 2000 µL N,N-dimethylformamide /kg bw (about 238, 475, 950 and 1900 mg/kg bw/day) by gavage on 5 days/week during four weeks.
In the highest dose group all animals died, mostly at the beginning of the study. At 1000 µL/kg bw/day all animals affected by reduced food consumption and reduced body weight, males already at the beginning, females at the end of the study. Hepatic injury was characterized by changes in clinical chemistry values, e.g. increased enzyme activities. Relative liver weights were increased in both sexes. Histological examination revealed an acute to subacute haemorrhagic liver dystrophy with necrosis in both sexes in the two high dose groups. Disturbances in kidney function were characterized by elevated urea (females) and creatinine values, the latter one in both sexes. Relative kidney weights were increased in the males. At 250 and 500 μL/kg bw/day reduced food consumption in the males and at 500 μL/kg bw/day reduced body weight was observed in the males. For the observation of increased relative liver weights in both sexes and of increased relative kidney weights in the males no histopathological correlate was found.
NOAEL of 238 mg/kg bw and LOAEL of 475 mg/kg bw were established for both sexes.
Table 1: Effect of DMF on Sorbitol Dehydrogenase Activity in Male and Female Ratsa
a % of body weight.
b Livers evaluated from 10 rats/sex/concentration.
c For males n =17,19,21and 26 livers evaluated for 0, 25, 100 and 400ppm, respectively. For females n = 22, 14, 12, and 23 livers evaluated for 0, 25, 100, and 400 ppm, respectively.
d For males n =31,42, 3 8, and 36 livers evaluated for 0,25, 100 and 400ppm, respectively. For females n = 42, 35, 36 and 47 livers evaluated for 0, 25, 100, and 400 ppm, respectively.
*Statistically significant at P <0.05.
Table 3: Incidence (%) of Compound-Related Morphological Observations in Rats Exposed to DMF for 24 Monthsa
Hepatic foci of alterations
Male: clear cell
Female: clear cell
a Data represent total percentage incidence for both unscheduled and scheduled deaths for the interval 12-24 months.
b The number of livers examined was 57, 59, 58, and 60 for 0, 25, 100 and 400 ppm males, respectively. For females exposed to 0, 25, 100 or 400ppm, the number of livers examined was 60, 59, 59 and 62, respectively.
* Statistically significant at P <0.05.
Table 4: Incidence (%) of Hepatic, Testicular and Mammary Tumors in Rats Exposed to DMF
Primary hepatic tumors
Primary testicular tumors
Testicular interstitial cell adenomas
Primary mammary tumors
a M, male; F, female.
b Numerator represents number of tumors, and the denominator represents number of tissues examined.
c For the 25 and 100 ppm concentrations, non-target organ tissues (such as testes and mammary gland) were examined only in animals which died prior to scheduled sacrifice or had grossly observable lesions.
d This lesion was not observed in males.
This fully reliable study was performed according to OECD TG 451 Carcinogenicity Study. The carcinogenic effect of the test substance was investigated in groups of 78 male and 78 female young adult mice. The rats were approx. 47 days of age at the beginning of the study. They were exposed to DMF vapors by whole body exposure at dose levels of 0, 25, 100 and 400 ppm for two years. The concurrent control group animals (0 ppm) were exposed to dehumidified air alone. Clinical pathology was investigated at 3, 6, 12, 18 and 24 months in each 10 male and 10 female /group. At 12 months interim sacrifice of 10 male and 10 female animals per group took place, thus again 10 rats per sex and group had to be selected for the 18 and 24 months examinations. After 2 weeks, 3 months and 12 months of testing cell proliferation in the liver was evaluated in 5 randomly selected rats per sex and group. An immunohistochemical evaluation was done on livers from animals of the 0 ppm and 400 ppm groups. Estrous cycle evaluation was done in all female animals of the control and the high dose group from test day 107 through test day 131. Moreover, examinations on body weight, organ weights, ophthalmoscopy, urinalysis and a complete necropsy including microscopical examinations were carried out.
Results and discussion
There were no compound-related differences in the survival of the animals in the present study (for male rats survival was 27, 34, 40 and 44 % for 0, 25, 100 and 400 ppm, respectively. For female rats survival was 35, 23, 19 and 39 %, respectively). Ophthalmologic examinations, haematology and urinalysis revealed no compound-related effects in the rats. Moreover, no compound- related effects were seen on the estrous cycles of rats exposed up to 400 ppm DMF. Body weight and body weight gain were reduced in both sexes of the 400 ppm group and in the male animals of the 100 ppm group. Serum sorbitol dehydrogenase activity was increased in the animals of the 100 and 400 ppm groups. These animals also showed increased mean relative liver weights and centrilobular hepatocellular hypertrophy as well as an increased centrilobular accumulation of lipofuscin/hemosiderin. At 400 ppm there was also an increased incidence of hepatocellular single cell necrosis. The incidence of clear cell foci was increased in 100 ppm males and in both sexes of the highest dose group. An increased incidence of eosinophilic foci was seen in the 400 ppm females. Cell-labelling indices for hepatocytes were not statistically significant different between control and 400 ppm rats, however, rates were slightly higher for 400 ppm males at 2 weeks and 3 months but not at 12 months. An increased incidence of endometrial stromal polyp of the uterus (14.8 %) occurred in the females of the 400 ppm group. According to the authors endometrial stromal polyps are the most common uterine neoplasm in rats. Moreover, the incidence showed no clear dose-response relationship and was in the range of historical control incidences for the respective laboratory (2.0-15.0 %). Thus, the authors concluded, that the increased incidence is probably a chance variation rather than a compound-related effect. There were no compound-related lesions noted in the nose or respiratory tract for any exposure concentration. The incidences of hepatic tumors and testicular tumors in rats exposed up to 400 ppm DMF were similar to control values.
Conclusion: Exposure to DMF for 2 years did not cause a compound-related increase of tumors in rats. According to the authors, the NOEC in rats is 25 ppm (common toxicity) and the NOEC for oncogenicity is 400 ppm
Repeated dose toxicity: oral
A non-GLP in vivo study was conducted similar to OECD TG 407 (Repeated Dose 28-Day Oral Toxicity in Rodents) (BASF, 1977).
In this key oral sub-acute study, Sprague–Dawley rats received 250, 500, 1000 and 2000 μL DMF/ kg bw (about 238, 475, 950 and 1900 mg/kg bw/day) by gavage on 5 days/week.
In the highest dose group all animals died, mostly at the beginning of the study. At 1000 μL/kg bw/day all animals were affected by reduced food consumption and reduced body weight, males already at the beginning, females at the end of the study. Hepatic injury was characterized by changes in clinical chemistry values, e.g. increased enzyme activities. Relative liver weights were increased in both sexes. Histological examination revealed an acute to subacute hemorrhagic liver dystrophy with necrosis in both sexes in the two high dose groups. Disturbances in kidney function were characterized by elevated urea (females) and creatinine values, the latter one in both sexes. Relative kidney weights were increased in the males. At 250 and 500 μL/kg bw/day reduced food consumption in the males and at 500 μL/kg bw/day reduced body weight was observed in the males. For the observation of increased relative liver weights in both sexes and of increased relative kidney weights in the males no histopathological correlate was found. NOAEL of 238 mg/kg bw and LOAEL of 475 mg/kg bw were established for both sexes.
In a supporting 90 -day feeding study, Charles River CD strain rats received 200, 1000 and 5000 ppm DMF (about 12, 60 and 300 mg/kg bw/day) (TSCATS: OTS 0520880, 1960; TSCATS: OTS 0571664, 1960; TSCATS: OTS 0572893, 1960). This study was conducted in accordance with national standard methods with acceptable restrictions.
40 male and 40 female weanling rats were observed during a six-day pre-test period. At the end of this period 6 male and 6 female animals were assigned to 4 groups, one control group and 3 dose groups. Dose levels chosen were 200, 1000 and 5000 ppm. Body weight and food consumption were determined at least once weekly. Routine hematological examinations were performed for all animals on study days 30, 60 and 90. Alkaline phosphatase activity was also determined at these time points. At the end of the study for evaluation of liver function enzyme activities and phospholipid and cholesterol content were measured in the serum. At sacrifice the animals were submitted to gross and microscopic pathological appraisal and to organ weight determination (brain, liver, kidney, adrenal, lung, spleen and testis). For histology the following organs were preserved: organs that were weight and ovary, heart, pancreas, stomach and small intestine.
All treated animals survived the feeding study. At a dose of 1000 ppm DMF relative liver weights were slightly increased without a histopathological correlate. Leucocytosis was observed after 60 days of DMF feeding. The red blood cell count was slightly lower in the 1000 ppm group in comparison to the control. Hypercholesterolemia was observed in the females and elevated phospholipid values were seen in 2/6 females at 1000 ppm. In both sexes at 5000 ppm body weight gain was depressed during the entire study period (statistically significant only in male animals), food consumption was lower during the first 5-6 weeks when compared to control animals and food efficiency were also lower during the first two weeks of the study. Moreover slight anemia, leucocytosis, hypercholesterolemia and elevated phospholipid concentration together with mild liver injury (the latter finding in 3/6 males and 5/6 females) and increased relative liver weights were observed in both sexes of the 5000 ppm group. The increase in relative liver weights in both sexes at 1000 and 5000 ppm were dose-related. No effects were observed in animals of the lowest dose group. In conclusion, the liver was the predominant organ of DMF toxicity. NOAEL of 200 ppm and LOAEL of 1000 ppm were established for both sexes.
Male Wistar rats were dosed with N,N-dimethylformamide (DMF) in drinking water at four concentration levels (0, 0.1, 0.5 and 1.0 g/L) for 2 or 7 weeks (Elovaara et al., 1983).
The weight gain in the DMF-treated rats did not differ from the controls. A dose-related increase of relative liver weights was observed. In liver and kidneys increased amounts of reduced glutathione and increased activity of microsomal UDP Glucuronosyl Transferase and of Ethoxycumarine O-Demethylase were observed. Cytochrome P-450 and NADPH-Cytochrome C-Reductase activity in the liver were not influenced by the treatment. Oxidative N-demethylation of DMF by hepatic microsomes in vitro was not enhanced by oral treatment. No DMF-dependent formaldehyde liberation in vitro could be detected under conditions where formaldehyde liberation from N,N-dimethylnitrosamine could be demonstrated. However, the endogenous rate of formaldehyde generation by liver microsomes isolated from DMF-treated rats was enhanced with the highest oral dose of DMF. The daily intake of DMF lowered the activities of both formaldehyde and propionaldehyde dehydrogenases in the liver soluble fraction. No inhibition of these dehydrogenases was shown in vitro by DMF (≤ 10 mM) or by its main urinary metabolite N-methylformamide (≤ 10 mM). The observed impairment of aldehyde oxidation in liver and kidneys of the rat after the DMF intake could explain the mechanism behind the alcohol intolerance observed in man after DMF exposure.
Repeated inhalation exposures
A fully reliable study was performed according to OECD TG 451 Carcinogenicity Study in rats and mice. In this key chronic inhalation studies Crl:CD BR rats were exposed over a period of 2 years and Crl:CD-1 (ICR)BR mice were exposed for 18 months at concentrations of 25, 100 and 400 ppm (about 80, 300 and 1210 mg/m³) 5 d/w and 6 h/d (Malley et al., 1994). In the rats body weight and body weight gain were reduced in both sexes at 400 ppm and in the male animals at 100 ppm. Moreover, the animals in these groups showed increased enzyme activity (serum sorbitol dehydrogenase), increased liver weights and some histopathological findings in the liver. There was no compound related increase of tumors. Estrous cycles were not altered in the females. Similar findings were observed in mice . At 400 ppm liver weights were increased in both sexes and at 100 ppm in the males. At all concentrations tested minimal to mild hepatocellular hypertrophy was observed (incidence being dose-related). Individual hepatocellular necrosis together with some other histopathological findings (minimal to moderate kupffer cell hyperplasia with pigment accumulation of lipofuscin and hemosiderin) were seen in all groups (also control, incidence being greater in N,N-dimethylformamide-treated animals). A compound-related increase in tumors was not observed and there was no effect on estrous cycles in female mice. According to the authors, a NOEC (no-observable -effect level) was not achieved in mice due to morphological changes seen in the liver at all three test concentrations, nevertheless they expected the NOEC to be close to 25 ppm due to the minimal changes observed at this concentration. These minimal changes included a slightly (for the males significantly) increased incidence of hepatocellular hypertrophy, dose-related and statistically significantly increased incidence of hepatic single cell necrosis in both sexes, and dose-related (for the males significantly) increased incidences of hepatic kupffer cell hyperplasia and pigment accumulation. For rats, the NOEC is 25 ppm (80 mg/m³) based on the body weight changes, clinical chemistry changes and hepatotoxic effects observed at 100 and 400 ppm.
The other sub-chronic inhalation studies confirmed these findings (NTP, 1992 (Lynch et al., 2003) and Senoh et al., 2003):
In the NTP study (1992), groups of 30 rats (Fischer 344) and 10 mice (B6C3F1) of each sex were exposed to vapor concentrations of DMF at 0 (chamber controls), 50, 100, 200, 400, or 800 ppm, 6 h (plus T90) per day, 5 days/week, for 13 weeks. Each group of 30 rats was subdivided into a base study group (10) and two additional subgroups of 10 for evaluations of cardiac physiology and renal function, respectively. Animals were observed twice daily for mortality and moribundity. Body weights were measured weekly and at necropsy. In rats, haematology and serum chemistry analyses, urinalyses, renal function, and cardiac physiology (blood pressure and electrocardiograms) studies were performed. Additionally, sperm morphology and vaginal cytology evaluations were performed on rats and mice exposed at 0, 50, 200, or 800 ppm DMF. A complete necropsy was performed on all animals. Organs and tissues were examined for gross lesions. Tissues from all control and 800 ppm DMF exposed animals were examined microscopically whereby livers were examined in rats and mice of both sexes from all treatment groups.
Subchronic inhalation exposure to DMF produced hepatotoxicity characterized by statistically significant increased liver weights at all exposure concentrations, statistically significant increased activities of serum enzymes and other markers of liver function and histopathological changes in the liver with rats exhibiting more severe lesions. The liver was the only target organ identified and no histopathological changes were observed in any other organs or tissues in either species. Relative liver weights were significantly increased at all DMF concentrations in both sexes and both species. Activities of serum sorbitol dehydrogenase (SDH) were statistically increased in male and female rats (200 to 800 ppm) on study days 4, 24, and 91 (13 weeks). Activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICD) were statistically increased in both sexes of rats exposed to 800 ppm DMF at all time points. Cholesterol (CHOL) levels were statistically increased in male and female rats (50–800 ppm) at all sampling time points. Levels of total bile acids (TBA) were statistically increased in both sexes of rats (400–800 ppm) on days 24 and 91. Centrilobular hepatocellular necrosis (minimal to moderate) was seen in rats of both sexes exposed at 400 and 800 ppm, with the lesions more severe in females. Centrilobular hepatocellular hypertrophy (minimal to mild) was found in all groups of DMF-exposed male mice, and in female mice exposed at 100–800 ppm. No treatment-related hematological or renal function changes were observed in rats and no adverse effects on male reproductive endpoints were found. No evidence of cardiotoxicity was observed in rats exposed to DMF, which does not support the limited evidence of DMF-induced cardiotoxicity in the literature. Adverse effects on the estrous cycle were observed in female rats exposed at 800 ppm but not at lower concentrations of DMF. For rats of both sexes the no-observed-adverse-effect concentration (NOAEC) for microscopic liver lesions was 200 ppm based on the absence of microscopic liver lesions at this and lower exposure concentrations, although liver enzymes and liver weights were increased at all DMF exposure concentrations (50–800 ppm). The NOAEC was 50 ppm for female mice, but an NOAEC based upon the absence of microscopic liver injury was not determined in male mice.
A highly reliable GLP study was conducted according to OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study) and OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study).
In this supporting study, F344 rats and BDF1 mice of both sexes were exposed to DMF by inhalation (6 h/d × 5 d/wk) to 100, 200, 400, 800 or 1,600 ppm DMF for 2 weeks, and 50, 100, 200, 400 or 800 ppm DMF for 13 weeks (Senoh et al., 2003). Three male and 7 female rats died during the 2-week exposure to 1,600 ppm DMF, but no death of the exposed rats or mice occurred under any other exposure conditions. Massive, focal and single cell necrosis were observed in the liver of DMF-exposed rats and mice. The massive necrosis associated with the centrilobular fibrosis occurred at the highest exposure concentration. The single cell necrosis was associated with fragmentation of the nucleoli as well as an increased mitotic figure. The 13-week exposures of rats and mice to DMF were characterized by increases in the relative liver weight and the incidence of the centrilobular hepatocellular hypertrophy as well as increased serum levels of AST, ALT, LDH, total cholesterol and phospholipid. Lower confidence limits of the benchmark dose yielding the response with a 10 % extra risk (BMDL10) were determined for the relative liver weight and the incidence of hepatocellular hypertrophy of the 13-week exposed animals. For the increased relative liver weight, the BMDL10 value resulted in 1.1 and 13.1 ppm for male and female rats, and 1.1 ppm for male mice, respectively. Nevertheless, the BMDL10 value for the relative liver weight of female mice was not determined because of insignificant changes in the relative liver weight throughout the range of exposure concentrations. For the hepatocellular hypertrophy, the BMDL10 value resulted in 68.5 and 191 ppm for male and female rats, and 17.5 and 372.5 ppm for male and female mice, respectively. These BMDL10 values for hepatocellular hypertrophy are consistent with the finding by Lynch et al. 2003 that the NOAEL of hepatocellular hypertrophy were 50 and 200 ppm for female mice and rats of both sexes, respectively.
In a supporting study (non-GLP, non-OECD), Cynomolgus monkeys were exposed to DMF by inhalation during 13 weeks (TSCATS, 1990 Report No. 86 -910000212). The aim was to determine the target organ effects, concentration response, a NOAEL, to measure selected pharmacokintetic parameters, evaluate potential toxic effects on the male and female reproductive system, examine differences in response between sexes and to evaluate potential specimen differences in toxic responses (comparison with literature data) following exposure to DMF vapors. A total of 20 male and 12 adult female monkeys were required for this study. Three monkeys/sex/exposure group were exposed to the three concentrations of DMF (30, 100 or 500 ppm) or filtered room air (concurrent control). In addition, two males per exposure group were designated as the post-exposure group. The post-exposure group was held for 13 additional weeks with no exposure and was then necropsied.
The effects of the test substance were studied in groups of 5 male and 3 female monkeys (two males/group served as additional animals for the post-exposure period). There were no early deaths in this study and all animals were sacrificed on their scheduled day of necropsy. There were no treatment-related findings in the 13 week inhalation study except possible alterations in the menstrual cycle of DMF exposed females. The menstrual cycle of 1 low dose group female, 2 mid dose females and all high dose females were altered in length. According to the authors, the subchronic exposure of cynomolgus monkeys to DMF did not cause any adverse health effects (liver function, sperm production, and sperm motility appeared unaffected). With respect to the possible increase in mensis length with exposure to DMF and its relevance, the experts conclusions were that while the data are suggestive of an effect, there is no confirmed evidence that DMF caused an effect on menstrual cycle because of the monkeys recent importation history and lack of pre-exposure data. NOAEL of 500 ppm was established for male and female animals.
In a disregarded study*, carcinogenicity and chronic toxicity of N,N-Dimethylformamide (DMF) were examined by inhalation exposure of groups of 50 rats and 50 mice of both sexes to DMF vapor at a concentration of 0, 200, 400 or 800 ppm (v/v) for 6 h/d, 5 d/wk, for 104 wk (Senoh et al., 2004). In rats, incidences of hepatocellular adenomas and carcinomas significantly increased in the 400 and 800 ppm-exposed groups and in the 800 ppm-exposed group, respectively. The hepatocellular adenoma did not increase significantly in the 400 ppm exposed female rats, but its incidence exceeded a range of historical control data in the Japan Bioassay Research Center (JBRC). In mice, incidences of hepatocellular adenomas and carcinomas significantly increased in all the DMF-exposed groups. Incidence of hepatoblastomas significantly increased in the 200 and 400 ppm-exposed male mice, and 4 cases of hepatoblastomas in the 400 ppm-exposed female mice and the 800 ppm-exposed male mice exceeded the range of historical control data of the JBRC. Incidences of altered cell foci increased in the liver of exposed rats and mice in an exposure concentration-related manner, and those foci were causally related to the hepatocellular tumors. Liver weights increased in both rats and mice exposed to DMF at 200 ppm and above. Increased levels of γ-GTP, ALT, AST and total bilirubin in exposed rats of both sexes and AST and ALT in exposed mice of both sexes were noted. It was concluded that 2-yr inhalation exposure to DMF increased incidences of hepatocellular adenomas and carcinomas in rats and incidences of hepatocellular adenomas, carcinomas and hepatoblastomas in mice, and that hepatocarcinogenicity of DMF was more potent in mice than in rats.
In a disregarded study*, Male Wistar rats were exposed by inhalation to N,N-dimethylformamide (DMF) at 0 (control), 200 or 400 ppm (v/v) for 6 hr/day, 5 days/week and 4 weeks, and each inhalation group received DMF-formulated drinking water at 0, 800, 1,600 or 3,200 ppm (w/w) for 24 hr/day, 7 days/week and 4 weeks (Ohbayashi et al., 2008). Both the combined inhalation and oral exposures and the single-route exposure through inhalation or ingestion induced centrilobular hypertrophy and single-cell necrosis of hepatocytes, increased plasma levels of alanine aminotransferase (ALT), increased percentage of proliferating cell nuclear antigen (PCNA)-positive hepatocytes without glutathione-S-transferase placental form (GST-P)-positive liver foci, and increased relative liver weight. Those hepatic parameters of the DMF-induced effects were classified into hypertrophyc, necrotic and proliferative responses according to the pathological characteristics of affected liver. While magnitudes of the hypertrophic and necrotic responses were linearly increased with an increase in amounts of DMF uptake in the single-route exposure groups, those dose-response relationships tended to level off in the combined-exposure groups. Saturation of the hypertrophic and necrotic responses at high dose levels might be attributed to suppression of the metabolic conversion of DMF to its toxic metabolites. Percentage of PCNA-stained hepatocytes classified as the proliferative response was increased more steeply in the combined-exposure groups than in the single-route exposure groups. It was suggested that the proliferative response of hepatocytes to the combined exposures would be greater than that which would be expected under an assumption of additivity for the component proliferative responses to the single-route exposures through inhalation and ingestion.
In a disregarded study*, a group of 50 male F344 rats, 6 -week old, was exposed by inhalation to 0 (clean air), 200 or 400 ppm (v/v) of DMF vapor-containing air for 6 h/day and 5 days /week during a 104 week period, and each inhalation group was given ad libitum DMF-formulated drinking water at 0, 800 or 1600 (w/w) for 104 weeks (Ohbayashi et al., 2009). The study was designed in order to examine hepatocarcinogenic effect of combined inhalation and oral exposures of rats to DMF.
Incidences of hepatocellular adenomas and carcinomas and their combined incidences were significantly increased in the combined-exposure groups compared with the untreated control group or each of the inhalation-alone and oral-alone groups. Incidences of hepatocellular adenomas and carcinomas induced by the combined exposures were greater than the sum of the two incidences of the hepatocellular adenomas and carcinomas induced by the single-route exposures through inhalation and ingestion. The combined exposures enhanced tumor malignancy. The hepatocarcinogenic effect of the combined exposures is greater than the effect that would be expected under assumption that two effects of single-route exposures through inhalation and drinking are additive.
* The doses selected exceeded the maximum tolerated dose (MTD), which was exacerbated by probable exposure to an aerosol during atmosphere generation. In addition, the selection of test system used for this study may have contributed to increased tumor incidence observed. No historical data is available on the rat strain
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: The best documented study with the lowest NOAEL. Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint: The study with the longest duration. Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver
The classification is not warranted according to the criteria of Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Close Do not show this message again