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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented report which meets basic scientific principles.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1977
Report date:
1977
Reference Type:
publication
Title:
OECD SIDS Dimethylformamide, Final April 2004
Author:
OECD
Year:
2004
Bibliographic source:
OECD SIDS Dimethylformamide

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
Principles of method if other than guideline:
- Principle of test: Repeated dose 28-day oral gavage study in rats.
- Short description of test conditions: Sprague-Dawley rats received DMF at dose levels of about 238, 475, 950 and 1900 mg/kg bw/day by gavage on 5 days/week during four weeks.
- Parameters analysed / observed: Clinical signs, body weights and findings by necropsy were recorded.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
Dimethylformamide
IUPAC Name:
Dimethylformamide
Constituent 2
Chemical structure
Reference substance name:
N,N-dimethylformamide
EC Number:
200-679-5
EC Name:
N,N-dimethylformamide
Cas Number:
68-12-2
Molecular formula:
C3H7NO
IUPAC Name:
N,N-dimethylformamide
Details on test material:
- Name of test material (as cited in study report): N,N-dimethylformamide

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: WIGA, Sulzfeld, Germany
- Age at study initiation: 32 days
- Weight at study initiation: male: 104-120 g; female: 104 - 122 g
- Housing: 3 per cage
- Diet: Altromin-R, Altrogge, Germany ad libitum
- Water: tap water ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
no details given
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
5 d/w
Doses / concentrationsopen allclose all
Dose / conc.:
238 mg/kg bw/day (nominal)
Remarks:
250 µL/kg
Basis: nominal in water
Dose / conc.:
475 mg/kg bw/day (nominal)
Remarks:
500 µL/kg
Basis: nominal in water
Dose / conc.:
950 mg/kg bw/day (nominal)
Remarks:
1000 µL/kg
Basis: nominal in water
Dose / conc.:
1 900 mg/kg bw/day (nominal)
Remarks:
2000 µL/kg
Basis: nominal in water
No. of animals per sex per dose:
10
Control animals:
other: aqua bidest
Details on study design:
no information given

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 10 days before the start of the study and directly before the last substance administration.
- How many animals: all
- Parameters examined: mean cell haemoglobin concentration, haemoglobin, erythrocytes, haematocrit, thrombocytes, leucocytes, differential count, mean cell volume, mean cell haemoglobin.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 10 days before the start of the study and direclty before the last substance administration.
- How many animals: all
- Parameters examined: urea, chloride, creatinine, calcium, glucose total, bilirubin, albumin, phosphorus (as phosphate), total protein, lipids, sodium, potassium, carbon dioxide, alkaline phosphatase activity, glutamate-pyruvat transfaminase activity.

URINALYSIS: Yes
- Time schedule for collection of urine: day 21 or 22
- Parameters examined: pH, protein, glucose, bilirubin, sediment.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes: heart, lung, thyroid, stomach, duodenum, jejunum, ileum, mesenteric lymph nodes, liver, pancreas, spleen, kidneys, adrenals, urinary bladder, testes and ovaries and brain.
Other examinations:
Body weight and organ weights of heart, liver, kidneys, spleen, thyroid, adrenals, testes, uterus and ovary were determined.
Statistics:
Statistical calculations (t-Test; x2-Test) were done for clinical, pathological and clinical chemistry data as well as for data from haematology and urinalysis.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The animals in the highest dose group showed piloerection, apathy, anaemia, dyspnoea, hyperthermia, lateral position.
Mortality:
mortality observed, treatment-related
Description (incidence):
At the highest dose group all animals died, mostly during the first 5 days of substance application. The animals in the highest dose group showed piloerection, apathy, anaemia, dyspnoea, hyperthermia, lateral position.
At 950 mg DMF/kg the general state of health was reduced (in male animals already beginning in study week 1, in female animals at the end of study week 3). 4 male animals (on study days 7, 8, 14 and 19) and one female animal (after 15 substance applications) died.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The animals in the highest dose group showed reduced body weight gain already after the first treatment. At 950 mg DMF/kg significantly reduced body weight when compared to the controls (at the end of the study for male animals 28 % lower, and for female animals 21 % lower than control). At 475 mg/kg significantly reduced body weight when compared to the control animals (14.6 % lower than controls) were seen.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The animals in the highest dose group showed reduced food consumption already after the first treatment. At 950 mg DMF/kg the animals showed significantly reduced food consumption (up to 36 % reduced in the males and up to 40 % reduced in the females). At 238 and 475 mg/kg reduced food consumption in the male animals were seen.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
950 mg/kg: 1 male and 2 females showed an extreme decrease in thrombocytes and the males an increase in segmented granulocytes and decrease in lymphocytes.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At 950 mg DMF/kg hepatic damage was represented by changes in clinical chemistry values (increased total bilirubin, increased enzyme values, i.e. GPT, AP) and disturbances in kidney function were represented by elevated urea (in 2 of 9 female animals) and creatinine values (in all animals of the 950 mg/kg dose group).
Urinalysis findings:
no effects observed
Description (incidence and severity):
No abnormalities
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Relative liver weights were increased in both sexes' and relative kidney weights were increased in the male animals at 950 mg/kg. At 238 and 475 mg/kg in both sexes increased relative liver weights and in the males increased relative kidney weights were observed, however without histopathological correlates.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histologically an acute to subacute haemorrhagic liver dystrophy with necrosis was found in the animals of 950 mg/kg and the highest dose group.
Histopathological findings: neoplastic:
not examined

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
238 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no significant effects
Remarks on result:
not determinable due to absence of adverse toxic effects
Dose descriptor:
LOAEL
Effect level:
475 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: reduced body weight

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

Conclusions:
NOAEL of 238 mg/kg bw and LOAEL of 475 mg/kg bw were established for both sexes.
Executive summary:

Study design

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.

Results

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.

Conclusion

NOAEL of 238 mg/kg bw and LOAEL of 475 mg/kg bw were established for both sexes.