Reaction mass of Benzenamine, N,N-dimethyl- , molybdate, tungstate & phosphates

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from publication.

Data source

Reference

Reference Type:

publication

Title:

SUBCHRONIC (13-WEEK) TOXICITY STUDIES OF N,N-DIMETHYLANILINE ADMINISTERED TO FISCHER 344 RATS AND B6C3F, MICE

Author:

Kamal M. Abdo, Micheal P. Jokinen, Richard Hiles

Year:

2009

Bibliographic source:

National Toxicology Program, Research Triangle Park, North Carolina

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Subchronic toxicity study of test chemical in B6C3F1 mice to determine its toxic effects on different target organs.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N-dimethylaniline

EC Number:

204-493-5

EC Name:

N,N-dimethylaniline

Cas Number:

121-69-7

Molecular formula:

C8H11N

IUPAC Name:

Aniline, N,N-dimethyl-

Details on test material:

- Name of test material (as cited in study report):N,N-dimethylaniline- Molecular formula (if other than submission substance): C8H11N- Molecular weight (if other than submission substance):121.18g/mol- Impurities (identity and concentrations):98.2% pure- Substance type:Organic- Physical state: Liquid

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Charles River Breeding Laboratories- Age at study initiation: 6-8 weeks- Weight at study initiation: No data available- Fasting period before study: N/A- Housing: Five animals per sex were housed in polycarbonate cages in a controlled environment. - Diet (e.g. ad libitum): NIH-07 diet, ad libitum- Water (e.g. ad libitum):Tap water, ad libitum- Acclimatization period: 2 weeksENVIRONMENTAL CONDITIONS- Temperature (°F): 70-74°F- Humidity (%): 48-71%- Air changes (per hr): No data available- Photoperiod (hrs dark / hrs light): 12-hr dark/12-hr light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE- Justification for use and choice of vehicle (if other than water): Corn oil- Concentration in vehicle: 0, 31.25, 62.5, 125, 250 and 500 mg/kg/day- Amount of vehicle (if gavage): 5 ml corn oil/kg- Lot/batch no. (if required): No data available- Purity: No data availableOther details: Gavage solutions were prepared fresh once every week and stored in brown bottles at 4°C. Doses were adjusted weekly for changes in body weights.

Duration of treatment / exposure:

13 Weeks

Frequency of treatment:

Once daily, 5 days per week

Doses / concentrations

Remarks:

Doses / Concentrations:0, 31.25, 62.5, 125, 250 or 500 mg/kg/dayBasis:actual ingested

No. of animals per sex per dose:

Control: 10 males, 10 females31.25 mg/kg/day: 10 males, 10 females62.2 mg/kg/day: 10 males, 10 females125 mg/kg/day: 10 males, 10 females250 mg/kg/day: 10 males, 10 females500 mg/kg/day: 10 males, 10 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: twice daily (once in the morning and once in the afternoon) for morbidity and mortalityBODY WEIGHT: YesTime schedule for examinations-WeeklyCAGE SIDE OBSERVATIONS: Yes - Time schedule: Twice daily - Cage side observations checked in table [No.?] were included.DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: WeeklyBODY WEIGHT: Yes - Time schedule for examinations: WeeklyFOOD 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: No- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: NoFOOD EFFICIENCY:- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: NoWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No- Time schedule for examinations:No dataOPHTHALMOSCOPIC EXAMINATION: No- Time schedule for examinations:No data- Dose groups that were examined:No dataHAEMATOLOGY: No- Time schedule for collection of blood:No data- Anaesthetic used for blood collection: No data- Animals fasted: No data- How many animals:No data- Parameters checked in table [No.?] were examined.No dataCLINICAL CHEMISTRY: No- Time schedule for collection of blood:No data- Animals fasted: No data- How many animals:No data- Parameters checked in table [No.?] were examined. No dataURINALYSIS: No- Time schedule for collection of urine:- Metabolism cages used for collection of urine: No data- Animals fasted: No data- Parameters checked in table [No.?] were examined. No dataNEUROBEHAVIOURAL EXAMINATION: No- Time schedule for examinations:- Dose groups that were examined:- Battery of functions tested: sensory activity / grip strength / motor activity / other:OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: YesAll rats, including those that died during the study and those that survived to study termination, were necropsied and all gross lesions were recorded.HISTOPATOLOGY: YesTissues and organs were collected from each animal and fixed in 10% neutral buffered formalin. The fixed tissues were embedded in paraffin, sectioned at 5-6 um, and stained with hematoxylin and eosin. Selected tissues were stained with Perl's iron stain to confirm the presence of hemosiderin.

Statistics:

No data available

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

No mortality observed. Decrease in motor activity occurred in female mice at ≥125 mg/kg/day and in male mice in all treated groups, and lasted throughout the day.

Mortality:

mortality observed, treatment-related

Description (incidence):

No mortality observed. Decrease in motor activity occurred in female mice at ≥125 mg/kg/day and in male mice in all treated groups, and lasted throughout the day.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of all treated male mice were about 8% lower than the controls. Little difference in mean body weights was observed between treated and control female mice.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Splenomegaly was present in all mice receiving ≥125 mg/kg/day, in 7 of 10 male and 8 of 10 females at 62.5 mg/kg/day, and 4 of 10 male and 4 of 10 female mice at 31.25 mg/kg/day.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Comp.-related effects were noted in spleen,liver & kidney of male & female mice.The incidence &/or severity of the lesions increased with increasing dose levels,where treatment-related effects were present in all groups of treated mice at doses >31.65 mg

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Hyperplasia of the bone marrow and hematopoiesis in the spleen were observed in all rats in a dose-related manner

Details on results:

Death were attributed to gavage errorsMortalityDead at dose 500 mg/kgDead at dose 250 mg/kgDead at dose 125 mg/kgDead at dose 62.5 mg/kgDead at dose 31.25 mg/kgDead at dose 0 mg/kgMice Male1321Mice Female1The gavage deaths were confirmed by the presence of the vehicle (corn oil) in the lung.

Effect levels

Dose descriptor:

NOAEL

Effect level:

31.25 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effct were observed at this dose

Remarks on result:

other: No toxic effct were observed

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Histopathology:

Compound-related effects were noted in the spleen, liver, and kidney of male and female mice. The incidence and/or severity of the lesions increased with increasing dose levels, where treatment-related effects were present in all groups of treated mice at doses greater than 31.25 mg/kg/day.

Applicant's summary and conclusion

Conclusions:

NOAEL was considered to be 31.25 mg/kg body weight/day in male and female B6C3F1 mice. for test chemical

Executive summary:

In a repeated-dose toxicity study, 0, 31.25, 62.5, 125, 250 or 500 mg/kg/day of test chemical was administered to 10 male and 10 female B6C3F1 mice per dose via gavage 5 days/week for 90 days. No mortality was observed. Dose-related increases in splenomegaly, and extramedullary hematopoiesis and hemosiderosis of the spleen were observed in the mice when given greater than 31.25 mg/kg/day of test chemical . Splenomegaly was reported as minimal in 4/10 mice, and extramedullary hematopoiesis and hemosiderois were reported as mild in 1/10 mice.Compound-related effects were noted in the spleen, liver, and kidney of male and female mice. The incidence and/or severity of the lesions increased with increasing dose levels, where treatment-related effects were present in all groups of treated mice at doses greater than 31.25 mg/kg/day. Therefore the NOAEL was considered to be 31.25 mg/kg/day in B6C3F1 mice for 13 weeks by oral gavage.