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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
Combined repeated dose and reproduction / developmental screening test
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
m-toluidine
EC Number:
203-583-1
EC Name:
m-toluidine
Cas Number:
108-44-1
Molecular formula:
C7H9N
IUPAC Name:
m-toluidine
Test material form:
other: liquid
Details on test material:
purity: > 99.0 %

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
initial bw (females): 200-247 g
initial bw (males): 267-361g
acclimisation: 5 days
temperature of the animal room: 24 °C
relative humidity: 55 %
lighting 12 hours light 12 hours dark
food ad libitum,
water ad libitum
pregnant females should be caged individually

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Dosing of both sexes should begin 2 weeks prior to mating, continued through mating period(14d).
Males: dosing continued up to the day when females are killed.
Females. dosing continued throughout pregnancy and up to day 4 of lactation.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
data not given
Duration of treatment / exposure:
Males 42 days;
Females: from day 14 prior to mating to day 3 of lactation ( ca.42 days)
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 100, 300 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle
Details on study design:
As required by OECD TG 422
Positive control:
no

Examinations

Observations and examinations performed and frequency:
At least once per day:
--behavioual changes , signs of difficult or prolonged parturition, mortality and all signs of toxicity
--cage side observations: changes in skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system function
--food cinsumption, males and females should be weighed
--duration of gestation, examination of the litter as soon as possible: number and sex of pups, stillbirth, live birth, pup weight, and the presence of gross anomalies
clinical examinations: hematology, clinical chemistry, urinalysis

Pathology: gross necropsy, histopathology
Sacrifice and pathology:
--sacrifice:
male: day 43;
females: day 4 of lactation
--organ weights of all parental animals:
reported: liver, kidney,thymus, testes, epididymides , not reported: adrenals, brain, heart, spleen, ovaries and
--Gross necropsy
examination for macroscopic changes
--histological examination
preserved organs : male and female
brain, liver, thymus, spleen, heart, kidney, adrenal,urinary bladder, testis, epididymis, ovar
Other examinations:
As required by OECD TG 422
Statistics:
yes

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
no deaths occurred during the study,
clinical signs included: brownish urine, increased salivation in males and females receiving 100 mg/kg bw/day and more , pale extremies at 300 mg/kg bw in males and females

BODY WEIGHT AND WEIGHT GAIN
mean body weight gain during week 1 of the 300 mg/kg bw/day males and of the 100 and 300 mg/kg bw/day females was significantly lower than those of the controls

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
mean food consumption of the 300 mg/kg bw/day males and females was significantly reduced at week 1

HAEMATOLOGY (significant changes only)
No female data were mentioned
Males
in the 100 and 300 mg/kg bw/day males values for erythrocyte count, hemoglobin concentration and hematocrit were decreased and mean corpuscular volume was increased.
At 300 mg/kg bw/day males mean corpuscular hemoglobin was significantly increased, mean corpuscular hemoglobin concentration was decreased.At 300 mgU/kg bw/day: in the differential blood picture segmented neutrophils and monocytes were significantly reduced as well as lymphocytes and platelet count

CLINICAL CHEMISTRY
no female data were mentioned
males
in the 100 and 300 mg/kg bw/day males the A/G ratio, , serum bilirubin, potassium and chloride levels significantly increased with the dose
in the 300 mg/kg bw/day males significant increases in serum glucose and total cholesterol levels
in the 300 mg/kg bw/day males significant decreases in albumin, phospherous and GOT levels

NEUROBEHAVIOUR
low motor activity and pale extremities in males and females given 300 mg/kg bw/day

ORGAN WEIGHTS
relative kidney weights of the 300 mg/kg bw/day males and females were significantly greater than those of the controls

PATHOLOGY
HISTOPATHOLOGY: NON-NEOPLASTIC
--from30 mg/kg bw/day onwards a slight increase in severity of pigmentation or extramedullary hematopoiesis in the spleen in males and females were noted
--Pigment deposites and extramedullary hematopoiesis in the liver and spleen and congestion in the spleen in males and females that received 100 mg/kg bw/day and more.
--Swelling of hepatocytes in centrilobular zone in 100 mg/kg bw/day males and in the 300 mg/kg bw/day males and females;
--deposits of pigment in the renal tubular epithelium in 300 mg /kg bw/day males and females
--eosiophilic droplets in the renal tubular epithelium in males given 100 mg/kg bw/day and more;
--regenerated renal tubules in females given 100 mg/kg bw/day and more
--focal hyperplasia of epithelium in the urinary bladder in the 300 mg/kg bw/day males

Effect levels

Key result
Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on suggestive evidence of hemolytic anemia such as marginal pigment deposit and extramedullary hematopoiesis in the spleen probabely caused by methemoglobin formation.

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
30 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
spleen
Treatment related:
yes
Dose response relationship:
yes

Any other information on results incl. tables

no further data with respect of repeated dose toxicity

based on suggestive evidence of hemolytic anemia such as marginal pigment deposit and extramedullary hematopoiesis in the spleen probabely caused by methemoglobin formation.

Applicant's summary and conclusion

Executive summary:

In a study according to OECD TG 422 and GLP male and female SD (Crj:CD) rats received 0, 30, 100, or 300 mg/kg bw/day m-toluidine by gavage (MHLW 1995). Hematological and biochemical analysis was conducted only for males.


Compound related clinical signs were low locomotor activity and pale skin at 300 mg/kg bw. Erythrocyte countes, blood hemoglobin concentration and hematocrit were decreased at 100 and 300 mg/kg bw of males. Histopathological lesions of both sexes were deposit of pigmentation and extramedullary hematopoiesis in the liver at 100 and 300 mg/kg bw and in the spleen at 30 mg/kg bw and more. Other histological findings were very slight hepatocyte swelling at 100 mg/kg bw males and 300 mg/kg bw males and females and change in renal tubular epithelium with pigment deposit at 100 and 300 mg/kg bw of both sexes.


At the lowest dose of 30 mg/kg bw marginal deposit pigmentation and extramedullary hematopoiesis in the spleen were observed suggesting that a slight hemolysis occurred. Additionally there are sufficient evidences that this chemicals induced methemoglobinemia but methemoglobin content was not determined in this study. Therefore, the dose of 30 mg/kg bw/day should be considered to be adverse effect level because of suggestive evidence of hemolytic anemia. LOAEL for repeat dose toxicity was 30 mg/kg bw/day (UNEP 2003)

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