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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
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:
3-methylaniline
Details on test material:
purity: 99 %

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 exposure:
Dosing of both sexes should begin 2 weeks prior to mating, continued through mating period.
Males: dosing continued up to the day when females are killed.
Females. dosing continued throughout pregnancy and up to day 4 of lactation.
Details on mating procedure:
One female to one male until pregnancy occurs; day 0 of pregnancy is defined as the day sperm is found.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Details 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
Details on study schedule:
- Age at mating of the mated animals in the study: 10 weeks
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 requested by OECD TG 422.
Positive control:
No

Examinations

Parental animals: Observations and examinations:
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 ggross anomalies
clinical examinations: hematology, clinical chemistry, urinalysis
pathology: gross necropsy, histopathology
Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: Number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities
Postmortem examinations (parental animals):
Pathology: gross necropsy, histopathology
Postmortem examinations (offspring):
External malformation
Statistics:
yes, but methods not given
Reproductive indices:
number of mated pairs,
number of copulated pairs
copulation index,
number of pregnant animals,
fertility index,
pairing days undit copulation
implantation index
gestation index,
delivery index
Offspring viability indices:
number of pups born
number of pup alive
birth index
live birth index
sex ratio
number of pups alive on day 4
viability index
body weight of F1 pups up to day 4













Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

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
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 inalbumin, phospherous and GOT levek 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 bw7day 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
no effects on copulation index
no effect on fertility index
no effect on gestation index up to 100 mg/kg bw/day
gestation lenght no effect up to 100 mg/kg bw/day
total implantation loss at 300 mg/kg bw/day
implantation loss in 2/10 pregnant females at 100 mg/kg bw
no effect of delivery index up to 100 mg/kg bw/day

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: based on implantation losses in all animals at 300 mg/kg bw/day and in 2 of 10 at 100 mg/kg bw/day
Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Based on hemolytic anemia with deposit pigmentation and extramedulary hematopoiesis observed in all dosed rats
Remarks on result:
other: Generation: general toxicity

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING)
up to and including 100 mg/kg bw/day : no effect

CLINICAL SIGNS (OFFSPRING)
no findings mentioned

BODY WEIGHT (OFFSPRING)
up to day 4 of lactation: no effect

GROSS PATHOLOGY (OFFSPRING)
up to and including of 100 mg/kg bw/day no findings

OTHER FINDINGS (OFFSPRING)
live birth index : no effects
viability index: no effect
sex ratio: no effects

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
100 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: no significant differences in the pup viability, pup weights and incidence of morphological abnormalities of pups

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

In the available OECD combined reated dose and reproductive /developmental toxicity screening study according to OECD TG 422 and GLP male and female rats received doses of 0, 30, 100 and 300 mg/kg bw/day 14 days before mating to 14 days after mating in males and for 14 days before mating to day 3 of lactation in females (MHLW 1995).

The LOAEL (general toxicity) is 30 mg/kg bw/day based on deposit pigmentation and extramedullary hematopoiesis in all examined animals (UNEP 2003). Reproductive organs were not affected by treatment.

No compound-related adverse effects were detected with regard to the mating performances at and dose levels. However, 2/10 pregnant females receiving 100 mg/kg bw/day and all eleven receiving 300 mg/kg bw/day showed total implant losses in utero. Therefore the NOAEL for reproductive toxicity is considered to be 30 mg/kg bw/day (UNEP 2003).

2/11 pregnant females receiving 30 mg/kg bw/day and 3/10 receiving 100 mg/kg bw/day did not show nursing activity obiously and 11 or more than half number of their pups died after birth, while all live offsprings of other dams in 30 and 100 mg/kg groups had normally developed up to 4 days. Therefore this death of pups is considered as a result of maternal toxicity, probably due to anemia. Furthermore, change of pup weights and incidence of morphologic abnormalities of pups were not significant in 30 and 100 mg/kg . The NOAEL for developmental toxicity is considered to be 100 mg/kg bw/day (UNEP 2003)

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