m-toluidine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD guideline 422 study and GLP

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:

other: OECD TG 422

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

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)

Details on test animals or test system and environmental conditions:

Acclimatisation: 5 days
Temperature of the animal room: 22 °C
Relative humidity: 30-70 %
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 femalesare 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:

method not mentioned

Details on mating procedure:

One female to one male until pregnancy occurs; day 0 of pregnancy is defined as the day sperm is found.

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

Duration of test:

Males 42 days; females: from day 14 prior to mating to day 3 of lactation ( ca.42 days).

No. of animals per sex per dose:

13

Control animals:

yes, concurrent vehicle

Details on study design:

As requested by OECD TG 422

Examinations

Maternal 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

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:

- External examinations: Yes:

Statistics:

yes, but method not mentioned

Indices:

Copulation index
Fertility index
Gestation index
Implantation index
Delivery index
Birth index
Viability index

Historical control data:

No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects: yes

Details on maternal toxic effects:
no compound related effects adverse effects were detected with regared to the mating performance of any of the dosed rats. However, 2/10 pregnant females receiving 100 mg/kg bw/day and all the 11 females receiving 300 mg/kg bw/day showed toatal implantation losses in utero

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

other: developmental toxicity

3

Dose descriptor:

LOAEL

Effect level:

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

Basis for effect level:

other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects:
No significant differences in the pup viability, pup weights and incidence of morphological abnormalities of pups were apparent in the groups given 100 mg/kg bw/day or less when compared to controls.

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

LOAEL

Effect level:

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

Basis for effect level:

other: other

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

In the available OECD combined repeated 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 fron 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).

No compound-related adverse effects were detected with regard to the mating performances at any dose level. 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 obviously 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).