Registration Dossier

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Guideline study conducted in compliance with GLP regulations. Original report not available. Data, reliability and rationale adopted according to OECD SIDS (2003) (publicly available peer reviewed source). Study according to OECD 422; long male treatment to have 9 weeks exposure, like females. Organs were examined as in 422 but no biochemistry or hematology was measured.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2001
Reference Type:
secondary source
Title:
SIDS Initial Assessment Report for SIAM 13 (o-nitroaniline) November 6-9, 2001 Bern, Final July 2003.
Author:
OECD SIDS
Year:
2003
Bibliographic source:
UNEP Publications

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
As the reprotoxicity part of the OECD 422 guideline, 12 nulliparus females and 12 males were used up to the gestation period. 10 animals per sex were used to continue the reprotoxicity part of the study and the examinations.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
400
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: from 4 weeks prior to mating, during mating, gestation of the females: i.e: 9 weeks.
Females: from 4 weeks prior to mating, during mating, gestation and lactation periods until post-partum day 3. Approximately 9 weeks.
Frequency of treatment:
Daily (7 days a week)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 150, 450 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
The only signs related to treatment were piloerection, salivation and matted fur observed at post-dose observations. Matted fur was also observed as clinical signs performed at weekly intervals in males and females of the high-dose group.
No indication of cyanosis was noted as a parameter for hematotoxicity (MetHemoglobin formation).

BODY WEIGHT (PARENTAL ANIMALS)
Statistically significant reduction in body weight were observed at several weighing times in high- and mid-dose groups (males and females: 5 to 6%) during the treatment. A significant reduction in terminal bodyweight or bodyweight gain was observed in high-dose males (6%) compared to controls, and more important in dams on gestation day 20 (bwg: -15%) and on day +4 post-partum (weight loss in 5 females) in high-dose females.
This had a direct effect on pups (post-partum deaths were seen in dams with lower bwg at day 20 or loss at day +4): an increased incidence in the number of pups found dead was observed between days 0 and 2 post partum in the high dose, with a significant increase of male pup deaths.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Reproductive parameters : The copulatory and fertility index, as well as the pre-coital intervals, were not affected by treatment. Implantation and pre-birth loss were unaffected by treatment.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Parental terminal organ weights: No differences were observed in absolute and relative organ weights of male parents.

GROSS PATHOLOGY/HISTOPATHOLOGY (PARENTAL ANIMALS)
Macroscopic and microscopic observations of parental generation: macroscopic and microscopic examinations of all organs, including spermatogenic cycle, did not reveal any treatment-related effects. Control and treted females showed persistent corpora lutea which was considered to be a physiological condition during lactation.



Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: general toxicity
Remarks on result:
other: Generation: F0 and F1 (migrated information)
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: reproductive parameters

Results: F1 generation

Details on results (F1)

VIABILITY (OFFSPRING)
F1 results: litter viability and growth and sex-ratios: Litter size and litter weight were statistically significantly reduced on day 4 post-partum in the high-dose group when compared to controls, while a statistically significant increase in cumulative loss was also observed in the same group.
In addition, a statistically significant increase in male pup death was observed in the high-dose group compared to controls.

GROSS PATHOLOGY (OFFSPRING)
F1 results: Necropsy findings in decedent pups: the findings observed at necropsy in decedent pups were similar in the control and the treated groups. Necropsy findings in F1 pups at day 4 post-partum: in general there were no particular differences between control and treated groups, with the exception of 2 pups each in the mid- and highdose groups that showed abnormal size of the median lobe of the liver in association with an abnormal area and abnormal color.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

It was concluded that all reproductive parameters were unaffected by treatment at 450 mg/kg bw and the general toxicity NOAEL is = 50 mg/kg bw / day for F0 and F1 generations.

Applicant's summary and conclusion