Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Similar to guideline study (OECD 414), conducted under GLP. Justification for read-across : Is on the basis that Dioctyltin bis(IOMA) and dioctyltin bis(2-EHMA) are isomers of the same compound and are structural analogues of each other. Based on the recently conducted developmental toxicity studies in two species it is considered that DOTI is likely to be more toxicoligically active and therefore use of data on this substance would be considered to be a worst case assessment of the registered substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Dioctyltin bis(IOMA) [CAS No. 26401-97-8]:Octyltin tris(IOMA) [CAS No. 26401-86-5] (80:20% mixture)
-Solution : oily solution

Test animals

Species:
rat
Strain:
other: Han-Wistar SPF
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:no data
- Age at study initiation:no data
- Weight at study initiation:no data
- Fasting period before study:no data
- Housing:individually housed
- Diet (e.g. ad libitum): not precised, ad libitum
- Water (e.g. ad libitum):not precised, ad libitum
- Acclimation period:no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C):20-22
- Humidity (%):48-66%
- Air changes (per hr):no data
- Photoperiod (hrs dark / hrs light):12-h light/dark photoperiod

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on exposure:
From day 6 through day 15 of gestation, groups of dams (25 per treatment group) were intragastrically treated once per day with the test substance administered in peanut oil. Control rats received peanut oil only. Dose volume administered was 2 ml/kg/day (adjusted for body weight). Dosages tested were 0 (Group 1), 1 (Group 2), 5 (Group 3), and 25 (Group 4) mg/kg/day.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the test substance were analyzed for content at the start and at termination of the treatment period. Measured concentrations ranged from 34 to 149% of the nominal concentrations.
Details on mating procedure:
Sexually mature male and female Han-Wistar SPF rats were obtained in-house frp, Schering AG. Animals were mated and females were examined for the presence of sperm. The day sperm was detected in the vaginal smear was considered day 0 of pregnancy. Dam body weights on day 0 ranged from 171 to 237 g.
Duration of treatment / exposure:
days 6-15 of gestation
Frequency of treatment:
once/day x 10 days
Duration of test:
21 days
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
The general condition of the dams was observed at least daily from day 0 to day 21 of gestation. Individual body weights were recorded on days 0, 6, 15, and 21. Dams were examined at autopsy for macroscopic and pathological changes.
Ovaries and uterine content:
The number of corpora lutea in each ovary was recorded, as well as the number and uterine positions of implantation sites, living and dead fetuses, and early and late resorptions.
Fetal examinations:
Viable fetuses were individually weighed and sexed. All fetuses were examined for gross external anomalies. Structural deviations (arising during prenatal development) were classified with regard to the degree of the changes and to the possible consequences for functional disturbances.
Major anomalies (malformations) were defined as "severe congenital changes of the structure of organs, organ systems, or the whole body, not being transient and impairing the usual function, the health or even the survival of the affected individual. They seldom occur in control fetuses." Minor anomalies were defined as "slight to moderate congenital structural changes being mostly reversible and obviously without detriment to the individual. They occur frequently in control fetuses."
Variations were defined as "slight common congenital structural changes being reversible in nearly all cases and not causing functional limitations in the individual. They occur regularly in control fetuses."
Fetuses were examined at autopsy for macroscopic and pathological changes.
Statistics:
Mean values, group mean values, standard deviations, and reproductive indices were determined. Group mean calculations were normally based on individual data, except for group mean fetal weights. The litter was used as the statistical unit for calculation of fetal values. Dunnett-Test was used for multiple comparisons with the control group and for evaluating differences between group sizes. Analysis of Variance (ANOVA) and, if necessary, Scheffe-Test, was used to assess differences in adult and fetal body weights, adult body weight changes, and mean numbers of copora lutea, implantations, and fetuses.
Multiple Chi-Square Test and, if necessary, Fisher's Exact Test, were used over all groups to evaluate qualitative findings in dams, percentages of preimplantational loss, resorptions and post-implantational loss, sex ratio, percentage of anomalous fetuses in each treatment group, incidence of specific skeletal minor anomalies and variations, and percentage of unossified feet bones.
The Kruskal-Wallis Test was used to evaluate medians and quartiles of percentages of preimplantation loss, resorptions and post-implantational loss per dam (litter), and medians and quartiles of percentages of anomalous fetuses per litter and of unossified feet bone means per litter. The level of significance was p<=0.05.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Alopecia was observed in single animals of all four groups and was not attributed to treatment. There was a slight (nonsignificant) decrease in corrected body weight and corrected body weight gain from day 6 to day 21 in the high dose (25 mg/kg/day) group. This reduction was attributed largely to one single dam. Though clear-cut effects were found in only one dam of Group 4, the test substance was considered to induce marginal maternal toxicity at 25 mg/kg/day.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
There were no exceptional differences between the groups in regard to reproduction data. Fetal weights were comparable between all four groups. The only difference found was a statistically significant increase in the percentage of dead fetuses in Group 4. The seven dead fetuses in Group 4 all descended from one dam.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

The author concluded that "no adverse effects were observed up to the intermediate dose of 5 mg/kg/day whereas the high dose of 25 mg/kg/day produced marginal maternal toxic and embryo-fetolethal effects.  The latter dose was considered to represent the threshold dose with regard to  embryo-lethality."

Applicant's summary and conclusion

Conclusions:
At 25 mg/kg/day: slight but nonsignificant decrease in corrected body weight and corrected body weight gain of the dams indicating a marginal maternal toxic effect of the test substance.
The high dose group is not to evaluate since effects are seen on one dam only:
RAC opinion in RCOM 8 June 2012:
“Indeed there is only weak evidence on developmental effects from this rat study since dead fetuses were seen only from one dam.”
Thus no adverse effects which could be attributed to develomental toxicity are found.
Executive summary:

An embryotoxicity including teratogenicity study was carried out with Dioctyltin bis(IOMA) [CAS No. 26401-97-8]:Octyltin tris(IOMA) [CAS No. 26401-86-5] (80:20% mixture). Test doses were 1, 5 and 25 mg/kg bw/d and the test duration was 21 days. Suspected or definite compound-related changes noted included:

1 mg/kg/day: No substance-related effects.

5 mg/kg/day: No substance-related effects.

25 mg/kg/day: Slight but nonsignificant decrease in corrected body weight and corrected body weight gain of the dams indicating a marginal maternal toxic effect of the test substance. Significant increase in the percentage of dead fetuses remain from one dam.

RAC opinion in RCOM 8 June 2012:

“Indeed there is only weak evidence on developmental effects from this rat study since dead fetuses were seen only from one dam.”