Registration Dossier

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP Guideline study (OECD 416). 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:
1997
Report Date:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction 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] (78.8:16.9% mixture)
-oily liquid, insoluble in water.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Rats (Sprague-Dawley [Tif:RAIf (SPF)] obtained from Lippische Versuchstierzucht Hagemann GmbH.
Animals were individually caged (except during mating) and maintained at a temperature of 22 +/- 2 deg. C, a relative humidity of 50 +/- 15%, and a
12-h light/12-h dark photoperiod (~150 lux).

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
no
Details on mating procedure:
not reported
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Duration of dosing of F0 generation
males - 10 weeks prior to mating, during mating (3 weeks), and post mating until sacrifice;
females - 10 weeks prior to mating and during mating.
Mated females continued to receive test diets during gestation and lactation; unmated females received test diets until sacrifice. Test diets were prepared weekly and analyzed for homogeneity and stability.

Duration of dosing of F1 generation:
males - 14 weeks (starting at the end of lactation prior to mating), during mating (3 weeks), and post mating until sacrifice;
females - 14 weeks (starting at the end of lactation prior to mating) and during mating (3 weeks).
Frequency of treatment:
continuously (in diet)
Doses / concentrations
Remarks:
Doses / Concentrations:
20, 60, and 200 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
25 male/25 female Rats per group
Control animals:
yes, concurrent no treatment
Details on study design:
no
Positive control:
no

Examinations

Parental animals: Observations and examinations:
Animal behavior and general condition were observed daily. Food consumption was recorded at 2-3 day intervals. Body weights were measured weekly.
The following parameters were determined: mean pre-coital time, mean duration of pregnancy, number of pups (live and dead), sex of pups, number of stillbirths, number of runts, number of pups with malformations, and pup body weights.
All animals, including pups, were necropsied (males and dams after weaning; pups on day 22, except those used as parents for the subsequent generation). The number of implantation scars on the endometrium was recorded in all parental females. Uteri of non-pregnant females were examined.
Oestrous cyclicity (parental animals):
no
Sperm parameters (parental animals):
no
Litter observations:
Functional tests (mid-air righting reflex, auditory startle reflex, and pupillary reflex) were performed on all pups. Morphological examinations (pinna detachment, ear opening, eye opening, testicular descent, and vaginal opening) were recorded for all pups.
Postmortem examinations (parental animals):
The following organs and tissues were collected and examined from all parental animals: all gross lesions, ovary, uterus, cervix, vagina, testis, epididymis, seminal vesicle with coagulation gland, prostate, spleen, thymus, iliac lymph node, mammary gland, pituitary, adrenals, and thyroids. Organs and tissues were examined histopathologically.
Postmortem examinations (offspring):
The following organs and tissues were collected and examined from one male and one female pup from each F1 and F2 litter at necropsy: spleen, thymus, iliac lymph node. The following organ weights were recorded in all parental F0 and F1 animals: ovary, uterus, testis, pituitary, adrenals, thyroid, spleen, thymus, iliac lymph node. The following organs weights were recorded in one male and one female pup from each F1 and F2 litter: spleen, thymus, iliac lymph node. Organs and tissues were examined histopathologically.
Statistics:
no data
Reproductive indices:
no data
Offspring viability indices:
no data

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

No substance-related mortality or changes in behavior or external appearance.
Body weights were comparable to the control group.
The absolute food consumption of female rats in the 200 ppm dose group was lower than the controls (-6% on lactation days 7-14, -9% on lactation days 14-21). Concentrations of 20 and 60 ppm in the diet did not influence the reproduction parameters. However, at 200 ppm in the diet, there was a slight increase in pup mortality, and a significant difference in the viability index at day 4 of lactation and in the lactation index after 21 days lactation.
The body weight of pups from dams treated with 200 ppm test substance was significantly decreased for males and females after 14 and 21 days lactation. Functional tests and morphological landmarks revealed no substance-related findings at 20 and 60 ppm in the diet.
At 200 ppm, vaginal opening was slightly delayed. No substance-related pathological findings were observed. Organ weights at 20 ppm were comparable to the control. At 60 ppm, parental males had a slightly decreased relative thymus weight. At 200 ppm, the relative thymus weights of males and females were significantly decreased.
The incidence of thymic involution was significantly increased in males at 200 ppm. No substance-related pathological findings were observed.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
20 ppm
Sex:
male/female
Basis for effect level:
other: based on a reduction in the relative thymus weight of males

Results: F1 generation

General toxicity (F1)

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

Details on results (F1)

No substance-related mortality, changes in behavior, or in external appearance.  At 20 and 60 ppm, body weights were comparable to controls.  
At 200 ppm in the diet, the body weight of males was significantly lower during the pre- and post-mating phase.  The body weight of females at 200 
ppm was comparable to the control.  There was a significant reduction in food consumption of females at 200 ppm during lactation.  
Concentrations of 20 and 60 ppm in the diet did not influence the reproduction parameters.  

At 200 ppm, there was an increase in the number of stillbirths (26 vs. 5 in the control group). There was a slight increase in stillbirths at 60 ppm.
At 200 ppm in the diet, pup mortality increased during lactation; the viability index decreased (82.0% vs. 85.7% controls); pup body weight decreased; pinna unfolding and eye and ear opening were slightly delayed; and there was a slight increase in the number of negative findings of the auditory startle reflex. No substance-related pathological findings were observed.
At 60 ppm, there was a slight decrease in the relative thymus weights; significant for females only. At 200 ppm, the relative thymus weights were significantly decreased in both sexes, and the relative spleen weight of females was significantly decreased. F2 generation: Organ weights were comparable to the control group. No histopathological changes were observed. No teratogenic effect was observed.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
20 ppm
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL for a DOT(IOMA)/MOT(IOMA) mixture was 20 ppm for the F0 parental generation (effects on thymus weight) and for the F1 generation the NOAEL was 20 ppm (based on a decrease in relative thymus weights in male and female pups, a slight decrease in the relative thymus weight of males and an increase in stillbirths at 60 ppm). No teratogenic effects were observed.
Executive summary:

An OECD Guideline 416 (Two-Generation Reproduction Toxicity Study) was carried out with the mixture Dioctyltin bis(IOMA) [CAS No. 26401-97-8]:Octyltin tris(IOMA) [CAS No. 26401-86-5] (78.8:16.9% mixture); Rats were exposed to 20, 60 and 200 ppm in the diet . An untreated control group was tested concurently. Various general toxicological parameters were studied as well as reproductive/developmental observations of parent animals and off-spring.

Under the experimental conditions, the NOAEL for the F0 parental generation was 20 ppm (~1.5 mg/kg bw/d), based on a reduction in the relative thymus weight of males at 60 ppm. No substance-related pathological findings were observed.

The NOAEL for the F1 generation until weaning was 20 ppm (~1.6 mg/kg bw/d), based on a decrease in relative thymus weights in male and female pups at 60 ppm. The NOAEL for the F1 generation post lactation was 20 ppm, based on a slight decrease in the relative thymus weight of males and an increase in stillbirths at 60 ppm. No teratogenic effect was observed.