2-ethylhexyl 10-ethyl-4,4-dioctyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate

Toxicity to reproduction

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

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dioctyltin bis(IOMA) [CAS No. 26401-97-8]:Octyltin tris(IOMA) [CAS No. 26401-86-5] (78.8:16.9% mixture)

IUPAC Name:

Dioctyltin bis(IOMA) [CAS No. 26401-97-8]:Octyltin tris(IOMA) [CAS No. 26401-86-5] (78.8:16.9% mixture)

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 or test system 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 generation)

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

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.