Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
0.3 mg/kg bw/day
Additional information

All dibutyltin compounds degrade into dibutyltin and the appropriate ligand, and so on this basis, it is possible to read-across between the different dibutyltin compounds to address the toxicity to reproduction endpoints. As no toxicity to reproduction data are available for dibutyltin dilaurate this endpoint has been addressed by the submission of studies performed on dibutyltin dichloride and using read-across from these studies.In a single-generation reproduction screening study, any influence of dibutyltin chloride on reproduction occurred only at maternally toxic levels; a maternal NOAEL of ca. 0.3 mg/kg bw/day was estimated.

Summary of data:

The study, Waalkens-Berendsen, D. H. (2003), was performed in compliance with GLP and to the OECD guideline 421. Accordingly the study was assigned a reliability score of 1 and considered reliable and adequate for assessment. The study a single-generation reproduction screening study, noted that any influence of dibutyltin chloride on reproduction occurred only at maternally toxic levels; a maternal NOAEL of ca. 0.3 mg/kg bw/day was estimated.


Short description of key information:
The following study has been submitted to address the toxicity to reproduction endpoint:

Waalkens-Berendsen DH (2003). Dibutyldichlorostannane (CAS # 683-18-1): Reproduction/developmental toxicity screening test in rats. Testing laboratory: TNO, Project Organisation, Ecotoxicology, Utrechtseweg 48, P. O. Box 370, 3700 AJ Zeist, The Netherlands. Report no.: V 4906. Owner company: Organotin Environmental Programme (ORTEP) Association, Stabilizer Task Force. Report date: 2003-12-04.

This study has been allocated a Klimisch score of 2 on the basis that it was performed to the appropriate guideline under GLP and the test material was a read-across substance for dibutyltin dilaurate.

Effects on developmental toxicity

Description of key information
The following studies have been submitted to address the developmental toxicity/teratogenicity endpoint:
Ema M & Harazono A (2000). Adverse effects of dibutyltin dichloride on initiation and maintenance of rat pregnancy.
Ema et al (1991). Teratogenicity of di-n-butyltin dichloride in rats.
Ema et al (1992). Susceptible period for the teratogenicity of di-n-butyltin dichloride in rats.
Ema et al (1995). Comparative Developmental Toxicity of Butyltin Trichloride, Dibutyltin Dichloride and Tributyltin Chloride in Rats.
Ema et al (1996). Comparative Developmental Toxicity of Di-, Tri- and Tetrabutyltin Compounds after Administration during Late Organogenesis in Rats
Noda T et al (1993). Teratogenic effects of various di-n-butyltins with different anions and butyl(3-hydroxybutyl) tin dilaurate in rats
Osterburg I (1993). Dibutyltin dichloride oral (gavage) teratogenicity study in the rat
Waalkens-Berendsen DH (2003) Dibutyldichlorostannane (CAS # 683-18-1): Reproduction/developmental toxicity screening test in rats
Osterburg (1993) has been allocated a Klimisch score of 2 as the study was conducted to recognised guidelines and GLP using dibutyltin dichloride to read-across to the substance in question.
All other references have been allocated a Klimisch score of 4.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
5 mg/kg bw/day
Additional information

As no adequate developmental toxicity studies are available on dibutyltin dilaurate, this endpoint has been addressed by the submission of studies performed on dibutyltin dichloride and using a read-across approach, with the available data on dibutyltin oxide as a supporting study. In several studies of development and teratogenicity, dibutyltin chloride as well as several other organotins were repeatably and reliably associated with a syndrome of malformations of the oroglossal region. Malformations appear to be limited to dose levels also associated with maternal toxicity; however, it is not clear how relevant maternal toxicity may be to the syndrome of malformations reported.

SUMMARY OF AVAILABLE DATA

Osterburg. I (1993) was performed in compliance with GLP and conducted according to the guideline OECD 414. The study was accordingly assigned a reliability score of 2 and considered adequate for assessment of the endpoint. The study was performed in Wistar rats, dosed via the oral route (gavage). The test material was determined to have a NOAEL of 1.0 mg/kg bw/day for maternal toxicity and 5.0 mg/kg bw/day for teratogenicity.

 

Seven studies were provided as supporting information and are briefly summarised below.

 

Reference: Ema M & Harazono A (2000)

Reliability and rationale for score: 2 (reliable with restrictions) Study meets generally accepted scientific standards, is well documented, and acceptable for assessment. Partial organogenetic period exposures.

Results: The study was conducted to evaluate the adverse effects of dibutyltin dichloride (DBTCl) on initiation and maintenance of pregnancy after maternal exposure during early pregnancy in rats. The NOAEL for maternal toxicity was determined to be <3.8 mg/kg/day and for teratogenicity was 15.2 mg/kg/day.

 

 

Reference: Ema et al (1991)

Reliability and rationale for score: 2 (reliable with restrictions) Study was conducted using less than the recommended number of animals (20). Purity of test material not reported. Doses were not adjusted for body weight reductions. Body weights were reduced in the two highest treatment groups; therefore, these animals may have received higher doses than reported. The number of fetuses examined for internal malformations was less than the EPA-recommended number. The two highest dose levels tested, 7.5 and 10 mg/kg, were generally lethal, killing 42% and 75% of the dams, respectively.

Results: Pregnant rats were given di-n-butyltin dichloride (DBT) by gastric intubation at a dose of 0, 2.5, 5.0, 7.5or 10.0 mg/kg on days 7-15 of pregnancy.The NOAEL for maternal toxicity was determined to be 5.0 mg/kg/day and for teratogenicity was 2.5 mg/kg/day.

 

 

Reference: Ema et al (1992)

Reliability and rationale for score: 2 (reliable with restrictions) Study meets generally accepted scientific standards, is well documented, and acceptable for assessment. Purity of test material not reported. Partial organogenetic period exposures.

Results: Pregnant rats were given di-n-butyltin dichloride (DBT) by gastric intubation at a dose of 20 mg/kgon days7-9,10-12 or 13-15 of pregnancy or at a dose of 20 or 40 mg/kg on day 6, 7, 8 or 9 of pregnancy.It could be concluded that, following maternal exposure to DBT in rats, developing offspring are not susceptible to teratogenic effects of DBT on day 6 and that day 7 is the earliest susceptible period, day 8 is the highest susceptible period and day 9 is no longer a susceptible period for teratogenesis of DBT.

 

 

Reference: Ema et al (1995)

Reliability and rationale for score: 2 (reliable with restrictions). Study meets generally accepted scientific standards, is well documented, and acceptable for assessment. Purity of test material not reported. Partial organogenetic period exposures.

Results: Butyltin trichloride (BT), dibutyltindichloride (DBT)and tributyltin chloride (TBT) were compared for their developmental toxicity including teratogenic potential following administration during the susceptible period for the teratogenesis of DBT. Pregnant rats were given DBT at a doseof 10or 15 mg/kgby gastric intubation on days 7and 8 of pregnancy.Treatmentwith DBT resulted in a significantly lower maternal weight gain, lower fetal weight and higher postimplantation embryo lethality. A significantly and markedly increased incidence of fetuses with malformations, such as exencephaly, cleft jaw, cleft lip, ankyloglossia, club foot, deformityofthe vertebral column in the cervical and thoracic regions and of the ribs and ano- ormicrophthalmia, was observedinboth groups treated with DBT.It could be concluded that BT, DBT and TBT are differentin thesusceptibility andspectrumof developmentaltoxicity.

 

 

Reference: Ema et al (1996)

Reliability and rationale for score: 2 (reliable with restrictions) Study meets generally accepted scientific standards, is well documented, and acceptable for assessment. Purity of test material not reported. Partial organogenetic period exposures.

Results: Dibutyltin dichloride (DBT), tributyltin chloride (TrBT) and tetrabutyltin (TeBT) were compared fortheir developmental toxicity and teratogenic potential following administration during the susceptibleperiod for teratogenesis of TrBT.

Pregnant rats were given DBT at a dose of 165 or 330µmol/kg on days 13-15 of pregnancy. The findings of the study suggest that DBT has no teratogenic effect when administered during late organogenesis at doses that induced overt maternal toxicity.It could be concluded that there is a difference in the manifestationand degree of developmental toxicity between DBT, TrBT and TeBT.

 

 

Reference: Noda T et al (1993)

Reliability and rationale for score: 2 (reliable with restrictions) The number of animals and dose groups used in this study were less than the recommended amounts in OECD Guideline 414. Study meets generally accepted scientific standards, is well documented, and acceptable for assessment. Partial organogenetic period exposures.

Results: In the oral (gavage) teratogenicity study in the rat the test material was determined, not to be toxic maternally, but was teratogenic to developing fetuses. The NOAEL is therefore 24.3 mg/kg for maternal toxicity and <24.3 mg/kg for teratogenicity.

 

 

Reference: Waalkens-Berendsen DH (2003)

Reliability and rationale for score: 2 (reliable with restriction) The study was performed in compliance with GLP and in accordance with the guideline OECD 421.

Results:In the Reproduction/developmental toxicity screening test in rats (TNO study number: V 4906) the test material was determined to have a NOAEL for general toxicity established on the low-dose level of 5 mg/kg diet and the NOAEL for reproductive toxicity was established at the mid-dose level of 30 mg/kg diet. No mortalities were observed. No clinical signs were observed in the male and female animals from the start of the study until sacrifice. Examination of the thymus revealed severe to very severe lymphoid depletion in 12/12 high-dose females, and moderate to severe lymphoid depletion in 6/12 (pregnant) mid-dose females.Three females showed late resorptions (autolytic fetuses) in the uterus during necropsy.

Justification for classification or non-classification

Based on animal data according to Directive 67/548/EEC the substance is assigned to Reproductive category 2 and is labelled with R60 – may impair fertility and R61 – may cause harm to the unborn child. Under GHS the substance is assigned to category 1B (Signal word: Danger; Hazard statement: H360 May damage fertility or the unborn child (Characteristic syndrome of oropharyngeal malformations).