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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

The following studies have been submitted to address the developmental toxicity/teratogenicity endpoint:

Manjunath (2016) Prenatal Developmental Toxicity of DBTE administered orally by gavage to Sprague Dawley rats.

The study has been conducted on a structural similar substance (DBTE) which shows in a simulated gastric hydrolysis study similar metabolites

The following studies on DBTC have been disregarded, since an in-vitro metabolism study could show that DBTC is not a valid surrogate for the registered substance

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

Effects on developmental toxicity

Description of key information
 The following studies have been submitted to address the developmental toxicity/teratogenicity endpoint:
    
    

Manjunath (2016) Prenatal Developmental Toxicity of DBTE administered orally by gavage to Sprague Dawley rats.

The study has been conducted on a structural similar substance (DBTE) which shows in a simulated gastric hydrolysis study similar metabolites

The following studies on DBTC have been disregarded, since an in-vitro metabolism study could show that DBTC is not a valid surrogate for the registered substance

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

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 as the test material. Noda et al (1993), was allocated a Klimisch score of 2 on the basis that the number of animals and dose groups were less than the recommended amounts in OECD Guideline 414 and there were partial organogenetic period exposures. The study meets generally accepted scientific standards, is well documented, and acceptable for assessment. The Osterburg study was selected as the key study for this endpoint as the methodology is more comprehensive in studying developmental effects.
All other references have been allocated a Klimisch score of 4.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
8.5 mg/kg bw/day
Additional information

Based on experimental studies, all dibutyltin compounds are assumed to degrade into dibutyltin and the appropriate ligand (in gastric conditions, dibutyltin dichloride), on this basis, it is possible to read-across between the different dibutyltin compounds to address in vivo toxicity endpoints.

As no adequate developmental toxicity studies are available on the registration substance, this endpoint has been adressed 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, 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/kg on days 7-9,10-12 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 dose of 10 or 15 mg/kg by gastric intubation on days 7 and 8 of pregnancy. Treatment with 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, deformity of the vertebral column in the cervical and thoracic regions and of the ribs and ano- ormicrophthalmia, was observed in both groups treated with DBT. It could be concluded that BT, DBT and TBT are different in the susceptibility and spectrum of developmental toxicity.

  

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 330 µmol/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 manifestation and 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

The substance is classified with Repro. Cat. 2; R60 -61 according to Directive 67/548/EEC. According to Regulation (EC) no 1272/2008 the test substance would be classified as a Repr. 1B with Hazard statement: H360FD: May damage fertility or the unborn child and should be accompanied with the signal word 'Danger'.

Additional information