Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproduction/Developmental Toxicity Screening Test

According to Annex VIII of Regulation (EC) No 1907/2006 as amended with COMMISSION REGULATION (EU) 2015/282 of 20 February 2015 the Reproduction/Developmental Toxicity Screening Test (OECD 421) does not need to be conducted if a Prenatal Development Toxicity Study (OECD 414) is available.

Therefore no OECD 421 study was conducted with the registered substance as a OECD 414 study from the read- across substance Bis(2-propylheptyl) hexanedioate was available.

 

Extended one-generation study

REACH allows the assessment of the reproductive toxicity of a given chemical with the help of findings from studies with repeated administration. This is in line with the idea that the information requirements under REACH are regarded as the evaluation of endpoints which does not necessarily require data from specific studies.

The read-across substance Bis(2-propylheptyl) hexanedioate was tested in a 90 day repeated dose study (BASF SE 2015) and a prenatal develeopmental toxicity study (WIL 2015). None of these studies showed any concern regarding reproductive toxicity of the read-across substance and thereby indicating no concern for the test substance. Thus, an extended one-generation study is not necessary. This waiving argument is in line with the guidance document R7a and scientifical argumentation as below.

 

Because of a high correlation, histopathology data and organ weights from repeated dose studies may be used to assess male fertility (Mangelsdorf et al. 2003). These parameters, taken from 90 day studies, were in fact shown to be more sensitive than fertility parameters that were measured during multi-generation studies. It could also be shown that exposure for 4 weeks suffices for an assessment of male fertility, although 90 day studies have been regarded as superior in the past because they cover a complete cycle of spermatogenesis (Mangelsdorf et al. 2003). If such a 28 day study shows neither relevantly elevated testis or ovary weights nor histopathological alterations in those organs, the weight of the evidence is that effects on reproduction are also not expected (BAuA Forschungsbericht Fb 984, 2003). A comparison of more than one hundred 90 day studies with two-generation studies that used the same test substance additionally showed that the NOAELs differed by less than the variation limit of studies, i.e. a factor of two (Janer et al. 2007). Therefore, the information gained from an extended one-generation study can be regarded as minimal if a 90 day study has been performed.

 

The available information for the read-across source chemical is considered appropriate for assessement of the reproduction toxicity hazard attributed to the target chemical. An extended 1-generation toxicity study for the test substance is therefore not considered required.

 

References

 

BAuA (2003). Extrapolation from results of animal studies to humans for the endpoint male fertility. Forschungsbericht Fb 984.

 

Janer G, Hakkert BC, Piersma, AH, Vermeire T, Slob W (2007). A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reproductive Toxicol 24: 103-113

 

Mangelsdorf I, Buschmann J, Orthen B (2003). Some aspects relating to the evaluation of the effects of chemicals on male fertility. Reg Toxicol Pharmacol 37: 356-369

Effects on developmental toxicity

Description of key information
The read-across substance Bis(2-propylheptyl) hexanedioate was tested in a prenatal developmental toxicity study according to OECD test guideline 414 (WIL 2015). Pregnant rats were treated via oral gavage with doses up 600 mg/kg bw/d. The NOAEL of the study was 200 mg/kg bw/d for maternal and developmental toxicity.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Due to a lack of experiments with the test substance and the existence of a structural analog (read-across substance) part of or the complete data was derived from the read-across substance. For details on the read-across reliability please refer to IUCLID Section 13. 

The read-across substance Bis(2-propylheptyl) hexanedioate was tested in a prenatal developmental toxicity study according to OECD test guideline 414 (WIL 2015). Pregnant rats were treated with doses of 0, 60, 200 or 600 mg/kg bw/d via oral gavage from gestation day 6 to 20 (inclusive). Females at 200 and 600 mg/kg bw/d showed higher absolute and/or relative liver weights. Relative liver weights were increased with approximately 7 and 22 % at 200 and 600 mg/kg bw/d, respectively. Clinical biochemistry examinations revealed decreased total protein and higher urea levels in high dose dams. At this dose level, the changes in clinical biochemistry parameters and liver weights were considered to be adverse treatment-related effects. The liver was also shown to be the target organ of the read-across substance in a 90d study (BASF SE 2015) were the highest tested dietary levels of 12000 ppm for males (corresponding to 875 mg/kg bw/d) and 15000 ppm for females (corresponding to 1361 mg/kg bw/d) caused changes in respective clinical biochemistry parameters as well as increased absolute and relative liver weights and diffuse hepatocellular hypertrophy indicating a liver cell swelling because of liver enzyme induction. At 600 mg/kg bw/d, the highest tested dose in the prenatal toxicity study where marked maternal toxicity was observed, the read-across substance caused reduced fetal body weights (approximately 8 % lower than concurrent control) along with a correspondingly higher incidence of reduced ossification parameters. An increase in unossified metacarpal(s) and/or metatarsal(s) was the most pronounced effect and an increase in reduced ossification of the skull also occurred, but to a lesser degree. An increase in skeletal variations at 600 mg/kg bw/day that were not body weight dependent included increased incidence of 14th rudimentary rib(s), 14th full rib(s), 7th cervical rudimentary rib(s), and caudal shift of the pelvic girdle. These effects indicate a generalized delay in ossification, a well documented effect often associated with maternal toxicity of various different mechanisms and/or affected homeostasis (Carney and Kimmel 2007). In the present study, increased maternal liver weights and changes in clinical chemistry parameters indicate an adversely disturbed liver homeostasis. As concluded by Carney and Kimmel (2007) a generalized delay in ossification is expected to be readily repairable during early postnatal development and is not mechanistically linked to malformation. Furthermore, the observed developmental effects occurred associated with maternal toxicity and are therefore not considered as specific developmental toxicity. There were no treatment-related effects on fetal external, visceral or skeletal malformations, on external and visceral variations and on litter size, male/female ratios and placenta weights up to and including 600 mg/kg bw/day. No developmental toxicity was observed in the 60 and 200 mg/kg bw/day groups. Thus, the NOAEL for maternal and developmental toxicity under the conditions of this study was 200 mg/kg bw/d.

 

References:

Carney EW and Kimmel CA, Interpretation of skeletal variations for human risk assessment: delayed ossification and wavy ribs, Birth Defects Research (Part B) 80:473 -496 (2007)


Justification for selection of Effect on developmental toxicity: via oral route:
Most reliable study with the read-across substance

Justification for classification or non-classification

The available developmental toxicity data for the read-across substance do not trigger classification for reproduction or developmental toxicity according to Regulation (EC) No 1272/2008 (CLP, GHS) as amended for the seventh time in Regulation (EC) No 2015/1221.