Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

The reproductive NOAEL from the rat oral gavage O.E.C.D. 422 screening study is 1000 mg/kg/day. Consumer exposure to Vinyl Neononanoate is not anticipated. Therefore, a consumer DNEL is not required. The O.E.C.D. 416 "Two-Generation Reproduction Toxicity Study" as per REACH Annex IX, Section 8.7.3 is proposed in the analogue structure vinyl neononanoate.


Short description of key information:
Vinyl Neodecanoate was evaluated in a GLP, O.E.C.D. 422 Combined repeated-dose, developmental/reproductive toxicity study by the oral gavage route of administration. Based on the findings from this study Vinyl Neodecanoate is not a reproductive toxicant or developmental in laboratory rats. The NOAEL for adult animals and reproductive/developmental effects was the high dose of 1000 mg/kg/day.

Effects on developmental toxicity

Description of key information
It is concluded from the lack of developmental effects seen in the OECD 414 rabbit developmental toxicity study and confounding effects of maternal toxicity seen in the OECD 414 rat study that vinyl neononanoate is not classified as a reproductive/developmental hazard.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
High
Additional information

The read across test substance, vinyl neononoanoate was evaluated for the potential to cause developmental toxicity in an O.E.C.D. test guideline 414 study in the rat by the oral gavage route of exposure at dose levels of 0, 100, 300 and 600 mg/kg/day. The test substance, vinyl neononoanoate is a developmental toxicant in the rat at a matrnally toxic dose of 600 mg/kg/day. This is based upon findings of statistically significant (P < 0.01) increased % early resorptions and % post-implantation fetal loss, and decreased number of viable fetuses relative to control at the high dose level of 600 mg/kg/day. Substantial maternal toxicity was observed at 600 mg/kg/day basd upon clinical signs of neurotoxicty in 71% of the high dose animals. The maternal and embryo/fetal developmental NOAEL for this study was 300 mg/kg/day.

In this study all litters that showed more than 3 early resorptions were from dams that showed clinical signs of neurotoxicity including hypersensitivity, in many cases increased activity and in some cases abnormal gait and or tremors, either during or just before the time of implantation (typically GD 5-6 in Sprague-Dawley rats). The frequency of these signs and the fact one high dose female was sacrificed moribund due to severity leads to the conclusion that maternal toxicity at the high dose was excessive, confounding interpretation of any specific developmental toxicity. These maternal observations were made despite the absence of formal out-of- cage assessments of clinical signs or motor activity, which might have more clearly characterized the extent of neurotoxic signs. Autonomic nervous system parameters were not evaluated, although increased body temperature and heart rate are commonly seen with increased activity (Roche et al., 2007); as noted above increased activity was documented for a number of dams at 600 mg/kg bw/day during the pre-implantation period. Any of the hypothetical autonomic system effects resulting from maternal neurotoxicity could have adverse effects on embryo survival and/or successful implantation. Only a 1.5°C elevation of temperature above normal core temperature, during the pre-implantation period, can result in increased rates of embryonic death and resorption in a wide range of species (Bell, 1987).

Hood and Miller (2006) state there is little evidence generally for correlation between excessive maternal toxicity and specific fetal malformations. However, there seems to be more evidence that maternal toxicity can lead to decreased fetal weight and decreased ossification sites (Chernoff et al., 2008); minimal effects on both parameters were seen in the current study at the maternally toxic high dose. There is relatively little in the published literature relating to the relationship between maternal toxicity and early resorptions, although it is a reasonable supposition that this absence of literature may be due to the fact that many developmental toxicity evaluations are conducted during the period of major organogenesis starting at GD 6 after implantation is complete. (The OECD Guideline, in contrast, recommends dosing from GD 0 based on the presence of sperm in vaginal lavage or a sperm plug.) Interference with implantation can contribute to an increase in early resorptions. Alternatively increased maternal temperature, or other maternal autonomic nervous system changes hypothesized in the current study based on maternal clinical signs, may lead to embryonic or fetal mortality, resulting in resorption of implanted or implanting tissue.

In the absence of mechanistic data it is not possible to definitively ascribe the developmental toxicity seen in this study to maternal toxicity for classification purposes, which is consistent with the conclusions regarding classification based on maternal toxicity in Bayer et al. ( 2011). Clearly excessive maternal toxicity and the developmental toxicity were seen at the same exposure level in this study, and the severity of effects appears consistent, with a maternal moribund sacrifice and in some cases severe clinical signs of neurotoxicity correlating with increased early post implantation loss. Bayer et al. (2011) indicates that many classification decisions hinge on the relative severity of maternal and developmental effects; in this case they appear equally severe. The data suggest that the developmental toxicity would be unlikely to be seen in the absence of maternal toxicity, and a robust maternal and developmental NOAEL at a relatively high exposure level of 300 mg/kg bw/day throughout gestation is available for risk assessment.

 

Bell, A.W. (1987) Consequences of severe heat stress for fetal development. In: Heat Stress: Physical Exertion and Environment. J.R.S. Hales and D.A.B. Richards, eds. Amsterdam:Exerpta Medica, Elsevier Science, pp. 313–333.

Beyer, B.K., Chernoff, N., Bengt, R., Danielsson, K.D., Harrouk, W., Hood, R.D., Janer, G., Liminga, U., Kim, J.H., Rocca, M., Rogers, J. and Scialli, A.R. (2011) ILSI/HESI Maternal Toxicity Workshop Summary: Maternal Toxicity and Its Impact on Study Design and Data Interpretation.Birth Defects Research(Part B) 92:36–51

Chernoff, N., Rogers, E.H., Gage, M.I., Francis, B.M. (2008) The relationship of maternal and fetal toxicology bioassays with notes on the biological significance of the ‘‘no observed adverse effect level’’.Reprod Toxicol25:192–202.

Hood, R.D., Miller, D.B. (2006) Maternally mediated effects on development. In: Hood RD, editor. Developmental and reproductive toxicology, a practical approach. 2nd ed. Boca Raton: CRC Press. p 93–124.

Roche, M., Harkin A., .Kelly, J.P. (2007) Chronic Fluoxetine Treatment Attenuates Stressor-Induced Changes in Temperature, Heart Rate, and Neuronal Activation in the Olfactory Bulbectomized RatNeuropsychopharmacology

Female New Zealand White rabbits received Vinyl neononanoate orally once daily, at a dose of 30, 300 or 600 mg/kg/day, from Gestation Days 0 through 28 inclusive.Based on the above findings observed for the adult female at 600 mg/kg/day, which consisted primarily of reduced food consumption, reduced weight gain and subsequent euthanasia of several animals, No-Observed-Adverse-Effect-Level (NOAEL) for maternal exposure was considered to be 300 mg/kg/day. Since the fetal and litter incidences of increased early resorptions at doses of 30, 300 or 600 mg/kg/day were not statistically significant, the NOAEL for embryofetal development was also considered to be 300 mg/kg/day. No exposure-related teratogenicity was observed at doses of600 mg/kg/day.


Justification for classification or non-classification

Based on the available data, Vinyl Neodecanoate does not meet the criteria for Classification and Labeling as a Substance toxic to reproduction as per EU Directive 67/548/EEC Annex 6 and the CLP (Directive 1272/2008).