Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

The weight of evidence (WoE) assessment summarized here and provided in full as an attachment in IUCLID Section 13 (Reproductive toxicty WoE assessment), in accordance with the provisions of Annex XI section 1.2, was developed to justify the Registrant’s ultimate decision on the need to perform or to not perform a two-generation reproductive toxicity test, or whether to conduct the same in a second species for the registered substance,hydrogenated dimerization products of 1-octene, 1-decene, and 1-dodecene,as set out in Annex IX, section 8.7.3 columns 1 and 2, respectively. 

All of the evidence presented below to support the Annex X section 8.7.3 columns 1 and 2 information requirements should be considered in totality as part of an adaptation of the required standard information set out in Annex VII-X according to the general rules contained in Annex XI section 1.2. The information should not be considered on an individual basis when determining its adequacy. When considered in totality, the combined evidence is appropriate and adequate to draw a conclusion about the properties or the potential effects of the registered substance for this endpoint. Based on the weight of evidence, the registered substance is not expected to be a reproductive hazard and no new information will be gained through additional animal testing.

As REACH Annex X, 8.7.3. does not have a specific adaptation requirement as prescribed in Column 2, and REACH requires that all standard requirements of Annexes VII-IX applies in conjunction to Annex X, the Registrant refers to Annex IX, section 8.7.3 column 2, which states:

 the study shall be initially performed in one species. A decision on the need to perform a study at this tonnage level or the next on a second species should be based on the outcome of the first test and all other relevant available information.” 

Regarding the column 2 information requirement, ECHA’s Endpoint Specific Guidance (R.7.6.6.3) states that “the two-generation study is very rarely conducted in a species other than the rat, and it is envisaged that a second species study could not be justified.”

The preambles of Annex IX and X of REACH indicate it is the Registrant’s responsibility to conduct such assessment on the basis of the results of the first test and all other relevant available information, decide whether a 2 -generation reproductive toxicity test in a second species for this particular registered substance is justified or not.

The assessment made in this document contains a robust scientific assessment, which has been carried out with relevant and accurate Weight of Evidence (WoE). This Weight of Evidence is provided in accordance with the provisions of Annex XI section 1.2 and the useful Guidance documents on Adaptation of Information Requirements (Chapter R.5; September, 2011) and on Endpoint Specific Guidance (Chapter R.7a; August, 2013) developed by ECHA.

Based on the assessment detailed in this document and incorporated into IUCLID, the Registrant concludes that in accordance with REACH Guidance on WoE (R.5.2.1.2) it has provided a rationale to show that this information adequately describes the endpoint of concern. Therefore, the information requirement of a PNDT test in a second species is fulfilled by this WoE; there is no scientific need to perform a PNDT in a second species for the registered substance. The justification to support this decision is presented in this document.

Specifically, the WoE assessment supports the following to be true:

            the hypothesis that the registered substance, hydrogenated dimerization products of 1-octene, 1-decene, and 1-dodecene, a UVCB substance comprised of alkanes in the range C16-C24, is not a developmental toxicant,

            that the potential reproductive hazards to humans are adequately characterized,

            that reproductive toxicity testing in a second species would not be expected to further inform human health risk assessment

The WoE documentation provided herein offers a thorough consideration of all of the available information, which when assessed separately may be considered insufficient to support the conclusion, but together form the basis for the conclusion that there is no scientific need to perform a PNDT in a second species for the registered substance.

The following summarizes the approach offered to justify this position. 

1)     Assessment of chemical-specific and read across ADME and toxicity data in rats

a)           The homologous series of alkanes having a total of 8 to 60 carbons (C8-C60) that comprise the source and target substances possess similarities of chemical structure and physicochemical, toxicokinetic, and toxicological properties that provide a scientific basis for read across 

b)           Data from reproductive toxicity, developmental toxicity, repeat dose and genotoxicity studies are presented to demonstrate a similar lack of toxicity among all studies within the homologous series

c)           Based on available information on substances in this homologous series of alkanes, the repproductive toxicity potential for the registered UVCB substance (composed of alkanes ranging from C16-C24. with ≥85% of the final product consisting of C20 or C22 alkanes) can be predicted from the larger database of C8-C60 alkanes, based on interpolation.

2)     Assessment of chemical-specific and read across ADME and toxicity data across species

a)           Toxicokinetic, repeat dose and human studies were assessed to determine if there is any indication that data generated in the rat would not be protective of human health

b)           Ample evidence supports that both the toxicokinetic and toxicological behavior of C8-C60 alkanes are consistent across species, including humans. Based on this consistency, the rat is deemed a suitable model to assess the potential developmental hazards to humans. Based on this consistency, the rat is deemed a suitable model to assess the potential reproductive hazards to humans.

In summary, it is the Registrant’s scientific opinion that this WoE assessment leads to the conclusion that reproductive testing is not scientifically necessary and, therefore, would be an unnecessary use of animals. 

Furthermore, the section 8.7.2., Column 2 assessment leads to the conclusion that 2-generation reproductive toxicity testing in a second species is not scientifically justified for the registered substance. On the basis of this information, conducting such a study would not be in accordance with Article 25 of REACH[2]. 

Adequate and reliable documentation for works cited include robust study summaries within the dossier with attachments appended to IUCLID section 13, where applicable. 

For complete documentation of the WoE to address Annex X 8.7.3 columns 1 and 2, please refer to "Reproductive Toxicity WoE Assessment", attached in IUCLID section 13.

Effects on developmental toxicity

Additional information

This document provides the assessment for the registered substance,hydrogenated dimerization products of 1-octene, 1-decene, and 1-dodecenein accordance with the standard requirement, as set out in Annex X, section 8.7.2 column 1 of REACH, prenatal developmental toxicity study,secondspecies. The Registrant has already fulfilled the standard requirement of prenatal developmental toxicity study, one species, which was accepted by ECHA in the final decision dated 6 November 2012.

 

The assessment made in this document contains a robust scientific assessment, or Weight of Evidence (WoE), that is provided in accordance with the provisions of Annex XI section 1.2 and the useful Guidance documents on Adaptation of Information Requirements (Chapter R.5; September, 2011) and on Endpoint Specific Guidance (Chapter R.7a; August, 2013) developed by ECHA.

Based on the assessment detailed in this document and incorporated into IUCLID, the Registrant concludes that in accordance with REACH Guidance onWoE(R.5.2.1.2) it has provided a rationale to show that this information adequately describes the endpoint of concern. Therefore, the information requirement of a PNDT test in a second species is fulfilled by thisWoE; there is no scientific need to perform a PNDT in a second species for the registered substance.The justification to support this decision is presented in this document.

Specifically, theWoEassessment supports the following to be true:

·        the registered substance,hydrogenated dimerization products of 1-octene, 1-decene, and 1-dodecene, a UVCB substance, is composed of alkanes[1]in the range C16-C24, is not a developmental toxicant

·        that the potential developmental hazards to humans are adequately characterized

·        that developmental toxicity testing in a second species would not be expected to further inform human health risk assessment

TheWoEdocumentation provided herein offers a thorough consideration of all of the available information, which when assessed separately may be considered insufficient to support the conclusion, but together form the basis for the conclusion that there is no scientific need to perform a PNDT in a second species for the registered substance.

The assessment on the need to perform a PNDT study is elaborated in the next chapters and comprises the following key elements:

I.       Assessment of peer-reviewed literature on the concordance of PNDT tests across species

A.     Approach[2]:

1-     Assess literature discussing species concordance in PNDT studies

2-     Evaluate concordance between species based on historical datasets and available information.

3-     Determine concordance of 314 PNDT studies from the US EPA’sToxRefDBand IRIS databases

B.     Conclusions:

1-     Species concordance may have historically been underestimated

2-     Neither rat nor rabbit[3]are inherently more sensitive to developmental toxicants

3-     Where it has been observed for a small fraction of chemicals, species-dependent sensitivity is attributed to chemical-specific biochemical interactions

4-     Rat/rabbit species concordance is 90% based on the subset of chemicals in EPA’sToxRefDBand IRIS

II.     Assessment of chemical-specific and read across substance ADME and toxicity data 

A.     Approach:

1-     Develop and articulate the read across hypothesis and justification

2-     Assess existing hazard data for the registered substance and read across substances to inform developmental toxicity hazard potential for the registered substance

3-     Assess the available developmental toxicity endpoint information from read across substances in multiple species and humans

B.     Conclusions:

1-     The homologous series of alkanes having a total of 8 to 60 carbons (C8-C60) that comprise the source and target substances possess similarities of chemical structure and physicochemical, toxicokinetic, and toxicological properties that provide a scientific basis for read across 

2-     Based on available information on substances in this homologous series of alkanes, the developmental toxicity potential for the registered UVCB substance (comprised of alkanes ranging from C16-C24. with ≥85% of the final product consisting of C20 or C22 alkanes) can be predicted from the larger database of C8-C60 alkanes, based on interpolation.

3-     Ample evidence supports that both the toxicokinetic and toxicological behavior of C8-C60 alkanes are consistent across species, including humans. Based on this consistency, the rat is deemed a suitable model to assess the potential developmental hazards to humans.

III.   Uncertainty analysis according to Substance-tailored exposure-driven testing approach

Even though the aspects of theWoEsummarized above robustly support the hypothesis that the substance is not a developmental toxicant and that testing in a second species is not necessary, to address remaining actual or perceived uncertainty due to not conducting a second species test, a substance-tailored exposure-driven assessment was used to assess uncertainty. This was carried out according to ECHA guidance[4],[5].

A.     Approach:

1-     A reference value (here called a “reference DNEL”;rDNEL) was developed, conservatively accounting for uncertainty that may exist as a result of not having conducted a test in a 2nd species.

2-     All relevant exposures for uses of the substance were assessed and “reference risk characterization ratios” were calculated

B.     Conclusions:

1-     By utilizing the lower 95thconfidence interval as the point of departure, which assumes the second species has greater sensitivity, the Registrant accounts for uncertainty that may exist as a result of not having conducted a test in a 2ndspecies. By applying this conservatively health protective approach,arDNELwas derived, an exposure assessment was conducted and reference risk characterization ratios were calculated. 

2-     The results of the conservatively derived risk characterization indicate that exposures to the substance are always well below therDNELfor consumer and professional populations (RCR0.001) and below therDNELin industrial settings (RCR range <0.001 – 0.57).   

In summary, it is the Registrant’s scientific opinion that thisWoEassessment leads to the conclusion that PNDT testing in a second species is not scientifically necessary for this particular registered substance. On the basis of this information, conducting such PNDT testing for the specific non-hazardous registered substance would not be in accordance with Article 25 of REACH[6]. 

Adequate and reliable documentation for works cited include robust study summaries within the dossier with attachments appended to IUCLID section 13, where applicable. 

For complete documentation of the WoE to address Annex X 8.7.2, please refer to "Developmental toxicity, 2ndspecies Weight of Evidence Assessment ", attached in IUCLID section 13.

 


[1]An alkane, or paraffin, is a saturated hydrocarbon. Alkanes consist only of hydrogen and carbon atoms, all bonds are single bonds (i.e. fully saturated).

[2]European Teratology Meeting 2013.Foreman J.E., Kung M.H., and Minsavage G.D. Weight of evidence considerations for determining the necessity of a prenatal developmental toxicity study (OECD 414) in a second species within the REACH framework.Reproductive Toxicology Volume 41 (2013).

[3]Because ECHA imposed in its final decision of 6 November 2012 to conduct the PNDT in rabbit, the assessment is merely focused on rabbit as a species.

[4]How to bring your registration dossier in compliance with REACH – Tips and Hints (part 3) 14 May 2013 (ECHA)

[5]European Teratology Meeting 2013.Foreman J.E., Kung M.H., and Minsavage G.D. Weight of evidence considerations for determining the necessity of a prenatal developmental toxicity study (OECD 414) in a second species within the REACH framework.Reproductive Toxicology Volume 41 (2013).

[6]See alsoBoA, ECHA versus Honeywell Belgium NV, A-005-2014,29April 2013.

Justification for classification or non-classification

The provided data in combination present a reasonable weight of evidenceto support a rational judgment regarding hazard identification, classification and labeling, and risk assessment for the registered substance. Based on these data, the registered substance is not expected to be a reproductive toxicant. Therefore,the registered substance does not meet the criteria for classification as a repeated dose toxicant under the EU Dangerous Substances Directive 67/548/EEC or CLP EU Regulation 1272/2008.