Alkenes, C6-11 (branched), hydroformylation products, distn. residues, heavy cracked fraction

Toxicity to reproduction

Administrative data

Endpoint:

extended one-generation reproductive toxicity - with F2 generation (Cohorts 1A, and 1B with extension)

Remarks:

based on test type (migrated information)

Type of information:

experimental study planned

Study period:

Study will be initiated following final approval from ECHA

Justification for type of information:

TESTING PROPOSAL ON VERTEBRATE ANIMALS
Extended One Generation Reproductive Toxicity Study (EOGRTS) OECD 443 including Cohorts 1A and 1B with extension to include a F2 generation

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: Alkenes, C6-11, hydroformylation products, distn. residues, heavy cracked fraction.

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
Based on the available toxicity data, it is unlikely that the substance identified as Alkenes, C6-11, hydroformylation products, distn. residues, heavy cracked fraction would have any effect on fertility, however, the existing information do not meet the criteria established by Echa for providing an adaptation to fulfill the information requirement under REACH.
The information submitted here is a non-confidential summary of the efforts that have been undertaken to justify the submission of a testing proposal and which are described in far greater detail in the document attached to the dossier.

- Available GLP studies
While assessing the endpoint of “reproductive toxicity”, there are 3 elements which need to be evaluated from different sources of data:
1. Reproductive Organ Effects (e.g. weight and pathological changes). These effects can be assessed in repeat-dose or reproductive toxicity tests.
2. Developmental Toxicity (e.g. fetal development and structural malformations), which can be assessed in classical developmental toxicity tests, or, to a certain extent, in reproductive toxicity tests, and
3. Fertility (e.g. mating, pregnancy, influence of gestational exposures), which can be fully assessed in multi-generational studies with equivalent information provided by reproductive studies of other designs (e.g. a combination of 1-generation reproductive toxicity studies combined with repeat-dose studies that evaluate spermatogenesis in males and all 4 stages of the estrus cycle in females).
An OECD Test Guideline 407: Repeated dose 28-day oral toxicity study in rodents on the registered substance found no effects on reproductive organs or organ weights up to a dose of 1,000 mg/kg/d.
A subchronic aerosol inhalation study of Alkenes, C6-10, hydroformylation products, high boiling (CAS# 68526 -82 -6) was conducted in 1987 similar to an OECD TG 412. Sprague-Dawley rats of each sex were exposed to atmospheres containing the test substance six hours a day, five days a week for 13 weeks. The target levels of test substance were 0, 100, 300, and 1000 mg/m3 and the achieved concentrations were very near target levels. No changes attributed to treatment in any organ system related to reproductive function were mentioned in the laboratory report although most reproductive organs from high dose and control animals underwent macroscopic and microscopic evaluation.
No available GLP studies for reproductive (OECD 415, 416, or 443) or developmental (OECD 414) toxicity are available for the substance.
Existing GLP study data does not meet the standard to fill the information requirement as information on reproduction is missing.
- Available non-GLP studies:
No data available
- Historical human data
Relevant epidemiological data on Alkenes, C6-11, hydroformylation products, dist. residues, heavy cracked fraction does not exist. Information is available for some constituents of the registered substance. Both linear and branched aliphatic alcohols are absorbed through the gastrointestinal tract and are rapidly eliminated from the blood in humans. Aliphatic acetals are utilized as flavoring agents and are routinely tested for safety by the Joint FAO/WHO Expert Committee on Food Additives. They are recognized as safe (as evaluated by the Procedure for the Safety Evaluation of Flavouring Agents) in dietary use, with combined daily dietary intake being less than 2% the threshold for concern of this structural class of substances (1.8mg/kg per day in humans). The structures evaluated by the WHO in this study also determined that at current levels of intake, none of the ten substances evaluated would be expected to saturate their metabolic pathways. The study report provided no evidence of steady-state levels of aliphatic acetals or their metabolites, which suggests that the acetal component of the registered substance would not reach steady-state in blood or organs in humans. The documented widespread use of aliphatic acetals for daily dietary consumption in humans is not linked to adverse effects and they are recognized as safe. Although human evidence for several constituents does not indicate toxicity, data for all constituents or the substance is not available.
- (Q)SAR
OECD QSAR Toolbox 3.4 was used to identify substances with similar functional groups. This approach failed to identify analogs with sufficient similarity to provide scientifically supportable read-across. Details are provided in the attached read across analysis document.
- In vitro methods
Substance-specific in vitro testing, included in the dossier, assessing mutatgenicity and clastogenicity in mammalian cells (mouse lymphoma L5178Y and human lymphocytes, respectively) indicate genotoxicity is not expected. Thus waiver of the reproductive endpoint based on known genotoxic carcinogen or mutagen is not appropriate.
- Weight of evidence
The existing data does not support a weight of evidence approach to fill data gaps for this endpoint.
- Grouping and read-across
Grouping and read across was not deemed appropriate. Details are provided in the attached read across analysis document.
- Substance-tailored exposure driven testing
Substance tailored exposure based waiver cannot be applied as a DNEL cannot be derived according to Annex XI, 3.2 (a)(ii), footnote 1 “For the purpose of subparagraph 3.2(a)(ii), without prejudice to column 2 of Section 8.7 of Annexes IX and X, a DNEL derived from a screening test for reproductive/developmental toxicity shall not be considered appropriate to omit a prenatal developmental toxicity study or a two-generation reproductive toxicity study. For the purpose of subparagraph 3.2(a)(ii), without prejudice to column 2 of section 8.6 of Annexes IX and X, a DNEL derived from a 28-day repeated dose toxicity study shall not be considered appropriate to omit a 90-day repeated dose toxicity study.”
- Approaches in addition to above [if applicable]
Not applicable
- Other reasons [if applicable]
Not applicable

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- An acceptable column 2 adaptation for reproductive toxicity study could not be formulated.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Additional details on study decision and testing proposal justification are provided in the attached testing proposal document.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

A tiered approach to life stages testing for agricultural chemical safety assessment

Author:

Cooper RL, Lamb JC, Barlow SM, Bentley K, Brady AM, Doerrer NG, Eisenbrandt DL, Fenner-Crisp PA, Hines RN, Irvine LF, Kimmel CA, Koeter H, Li AA, Makris SL, Sheets LP, Speijers G, Whitby KE

Year:

2006

Bibliographic source:

Crit Rev Toxicol. 2006 Jan;36(1):69-98. Review. PubMed PMID: 16708695.

Reference 2

Reference Type:

publication

Title:

A retrospective analysis of the two-generation study: what is the added value of the second generation?

Author:

Janer G, Hakkert BC, Slob W, Vermeire T, Piersma AH

Year:

2007

Bibliographic source:

Reprod Toxicol. 2007 Jul;24(1):97-102. Epub 2007 May 6. PubMed PMID: 17572063

Reference 3

Reference Type:

publication

Title:

Profiling the reproductive toxicity of chemicals from multigeneration studies in the toxicity reference database.

Author:

Martin MT, Mendez E, Corum DG, Judson RS, Kavlock RJ, Rotroff DM, Dix DJ.

Year:

2009

Bibliographic source:

Toxicol Sci. 2009 Jul;110(1):181-90. doi: 10.1093/toxsci/kfp080. Epub 2009 Apr 10. PubMed PMID: 19363143.

Reference 4

Reference Type:

publication

Title:

Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring.

Author:

Piersma AH, Rorije E, Beekhuijzen ME, Cooper R, Dix DJ, Heinrich-Hirsch B, Martin MT, Mendez E, Muller A, Paparella M, Ramsingh D, Reaves E, Ridgway P, Schenk E, Stachiw L, Ulbrich B, Hakkert BC.

Year:

2011

Bibliographic source:

Reprod Toxicol. 2011 May;31(4):392-401. doi: 10.1016/j.reprotox.2010.11.013. Epub 2010 Dec 3. PubMed PMID: 21130863.

Reference 5

Reference Type:

publication

Title:

On the impact of second generation mating and offspring in multi-generation reproductive toxicity studies on classification and labelling of substances in Europe.

Author:

Rorije E, Muller A, Beekhuijzen ME, Hass U, Heinrich-Hirsch B, Paparella M, Schenk E, Ulbrich B, Hakkert BC, Piersma AH.

Year:

2011

Bibliographic source:

Regul Toxicol Pharmacol. 2011 Nov;61(2):251-60. doi: 10.1016/j.yrtph.2011.08.005. Epub 2011 Aug 23. PubMed PMID: 21878359.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Justification for study design:

1B with exstention -
A. Uses leading to significant exposure of consumers or professionals AND one of the following:
The range of professional worker and consumer uses specified for the substance (above), in conjunction with the high annual production volume of the substance (>1000 tons), may lead to “significant exposure” to this substance.
B. (i) Genotoxicity/mutagenicity observed in vivo which could lead to classifying it as Mutagen Category 2
Mutagenicity studies conducted on this substance are negative. Mutagenicity is not a consideration for continuance of cohort 1B extension to the F2 generation.
(ii) Available data indicates internal dose of parent compound/metabolites will reach steady-state after extended exposure
An aquatic bioaccumulation study exists on this substance (alkenes, C6-11, hydroformylation products, distn. residues, heavy cracked fraction), reporting a biomagnification factor (BMF) of 1.43 and a half-life of 84.4 days . A BMF of 1.43 indicates this substance may meet the criteria for Bioaccumulative (B) or very Bioaccumulative (vB), indicating the potential for bioaccumulation.
(iii) Indications of modes of action related to endocrine disruption from available in vivo studies or non-animal approaches
No indications of modes of action related to endocrine disruption were identified. Endocrine is not a consideration for continuance of cohort 1B extension to the F2 generation.

Excluding 2A and 2B
Excluding 3
Overall, there are no triggers to suggest developmental neurotoxicity or immunotoxicity testing is warranted. Supporting data and rationale can be found in documentation for testing proposal which is attached.

Test material

Test material information

Constituent 1

Reference substance name:

Alkenes, C6-11 (branched), hydroformylation products, distn. residues, heavy cracked fraction

EC Number:

701-314-7

Molecular formula:

CnH2n+2O2. n=24-33

IUPAC Name:

Alkenes, C6-11 (branched), hydroformylation products, distn. residues, heavy cracked fraction

Test animals

Species:

rat

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Analytical verification of doses or concentrations:

yes

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:

not specified