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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Quality of whole database:
High quality study but it is read across, awaiting final decision on testing proposal for an extended one generation reproduction study on 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 which is the most appropriate read across to for 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

We have no specific data on toxicity to reproduction for 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol CAS No 1218787-30-4 or for 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 which is considered to be the most appropriate read across substance, until the proposed reproduction study on for 2, 2’-(Octadec-9-enylimino) bisethanol is approved by ECHA. . The available information is on a related substance Ethanol, 2,2’-iminobis-,N-coco alkyl derivs CAS No 61791-31-9, this substance is predominantly C12 but does contain >10% C18 while 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 is predominantly C18 unsaturated and C16 and 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol which is predominately C18 and C16. The available study is an OECD 422 reproductive screening test. There were some indications of foetotoxicity in this study (post implantation loss) seen at the top dose, but this was considered not sufficient for classification, it was proposed to do additional testing to establish if there is true developmental toxicity caused by the test substance. However in this OECD422 study there were no indications of any effects on reproductive performance or fertility.

The read across to Ethanol, 2, 2’-iminobis-, N-coco alkyl derivs CAS No 61791-31-9 is not ideal due to the difference in carbon chain length distribution. As 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 is a high volume substance >1000 tonnes we have proposed to do both a pre-natal developmental toxicity OECD 414 study (now completed) and an extended one generation reproduction study (delayed due to a disagreement between ECHA and some member states). The potential for reproductive toxicity in particular the possibility that it may also produce post implantation loss with this substance will then be assessed based on the results of these studies which will be reviewed to see if any classification is required for 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol via read across.

Short description of key information:

There is no specific test data on potential reproductive toxic effect of 2, 2’-(C16-18 (evennumbered) alkyl imino) diethanol CAS No 1218787-30-4. 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 is considered to be the most appropriate read across substance.  As this is a >1000 ton substance a test proposal has been made for an extended one generation reproduction study on this read across substance, which is delayed awaiting a final decision from ECHA and the member states. The only available information is on a related substance Ethanol, 2,2’-iminobis-,N-coco alkyl derivs CAS No 61791-31-9, this substance is predominantly C12 but does contain >10% C18 while 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9  is predominantly C18 unsaturated with some C16.  The available study is an OECD 422 reproductive screening test.  There were no indications of adverse effects on reproduction in the parental animals. There were some indications of foetotoxicity in this study but this was considered not sufficient for classification, it is proposed to do additional testing (a reproduction study) to establish if there is true developmental toxicity (post implantation loss) caused by 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 and 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol, CAS No 1218787-30-4.

Justification for selection of Effect on fertility via oral route:

An Extened one generation reproduction study has been proposed for 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 which is the most appropriate read across substance for 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol CAS No 1218787-30-4. Until this is completed there is no specific test data on the potential adverse effects on fertility or other reproductive parameters.  The only available information is on a related substance Ethanol, 2,2’-iminobis-,N-coco alkyl derivs CAS No 61791-31-9, this substance is predominantly C12 but does contain >10% C18 while 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 is predominantly unsaturated C18, while for 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol is predominantly C18 and   C16. The available study is a Klimisch 1, full GLP, OECD 422 reproductive screening test due to the shorter carbon chain length it is considered a worst case read across.

Justification for selection of Effect on fertility via inhalation route:

Due to the low vapour pressure and the physical form of the substance, it being a waxy solid a room temperature inhalation is not an expected route of exposure in the workplace.  In addition the irritant properties to the skin would make such testing very technically difficult.

Justification for selection of Effect on fertility via dermal route:

Due to the irritant properties to the skin such testing is not scientifically justified due to animal welfare considerations.  It would be expected to be absorbed less through the skin than orally, therefore data from the oral dosing studies will be sufficient to calculate dermal DNELs based on the available oral repeat dose NOAEL data, following ECHA guidance.

Effects on developmental toxicity

Description of key information

There is an OECD414 pre-natal developmental toxicity study on 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 the appropriate read across substance for  2,2’-(C16-18 (evennumbered) alkyl imino)diethanol. This study showed no indication of developmental toxicity in the foetuses, the NOEL being 150mg/kg (the top dose).  There was however also no indication of toxicity in the pregnant females.  This study does not include dosing during the implantation period, the only available information concerning this is read across to the OECD422 study on Ethanol, 2, 2’-iminobis-, N-coco alkyl derivs CAS No 61791-31-9.  This substance is predominantly C12 but does contain >10% C18 while 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 is predominantly C18 unsaturated.  The available study is an OECD 422 reproductive screening test.  There were some indications of foetotoxicity (increased post implantation loss)  in this study but this was considered not sufficient for classification, it has been proposed to do a reproduction study to establish if this is also seen with 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
This study is high quality and replaces the read across to Ethanol, 2,2’-iminobis-,N-coco alkyl derivs CAS No 61791-31-9 for developmental toxicity but it does not cover the period immediately after implantation so it does not supersede the read across to the OECD422 study where increased post implantation loss was seen with Ethanol, 2,2’-iminobis-,N-coco alkyl derivs CAS No 61791-31-9. This will be resolved when the proposed reproduction study on 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 is available.
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

The OECD414 pre-natal development study included dose levels of 15, 50 and 150mg/kg bodyweight of 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9, administered by gavage for days 5 to 19 of pregnancy as a solution in arachis oil. This substance is the appropriate read across substance for the appropriate read across substance for 2, 2’-(C16-18 (evennumbered) alkyl imino) diethanol. The dose levels were selected based on those used in the 28 day and 90 day repeat dose studies. The adult females did not show any signs of toxicity in this study such as on bodyweights, or food or water consumption, but there was no histopathological examination of their stomachs, making it not possible to see local adverse (irritant/corrosive) effects due to the corrosive/irritant nature of the test material as seen in the other repeat dose studies.

The absence of toxic effects in the adult females is not considered to be of concern as we have good evidence from the 28 day repeat dose study that higher doses could result in mortality or severe toxicity due to local effects in the stomach. 

The number of implantations, subsequent embryofoetal survival and litter size, sex ratio and mean foetal, litter and placental weights on Day 20 of gestation were unaffected by maternal treatment at 15, 50 or 150 mg/kg bw/day.

There was no effect of maternal treatment on morphological development of the foetuses at 15, 50 or 150 mg/kg bw/day.

Conclusion

The No Observed Effect Level (NOEL) for the pregnant females and the survival, growth and embryofoetal development of the offspring was considered to be 150 mg/kg bw/day. 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9, even at this dose level it did not show any indications of potential for developmental toxicity in this study. The proposed reproduction study will allow an assessment if the increased post implantation loss seen with the read across substance 2,2’-iminobis-,N-coco alkyl derivs CAS No 61791-31-9 is also seen with 2, 2’-(Octadec-9 -enylimino) bisethanol CAS No 25307-17-9 and by read across also with 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol.

Justification for selection of Effect on developmental toxicity: via oral route:

We have a Klimisch 1 full GLP compliant OECD414 study on 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 the appropriate read across substance for  2,2’-(C16-18 (evennumbered) alkyl imino)diethanol  CAS No 1218787-30-4.

Justification for selection of Effect on developmental toxicity: via inhalation route:

Due to the low vapour pressure and the physical form of the substance, it being a waxy solid a room temperature inhalation is not an expected route of exposure in the workplace.  In addition the irritant properties to the skin would make such testing very technically difficult.

Justification for selection of Effect on developmental toxicity: via dermal route:

The skin irritant properties of this substance mean the repeated dose dermal studies are not scientifically justified due to concerns for animal welfare.  Also t would be expected to be absorbed less through the skin than orally, therefore it is possible to calculate dermal DNELs based on the available oral repeat dose NOAEL data, based on ECHA guidance.

Justification for classification or non-classification

There is no specific test data on potential reproductive toxic effect of for 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol CAS No 1218787-30-4, or for the appropriate read across substance 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9. The available information is on a related substance Ethanol, 2,2’-iminobis-,N-coco alkyl derivs CAS No 61791-31-9, this substance is predominantly C12 but does contain >10% C18 while 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 is predominantly C18 unsaturated and 2,2’-(C16-18 (evennumbered) alkyl imino)diethanol which is predominantly C18, and C16. The available study is an OECD 422 reproductive screening test. There were some indications of foetotoxicity (increased post implantation loss) in this study but this was considered not sufficient for classification, it was proposed to do additional testing to establish if there is true developmental toxicity. There were no indications of any adverse effects on the reproductive parameters such as fertility etc. in the adult rats of either sex.

The read across to Ethanol, 2, 2’-iminobis-, N-coco alkyl derivs CAS No 61791-31-9 is not ideal due to the difference in carbon chain length distribution. As 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9 is a high volume substance >1000 tonnes we have proposed to do both a developmental toxicity OECD 414 study (which is now completed) and an extended one generation reproduction study which is currently awaiting a final decision.

 

The OECD414 pre-natal development study in rats, showed no evidence of developmental toxicity even at the top dose of 150mg/kg bodyweight, therefore while this study does not include dosing during the pre-mating period until day 4, it does not indicate any potential for developmental toxicity (adverse effects on the morphological development of the foetus). Until the reproduction study is available it is not possible to know if the increased post implantation loss see in the OECD422 study with the read across substance Ethanol, 2,2’-iminobis-,N-coco alkyl derivs CAS No 61791-31-9 will also be seen with this substance and then by read across also to 2,2-(C16-18 (evennumbered) alkyl imino)diethanol. However the evidence from the OECD414 study indicates that 2, 2’-(C16-18 (evennumbered) alkyl imino) diethanol can be considered not to induce adverse effects on the morphological development of the foetus in rats, therefore it is clear that it is not necessary to classify this substance for reproductive or developmental toxicity based on current data from read across to 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9. A final conclusion concerning the post implantation loss and its relevance to this substance will be possible when the reproduction study is completed on 2, 2’-(Octadec-9-enylimino) bisethanol CAS No 25307-17-9.

Additional information