Polyethylene polyamine, pentaethylenehexamine fraction

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data are available.

An EOGRTS is proposed with the structural analogue substance Amines, polyethylenepoly-, triethylenetetramine fraction (CAS 90640 -67 -8) and Amines, polyethylenepoly-, (CAS 68131 -73 -7). Read-across and intrapolation from these two structural analogues should be sufficient for a proper hazard identification as well as risk assessment

Effect on fertility: via oral route

Endpoint conclusion:

no study available (further information necessary)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

No studies regarding developmental toxicity are available for Polyethylene polyamine, pentaethylenehexamine fraction.

However, developmental toxicity studies with the structural analogue substance Amines, polyethylenepoly-, triethylenetetramine fraction and Amines, polyethylenepoly-, are available. Oral in rat and dermal in rabbit. In all studies no teratogenic effects was observed.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Species:

rat

Dose descriptor:

NOAEL

Remarks:

oral, rat

Effect level:

>= 750 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: no adverse effects up to the highest dose tested

Remarks on result:

other: CAS 90640-67-8

Remarks:

CIBA-GEIGY, 1984

Dose descriptor:

NOAEL

Remarks:

oral, rat

Effect level:

200 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: no test substance related clinical signs or increased mortality at 200 mg/kg bw.

Remarks on result:

other: EC 701-226-7, Marsden, 2015

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Remarks:

oral, rat

Effect level:

>= 750 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

external malformations

skeletal malformations

visceral malformations

Remarks on result:

other:

Remarks:

CIBA-GEIGY, 1984

Dose descriptor:

NOAEL

Remarks:

oral, rat

Effect level:

>= 400 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see remarks

Remarks on result:

other: EC 701-226-7, Marsden, 2015

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

The source substances Amines, polyethylenepoly-, triethylenetetramine fraction and Amines, polyethylenepoly-, was devoid of any embryotoxic activity and did not reveal teratogenic potency in the rat after oral treamtent. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in reproductive toxicity.

Reference 2

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Species:

rabbit

Dose descriptor:

NOAEL

Remarks:

dermal, rabbit

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

mortality

Remarks on result:

other: CAS 90640-67-8

Remarks:

Tyl, 1988

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Remarks:

dermal, rabbit

Effect level:

>= 125 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

external malformations

skeletal malformations

visceral malformations

Remarks on result:

other:

Remarks:

Tyl, 1988

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

The source substances Amines, polyethylenepoly-, triethylenetetramine fraction and Amines, polyethylenepoly-, was devoid of any embryotoxic activity and did not reveal teratogenic potency in the rabbit after dermal treatement. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in reproductive toxicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

400 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises adequate, reliable and consistent studies, from a reference substances with similar structure and intrinsic properties. Read-across is justified based on similarities in PC/ECO/TOX properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

125 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

The available information comprises adequate, reliable and consistent studies, from a reference substances with similar structure and intrinsic properties. Read-across is justified based on similarities in PC/ECO/TOX properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex X, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

There are no data available on developmental toxicity with Polyethylene polyamine, pentaethylenehexamine fraction. A final decsion from ECHA is available ( CCH-D-2114482142-55-01/F) including OECD 414 in the first and second species. This studies are initiated and will be included as soon as available. In the meanwhile, in order to fulfil the standard information requirements set out in Annex VII-IX, 8.7., in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted. In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across). Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Amines, polyethylenepoly-, tetraethylenepentamine (TETA, CAS 90640 -67 -8), Amines, polyethylenepoly-, (PEPA, CAS 68131 -73 -7) and Polyethylene polyamine, pentaethylenehexamine fraction (EC701 -266 -7) are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoint for Polyethylene polyamine, pentaethylenehexamine fraction (EC 701 -266 -7). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Rat:

For TETA two reliable studies according to OECD guideline 414 in rats and rabbits are available.

Timed-pregnant Sprague Dawley rats were treated with TETA by daily oral gavage on gestational days (gd) 6 up to and including day 15 (CIBA-GEIGY, 1984). Groups of 24 females each received TETA formulated in distilled water applied at a volume of 10 mL/kg bw at dosages of 0, 75, 325 or 750 mg/kg bw per day. With regard to the vehicle control, food intake was slightly depressed in all dose groups during the second part of the treatment period. Body-weight gain appeared to be somewhat reduced in the experimental groups; however when corrected body weights were evaluated no differences were observed. No other toxic signs were observed in the mothers. A significant increase in the average body weight of the live foetuses was recorded for the high-dose group in the main study. The gross inspection of the live foetuses did not reveal any finding either in the experimental groups or in the vehicle control. The skeletal assessment revealed instances of irregular sternebral ossification in the dose groups and in the vehicle control. Concerning the status of skeletal maturation of the foetuses shortly before term, apart from a slightly raised number of still unossified calcanei in the high-dose group in the main study, no delay of ossification could be found for the experimental groups in comparison with the vehicle control.

Thus, under the conditions of this study, TETA produced no maternal toxicity except for slightly reduced food intake and no developmental toxicity at any dosages employed. Therefore, the NOAEL for maternal toxicity and developmental toxicity was considered to be equal or greater than 750 mg/kg bw/day in rats after oral exposure.

A second reliable study according to OECD guideline 414 in rats is available with the source substance Amines, polyethylenepoly-, (CAS 68131 -73 -7, Marsden, 2015). Under the experimental conditions of the study, oral (gavage) administration of the test substanceat 200, 400 or 800 mg/kg bw/day in the pregnant Wistar rat was not tolerated at the high dose with maternal mortality leading to the premature sacrifice of all remaining females despite an attempt to lower the dose from 800 to 600 mg/kg bw/day. Major clinical signs such as irregular/laboured breathing, intermittent tremors, closed/partly closed eyes, decreased activity/subdued behaviour, paresis, recumbency, palor, cold to touch and piloerection were noted for several of these females prior to death/sacrifice. This dose was also associated with adverse renal changes noted histologically (minimal to severe degeneration and regeneration of the cortical tubular epithelium in the kidney) that were clearly due to the test substance.

Treatment at 400 mg/kg bw/day group was associated with the unscheduled sacrifice of a single female in a moribund condition, a low incidence of irregular breathing, and reduced mean body weight gain and food consumption towards the end of gestation. The same microscopic renal changes as seen in the high dose group were also noted for the animal sacrificed moribund. The low dose of 200 mg/kg bw/day was a no observed effect level (NOEL) for maternal findings. Despite the maternal findings at 400 mg/kg bw/day, there was no embryo-foetal toxicity or indication of a teratogenic potential of Amines, polyethylenepoly-,. The dose of 400 mg/kg bw/day was therefore the NOEL for embryo-fetal toxicity and teratogenicity.

The higher dose of 800 mg/kg bw/day could not be evaluated due to the premature termination of the group due to marked maternal toxicity. However, it is worthy of note that 21 females in the group were pregnant and all had live implantations at the time of sacrifice.

Rabbit

Timed-pregnant New Zealand White rabbits were treated with TETA by occluded cutaneous application on gestational days (gd) 6 through 18, six hours per day (Tyl, 1988). Groups of 22 does each received TETA formulated in deionized water and applied in a volume of 2.0 mL/animal (approximately 0.5 mL/kg bw) at dosages of 0.0, 5.0, 50.0 or 125.0 mg/kg bw/day. Clinical observations of all study animals were undertaken daily and maternal body weights were measured on gd 0, 6, 12, 15, 18 and 29. In addition, daily observations of the dosing site of treated animals were recorded from the initiation of the treatment period and continued until the termination of the study. At scheduled necropsy on gd 29, does were evaluated for body weight, liver weight, lung and kidney weight, gravid uterine weight and status of implantation sites (i.e., resorptions, dead fetuses, live fetuses). Maternal blood and urine were evaluated for copper content. Live fetuses were dissected from the uterus, counted, weighed, examined for external, visceral and skeletal abnormalities and sexed internally. Maternal kidneys and liver sections were retained in fixative for possible subsequent histopathologic examination. Two does (9.1%) died at 125.0 mg/kg bw/day. Maternal toxicity was also indicated by a significant decrease in body weight gain (in the exposure period) at 125.0 mg/kg bw/day. Also, clinical observations indicated severe skin irritation at 50.0 and 125.0 mg/kg bw/day with some recovery in the post-dosing period. Slight irritation at the dosing site was observed at 5.0 mg/kg bw/day which was transient, with essentially total recovery after exposures ceased. There were no effects on maternal lung, kidney or liver weights (absolute or relative to body weight) or on gravid uterine weight. There were no differences among groups for maternal serum or urinary copper. There was no effect of treatment on number of ovarian corpora lutea, number of total, live, or non-viable implantations per litter, or percent preimplantation loss, percent live fetuses or sex ratio (% male fetuses). Fetal body weights per litter (males, females or total) were also unchanged across groups. There was no significant increase in the incidence of individual malformations or variations or of external, visceral, skeletal, or total (external, visceral, plus skeletal) malformations or variations by fetus or by litter in any TETA exposed group relative to the vehicle control group. One finding, poorly ossified hyoid bone exhibited a decreased incidence at 125.0 mg/kg bw/day relative to that in the vehicle control group. Thus, under the conditions of this study, TETA produced maternal toxicity other than at the dosing site only at 125.0 mg/kg bw/day but no developmental toxicity at any dosages employed.

Thus, under the conditions of this study, TETA resulted in mortality in the highest dose group. No developmental toxicity at any dosages employed was observed. Therefore, the NOAEL for maternal toxicity and was considered to be 50 mg/kg bw/day and the NOAEL for developmental toxicity equal or greater than 125 mg/kg bw/day in rabbits after dermal exposure.

 

In conclusion, the source substances Amines, polyethylenepoly-, triethylenetetramine fraction (CAS 90640 -67 -8) and Amines, polyethylenepoly-, (CAS 68131 -73 -7) show no developmental toxicity in rats after oral exposure. Further, Amines, polyethylenepoly-, triethylenetetramine fraction was devoid of developmental toxicity in rabbits after dermal exposure. Therefore, it is concluded that the target substance will also have no developmental toxicity potential.

Justification for classification or non-classification

Reliable data with structural analogues on developmental toxicity indicates that the registered substance does not meet the criteria for classification according to Regulation (EC) No. 1272/2008 in respect to developmental toxicity. However, no final decision on classification for toxicity to reproduction according to Regulation (EC) 1272/2008 can be made, as no information on fertility is available.