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Key value for chemical safety assessment

Effects on fertility

Description of key information
Developmental toxicity probe study in rats
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

No data available on test substance, however, results 'read across' from study on Ethylenediamine, ethoxylated and propoxylated, as permitted by Annex XI para 1.5, based on the justification in the report from Paul Illing Consultancy Services Ltd and Marlin Consultancy (Illing and Barratt, 2009). The report identifies that Ethylenediamine, ethoxylated and propoxylated is the most bioavailable of the NLP polyols linked by an amine group. Consult Illing and Barratt, (2007 and 2009), for further details.

A reproduction toxicity screening study (oral gavage) following the OECD guideline 421 is available for the endpoint.

Survival rate of F0 animals was not reduced by treatment with ethylenediamine, ethoxylated and propoxylated at a dose level up to and including 1000 mg/kg bw/day. Salivation directly after the administration was observed in both genders at the 1000 mg/kg dose level but an adverse effect is not concluded from this finding. Body weight development was not affected to a toxicologically relevant extent in males at a dose level up to and including 1000 mg/kg. Females of the 1000 mg/kg group revealed a mild body weight gain depression during lactation.

The lowest-observed-effect-level (LOEL) and the no-observed-effect level (NOEL) for salivation after administration were as follows:

Males: LOEL: 1000 mg/kg bw/day; NOEL: 300 mg/kg bw/day

Females LOEL: 1000 mg/kg bw/day; NOEL: 300 mg/kg bw/day

There were no detectable effects in offspring. The NOAEL (reproduction/development) is >1000 mg/kg bw/day.

Adequate testing has been undertaken on a sufficient number of the core substances and repeating units. None of the tested core substances and none of the repeating units is classifiable as a reproductive toxin. Hence it would be anticipated that the NLP polyols, as a category, would also not be reproductive toxins. Three of the NLP polyols, nitrilotriethanol, propoxylated, diaminotoluene, propoxylated and ethylenediamine, ethoxylated and propoxylated, were tested to fulfil the requirements of Annex VIII (>10 tonnes/y). The results from these screening reproductive tests confirmed the pre-existing information. The NLP polyols are not reproductive or developmental toxins. Furthermore, a range of studies has been conducted on core substances and repeating units and screening tests have been conducted on most substances in the NLP polyol categories. It is possible to ‘read across’ the results from all of these sources to all substances in these categories. Sufficient data exist to permit robust conclusions that the substances are not reproductive or developmental toxins.

A testing proposal for an extended one generation reproductive toxicity study (basic design without extension) for this substance is submitted as part of this dossier.


Short description of key information:
The NOAEL (reproduction/development, oral gavage - OECD 421) is >= 1000 mg/kg bw/day

Effects on developmental toxicity

Description of key information
Developmental toxicity study in rats, OECD 414
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

No data available on test substance, however, results 'read across' from study on Ethylenediamine, ethoxylated and propoxylated, as permitted by Annex XI para 1.5, based on the justification in the report from Paul Illing Consultancy Services Ltd and Marlin Consultancy (Illing and Barratt, 2009). The report identifies that Ethylenediamine, ethoxylated and propoxylated is the most bioavailable of the NLP polyols linked by an amine group. Consult Illing and Barratt, (2007 and 2009), for further details.

The purpose of this study was to evaluate the maternal and developmental toxicity of Ethylenediamine, ethoxylated and propoxylated (>1-<8.5 mol of EO and PO) in Crl:CD(SD) rats following repeated gavage administration.

Groups of 24 time-mated female rats were administered Ethylenediamine, ethoxylated and propoxylated (>1-<8.5 mol of EO and PO) in ultrapure water by gavage at dose levels of 0, 100, 300, or 1000 mg/kg/day on gestation day (GD) 6 through 20. In-life maternal study parameters included clinical observations, body weight, body weight gain and feed consumption. On GD 21, all rats were euthanized and examined for gross pathologic alterations. Liver, kidneys and gravid uterine weights were recorded, along with the number of corpora lutea, uterine implantations, resorptions and live/dead fetuses. All fetuses were weighed, sexed and examined for external alterations. Approximately one half of the fetuses were examined for visceral and craniofacial alterations while skeletal examinations were conducted on the remaining fetuses. Gavage administration of Ethylenediamine, ethoxylated and propoxylated (>1-<8.5 mol of EO and PO) up to, and including the limit dose of 1000 mg/kg/day, resulted in no treatment-related maternal toxicity and no indication of embryo/fetal toxicity or teratogenicity.

Therefore, under the conditions of this study, the no-observed-effect level (NOEL) for maternal toxicity and developmental toxicity was the limit dose of 1000 mg/kg/day.

Ethylenediamine, ethoxylated and propoxylated is not classifiable as hazardous in respect to its developmental toxicity based on the OECD 414 study in rats. There is sufficient information from a qualitative and quantitative understanding of the toxicological properties of the core substance, the repeating unit, and OECD 414 study with the substance. There is also negligible human exposure based on the uses with the registered substance.

In addition, there were no observations of adverse effects on reproductive organs such as testes, epididymides, ovaries, oviducts, uterus in the 28- nor 90-day repeated dose studies and reproductive/developmental toxicity screen (OECD TG 421) resulting from EDA/EO/PO MW 280 g/mole treatment. No effects on mating behavior, fertility, live birth incidences, gestation parameters, number of implantation sites or prenatal loss, litter size, number of pups born, sex ratio, viability of pups or pup weights were seen. Clinical or necropsy findings in pups were not shown for the substance nor were adverse effects during birth or lactation behaviors of dams. The reproductive/developmental toxicity NOAEL with EDA/EO/PO substance was 1000 mkd.

Adequate testing has been undertaken on the core substances and repeating units. None of the tested core substances and none of the repeating units is classifiable as a reproductive toxin. Hence it would be anticipated that the NLP polyols, as a category, would also not be reproductive toxins.

Two of the NLP polyols with an amine linkage, diaminotoluene, propoxylated and ethylenediamine, ethoxylated and propoxylated, were tested to fulfil the requirements of Annex VIII (>10 tonnes/y). The results from these screening reproductive tests confirmed the pre-existing information. Sufficient data exist to permit robust conclusions that the substances are not reproductive or developmental toxins.

A testing proposal for a developmental toxicity study in a second species (rabbit) for this substance is submitted as part of this dossier.

Toxicity to reproduction: other studies

Additional information

No data available on test substance, however, results 'read across' from study on Ethylenediamine, ethoxylated and propoxylated, as permitted by Annex XI para 1.5, based on the justification in the report from Paul Illing Consultancy Services Ltd and Marlin Consultancy (Illing and Barratt, 2009). The report identifies that Ethylenediamine, ethoxylated and propoxylated is the most bioavailable of the NLP polyols linked by an amine group. Consult Illing and Barratt, (2007 and 2009), for further details.

The purpose of this study was to make a preliminary evaluation of the maternal toxicity and embryo/fetal lethality potential of Ethylenediamine, ethoxylated and propoxylated (>1 – <8.5 mol of EO and PO) in Crl:CD(SD) rats following repeated gavage administration. Results from this study were used to set dose levels for a subsequent developmental toxicity study in Crl:CD(SD) rats.

Groups of five time-mated female Cr1:CD(SD) rats were administered 0 or 1000 mg/kg/day Ethylenediamine, ethoxylated and propoxylated (>1 – <8.5 mol of EO and PO) in ultrapure water by oral gavage at a dose volume of 4 ml/kg on gestation day (GD) 6 through 20. In-life parameters evaluated for all groups included clinical observations, body weight, body weight gain, and feed consumption. On GD 21 all surviving animals were euthanized and examined for gross pathologic alterations. Liver and kidney weights were recorded, along with the number of corpora lutea, implantations, resorptions, and live/dead fetuses.

Oral administration of Ethylenediamine, ethoxylated and propoxylated (>1 – <8.5 mol of EO and PO) to time-mated Crl:CD(SD) rats up to and including the limit dose of 1000 mg/kg/day resulted in no maternal toxicity and no indication of embryonal/fetal lethality.

Justification for classification or non-classification

On the basis of 'read across' from ethylenediamine, propoxylated and ethoxylated, the findings in the available studies do not warrant classification according to the EU criteria.

A reproduction toxicity screening study (oral gavage) following the OECD guideline 421 is available for the endpoint. Possible minor effects on body weight and salivation do not constitute 'serious damage', the regulatory requirement relevant to classification.

No effects were observed at any dose level in the developmental toxicity OECD 414 study or in the developmental toxicity probe study.

Based on the results of these studies, ethylenediamine, propoxylated, will not be classified for reproduction toxicity.

Additional information