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Key value for chemical safety assessment

Effects on fertility

Description of key information

Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, oral (OECD 422), rat:

Reproductive toxicity: NOAEL >= 1000 mg/kg bw/day for males and females

Read-across from structural analogue source substance reaction mass of 7,7,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diylbismethacrylate and 7,9,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diylbismethacrylate CAS 72869-86-4

Link to relevant study records
Reference
Endpoint:
screening for reproductive / 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:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: Source: CAS 72869-86-4, Pasics Szakonyiné, 2017
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: Source: CAS 72869-86-4, Pasics Szakonyiné, 2017
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects at highest dose tested
Remarks on result:
other: Source: CAS 72869-86-4, Pasics Szakonyiné, 2017
Critical effects observed:
yes
Lowest effective dose / conc.:
300 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Key result
Dose descriptor:
NOAEL
Remarks:
developmental
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects at highest dose tested
Remarks on result:
other: Source: CAS 72869-86-4, Pasics Szakonyiné, 2017
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Executive summary:

Toxicity to reproduction after oral exposure of the target substance reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate is estimated based on an adequate and reliable combined repeated dose toxicity study with the reproduction/developmental toxicity screening test of the structural analogue source substance reaction mass of 7,7,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diylbismethacrylate and 7,9,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diylbismethacrylate (CAS 72869 -86 -4). Oral exposure of male and female rats for up to 64 days via gavage with the source substance had no effect on reproductive performance and hence resulted in a NOAEL value of ≥ 1000 mg/kg bw/day, corresponding to the highest dose tested. As explained in the analogue justification, the differences in molecular structure between the target and the source substance are unlikely to lead to differences in toxicity to reproduction. Therefore, a NOAEL for toxicity to reproduction after oral exposure of ≥ 1000 mg/kg bw/day for the target substance is considered for the hazard assessment and C&L purposes.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information on toxicity to reproduction comprises an adequate, reliable (Klimisch score 1) and consistent study from a source substance with similar structure and intrinsic properties. Read-across is justified based on common functional groups, breakdown products, and similar physico-chemical and toxicological properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, Item 8.7, of Regulation (EC) No. 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There is no data on toxicity to reproduction available for reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate (EC 944-336-4). Thus, a read-across approach was applied using the structurally similar substance reaction mass of 7,7,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diol-dimethacrylate (CAS 72869-86-4). The potential reproductive or developmental toxicity of the source substance was assessed in a combined repeated dose toxicity study with the reproductive/ developmental toxicity screening test in Hsd.Han: Wistar rats performed according to OECD guideline 422 and in compliance with GLP (Pasics Szakonyiné, 2017). Three groups of 12 male and 12 female rats received the test substance in polyethylene glycol as vehicle at doses of 100, 300 or 1000 mg/kg bw/day orally via gavage. A control group of 12 animals/sex received the vehicle only. In addition, 5 animals/sex were added to the control and high dose group to assess the reversibility of any effects observed at the high dose level (recovery group). All animals of the parental generation were dosed prior to mating (14 days) and throughout mating. In addition, males received the test item or vehicle after mating up to the day before necropsy (altogether for 56 days). Females were additionally exposed through the gestation period and up to lactation days 13 - 21, i.e. up to the day before necropsy (altogether for 56, 57 or 64 days). Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, lactation as well as development of offspring. Estrous cycle was monitored by examining vaginal smears prior to treatment, from the beginning of the treatment period (two weeks pre-mating period) and during the mating period until evidence of mating. The dams were allowed to litter, and rear their offspring up to day 13 post-partum. Blood samples were collected for determination of serum levels of thyroid hormones (T4) from all parental male animals at termination. Gross pathology of the parental males included body weight, brain weight and weight of the testes, epididymides, prostate and seminal vesicles with coagulating gland (as a whole). Histopathological examinations were performed in all parental animals of the control and high dose group on ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland in the control or high dose group. These organs were processed and examined histologically in not mated male animals (at 100 mg/kg bw/day and 300 mg/kg bw/day) and in non-pregnant female and its male partner at 100 mg/kg bw/day and in one dam at 300 mg/kg bw/day based on macroscopic observation. Five dams and the male mating partners were randomly selected from each group to examine further signs of toxicity such as functional observations, blood analysis (hematology and clinical chemistry), gross necropsy, organ weighing and histopathology. Animals allocated to the recovery group were observed for additional 14 days after termination of treatment and subjected to clinical pathology and gross pathology examinations, organ weighing and full histological examinations.

At the lowest dose (100 mg/kg bw/day) no treatment-related changes in any of the parameters were observed. An oral dose of 300 mg/kg bw/day induced pale liver in one male animal. Histopathological examination revealed centrilobular microvesicular vacuolation in the hepatocytes (hepatic lipidosis) in male animals at the termination of treatment. At the highest dose of 1000 mg/kg bw/day pale liver with high incidence at necropsy as well as hepatic lipidosis at histopathological examination was observed in male and female animals. These test item related hepatic and hepatocellular changes were considered reversible as these were not seen at the end of the 14-day post treatment observation period.

There were no test item related changes in body weight and body weight gain, food consumption, haematology, organ weights and clinical chemistry parameters. The T4 serum levels were similar between control and treatment groups. A test item influence on the oestrous cycle as well as on the reproductive performance was not detected at any dose level. Thus, under the conditions of this study, the NOAEL of the test substance for systemic toxicity is 100 mg/kg bw/day in male rats and 300 mg/kg bw/day in female rats. In terms of reproductive effects, no treatment-related findings were observed at any dose level tested; therefore, the high dose of 1000 mg/kg bw/day is considered to be the NOAEL for reproductive toxicity.

As explained in the analogue justification, the differences in molecular structure between the target and the source substance are unlikely to lead to differences in toxicity to reproduction. Therefore, it can be concluded that the target substance reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate (EC 944-336-4) has as well no potential to cause any toxicity to reproduction. In conclusion, the NOAEL for reproductive toxicity of the target substance is 1000 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, oral (OECD 422), rat: NOAEL developmental = 1000 mg/kg bw/day

Read-across from structural analogue source substance reaction mass of 7,7,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diylbismethacrylate and 7,9,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diylbismethacrylate (CAS 72869-86-4).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Experimental exposure time per week (hours/week):
168
Species:
rat
Quality of whole database:
The available information on developmental toxicity comprises an adequate, reliable (Klimisch score 1) and consistent study from a source substance with similar structure and intrinsic properties. Read-across is justified based on common functional groups, breakdown products, and similar physico-chemical and toxicological properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, Item 8.7, 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 study available
Additional information

There is no data on developmental toxicity available for reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate (EC 944-336-4). Thus, a read-across approach was applied using the structurally similar substance reaction mass of 7,7,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diol-dimethacrylate (CAS 72869-86-4). The potential developmental toxicity of the source substance was assessed in a combined repeated dose toxicity study with the reproductive/developmental toxicity screening test in Hsd.Han: Wistar rats performed according to OECD guideline 422 and in compliance with GLP (Pasics Szakonyiné, 2017). For details on treatment and the experimental procedure please refer to “Additional information” under “Toxicity to reproduction”.

The development of the offspring was observed until euthanisation on post-natal day 13 or shortly thereafter. Litter weights were recorded and any abnormalities occurring were noted. Blood samples were collected for determination of serum levels of thyroid hormones (T4) from all pups per litter at termination on post-natal day 13.

No adverse effect on mortality, clinical signs, body weight or necropsy findings were detected in the offspring terminated as scheduled. Thyroid hormone levels (T4) in pups on post-natal day 13 were not affected by treatment. In addition, there were no abnormal findings on the anogenital distance (male and female) or nipple retention (male). In the absence of any signs of toxicity, the NOAEL developmental is 1000 mg/kg bw/day.

As explained in the analogue justification, the differences in molecular structure between the target and the source substance are unlikely to lead to differences in developmental toxicity. Therefore, it can be concluded that the target substance reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate (EC 944-336-4) has as well no potential to cause any developmental toxicity. In conclusion, the NOAEL developmental of the target substance is 1000 mg/kg bw/day.

Justification for classification or non-classification

Based on read-across from a structurally similar substance, the available data on toxicity to reproduction and developmental toxicity do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP). The data are conclusive but not sufficient for classification.