Hexahydro-2H-azepin-2-one, sodium salt

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Not toxic to reproduction

Link to relevant study records

Reference

Endpoint:

three-generation reproductive toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Please refer to the Read-across Statement attached in Section 13.2.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The underlying hypothesis for the read-across is that the target substance is very prone to hydrolysis resulting in the formation of epsilon-caprolactam and sodium hydroxide. As hydrolysis of the target substance will inevitably occur both under physiological and under environmental conditions, the evaluation of the data of epsilon-caprolactam and sodium hydroxide is considered to be sufficient for hazard assessment. Thus, the toxicological behavior of BRUGGOLEN® C10 can be considered to be determined by the hydrolysis products caprolactam and caustic soda.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target substance: sodium caprolactamate, CAS-No. 2123-24-2 (for detailed composition please refer to the Read-across Statement attached in Section 13.2)
Source substances: epsilon-caprolactam, CAS-No. 105-60-2 and sodium hydroxide, CAS-No. 1310-73-2

3. ANALOGUE APPROACH JUSTIFICATION
The justification of the read-across hypothesis is mainly based on the hydrolysis of the target substance into the source substances.
BRUGGOLEN® C10 is a combination of sodium caprolactamate (17 – 20 %) and epsilon-caprolactam (80 – 83 %). If diluted in water, sodium caprolactamate easily degrades to caprolactam and sodium hydroxide (caustic soda). Reason is the instability of the ionic N-Na-bond of the sodium caprolactamate.
Thus, the toxicological behavior of BRUGGOLEN® C10 can be considered to be determined by the hydrolysis products caprolactam and caustic soda.

4. DATA MATRIX
Please refer to the Read-across Statement attached in Section 13.2.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day

Sex:

male/female

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

100 mg/kg bw/day

Sex:

male/female

Basis for effect level:

body weight and weight gain

Critical effects observed:

not specified

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

100 mg/kg bw/day

Sex:

male/female

Basis for effect level:

body weight and weight gain

Critical effects observed:

not specified

Reproductive effects observed:

not specified

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:

Two GLP compliant studies available.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Data obtained by Read-Across from epsilon-Caprolactam:

In a three-generation study F344 rats were continuously fed with caprolactam (CAP) at dose levels of ca. 100, 500, 1000 mg/kg bw throughout three successive generations (Serota et al., 1981). Following the 10 weeks premating exposure periods, no treatment-related clinical signs of toxicity, changes in reproductive performance or gross-pathological findings were noted within the parental generations. Compound-related findings were mainly related to body weight loss (signifigant in the high-dose group only). Histopathologic findings noted in the high-dose P1 animals consisted of a slight increase in the severity of spontaneous nephropathies, occasionally accompanied by granular casts in 3 of 10 male animals. Based on these findings, the NOAEL for the parental P1-P3 generations was identified as 500 mg/kg bw.

Pregnancy and fertility indices were comparable between treated and control groups for each filial generation and no dose-related trends were apparent, thus the NOAEL for fertility was 1000 mg/kg bw.

The offspring data revealed no treatment-related effects with respect to gross appearance, gross pathology, survival, number of pups, and percentage of male pups or kidney weight. The only effect observed in offspring were lower mean body weights in male and female pups at the two highest dose levels in all filial generations, the NOAEL of F1-F3 offspring was 1000 ppm (100 mg/kg bw). Summarized no adverse effect on reproductive organs or function were found in this 3-generation study with rats.

These findings were supported by the 103-month Combined Chronic Toxicity / Carcinogenicity Study with Fischer rats (NTP 1982). No effects on reproductive organs (testes weights as well as information on gross and microscopic pathology for testes, prostate, ovaries, and uteri) were observed at the highest dose tested (375 mg/kg bw/day).

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Data obtained by Read-Across from sodium hydroxide:

No valid studies were identified regarding developmental toxicity nor toxicity to reproduction in animals after oral, dermal or inhalation exposure to NaOH.

It is not useful to do a reproduction or developmental toxicity test with NaOH in rats because the hazard of sodium for humans has been characterized sufficiently (e.g. Fodor et al., 1999). It is also not useful to study the reproduction/developmental toxicity of hydroxide via an oral study because at high concentrations the substance is corrosive or irritating, while at low concentrations the

hydroxide will be neutralized in the stomach by gastric juice, which has a very low pH.

Furthermore it should be realised that oral exposure to NaOH is negligible under normal handling and use conditions and therefore an oral reproduction/developmental toxicity is inappropriate.

NaOH is not expected to be systemically available in the body under normal handling and use conditions and for this reason it can be stated that the substance will not reach the foetus nor reach male and female reproductive organs (see sections 3.1 and 3.6). It can be concluded that a specific study to determine the developmental toxicity or the toxicity to reproduction is not necessary.

Justification for selection of Effect on fertility via oral route:
Since sodium caprolactamate hydrolyses under physiological conditions with the formation of epsilon-Caprolactam and sodium hydroxide, cross-reading from toxicological studies of epsilon-Caprolactam is justified. For the substance’s endpoint assessment also the impact of sodium hydroxideis taken into consideration, however avaiable literature indicated that no contribution is to be expected.

Effects on developmental toxicity

Description of key information

No developmental toxicity is to be expected.

Link to relevant study records

Reference

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:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Please refer to the Read-across Statement attached in Section 13.2.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The underlying hypothesis for the read-across is that the target substance is very prone to hydrolysis resulting in the formation of epsilon-caprolactam and sodium hydroxide. As hydrolysis of the target substance will inevitably occur both under physiological and under environmental conditions, the evaluation of the data of epsilon-caprolactam and sodium hydroxide is considered to be sufficient for hazard assessment. Thus, the toxicological behavior of BRUGGOLEN® C10 can be considered to be determined by the hydrolysis products caprolactam and caustic soda.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target substance: sodium caprolactamate, CAS-No. 2123-24-2 (for detailed composition please refer to the Read-across Statement attached in Section 13.2)
Source substances: epsilon-caprolactam, CAS-No. 105-60-2 and sodium hydroxide, CAS-No. 1310-73-2

3. ANALOGUE APPROACH JUSTIFICATION
The justification of the read-across hypothesis is mainly based on the hydrolysis of the target substance into the source substances.
BRUGGOLEN® C10 is a combination of sodium caprolactamate (17 – 20 %) and epsilon-caprolactam (80 – 83 %). If diluted in water, sodium caprolactamate easily degrades to caprolactam and sodium hydroxide (caustic soda). Reason is the instability of the ionic N-Na-bond of the sodium caprolactamate.
Thus, the toxicological behavior of BRUGGOLEN® C10 can be considered to be determined by the hydrolysis products caprolactam and caustic soda.

4. DATA MATRIX
Please refer to the Read-across Statement attached in Section 13.2.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

body weight and weight gain

other: maternal toxicity

Abnormalities:

not specified

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

fetal/pup body weight changes

changes in postnatal survival

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: teratogenicitiy

Abnormalities:

not specified

Developmental effects observed:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Two GLP compliant studies 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

Data obtained by Read-Across from epsilon-Caprolactam:

In a Developmental toxicity study performed accorsing to the current OECD guideline 414, 20 F344 rats/group were gavaged with dose levels of 100, 500 and 1,000 mg/kg/d bw on days 6-15 of gestation. The maternal survival rate was statistically lower in the high-dose group when compared with the control. Nine high-doses females were found dead during the treatment phase of this study. Clinical observations such as urine stains, rough hair coat, red discharge from the vagina, bloody crust on eyes, mouth and nose, and thin and/or hunched appearance were observed in dose dependent manner in all treated groups.

The mean body weight values of the high dose group were significantly (p<0.05) lower than in controls on days 15 (10%) and 20 (11%) of gestation. Furthermore, the mean body weight changes of the mid- and high-dose groups for the days 6-11 and 6-15 were significantly (p<0.05) lower than the control values at these intervals. These effects on body weights were accompanied by significantly lower values of mean food consumption in the mid- and high-dose groups. In these maternally toxic doses, a slight reduction in fetal body weight was observed. The mean number of corpora lutea and implantations per group were not affected by treatment, but the mean implantation efficiencies were slightly reduced in the high-dose group. No treatment-related visceral or skeletal anomalies were observed.

Based on these results in rats, the NOAEL for maternal toxicity was identified as 100 mg/kg bw/d, for embryotoxicity as 500 mg/kg bw/d and for teratogenicity as 1000 mg/kg bw/d.

 

In an analogous developmental toxicity study (Bio-Research, 1983) with New Zealand White Rabbits, 25 animals/group were gavaged with dose levels of 50, 150 and 250 mg/kg bw on days 6-28 of gestation. In the high dose group 4 rabbits died during the treatment period. Also exclusively in the high dose group, adverse clinical findings were observed. The absolute weight gain between day 6 and 29 was decreased in the high dose group, whereas the corrected body weight gain (body weight gain day 6-29 minus weight of gravid uterus) was significantly decreased in mid dose animals.

Fetotoxicity was evidenced by lower fetal weights at the mid and high dose groups, and an increased incidence of thirteenth ribs was observed in the high dose group. Neither embryotoxicity nor teratogenicity occurred. Based on these findings in rabbits, the NOAEL for maternal toxicity and fetotoxicity was identified as 150 and 50 mg/kg bw, respectively. No teratogenicty was observed with the highest dose tested (NOAELtera 250 mg/kg bw/day).

 

In a BASF study (1978), no signs of maternal toxicity and fetotoxicity were observed in rats after dosing 166 mg CAP/kg bw by oral-gavage. Thus, the NOAEL for maternal, fetal and developmental toxicity was above 166 mg/kg bw/d. 

 

Combining all data, no teratogenic effects from the oral application of CAP were observed in rats or rabbits. Fetotoxic effects were only observed in rats and rabbits at doses that also produced maternal toxicity.

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Data obtained by Read-Across from sodium hydroxide:

No further data available.

Justification for classification or non-classification

No indications of reproductive toxicity were identified in a 3 -gen study in rats and no developmental toxicity was identified in developmental toxicity studies in ras and rabbits. Therefore no classification for toxicity to reproduction is warranted.