trisodium (2S)-2,6-bis(3-carboxylatopropanamido)hexanoate

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

See attached justification

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Justification for type of information:

Justification for Read Across is detailed in the report attached to the IUCLID section 13.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Details on mating procedure:

Premating exposure period: 14 days

Duration of treatment / exposure:

Males: 52 days
Females: from 14 days before mating to day 4 of lactation

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Vehicle control

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12 animals/sex/dose

Control animals:

yes, concurrent vehicle

Reproductive function: oestrous cycle:

effects observed, non-treatment-related

Description (incidence and severity):

In the observation of estrous cycle, there was no intergroup difference in the mean estrous cycle. The abnormal estrous cycle was observed in 1 animal each in the 100 and 1000 mg/kg groups. There was no intergroup difference in the incidence of abnormal estrous cycle.

Reproductive performance:

no effects observed

Description (incidence and severity):

Copulation and conception were all established, and both the copulation index and the fertility index were 100 % in all groups.
There was no abnormality in the numbers of corpora lutea, implantation sites

PARTURITION AND LACTATION
The gestation period was significantly shortened in the 100 and 1000 mg/kg groups compared with the control group. There was no abnormality in the conditions of parturition, and the numbers of corpora lutea, implantation sites, delivered offspring and live delivered offspring showed almost the same values. There were no intergroup differences in the delivery index, implantation index, parturition index, live birth index, sex ratio and viability index of neonates on day 4 of lactation.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: n.a.

Critical effects observed:

no

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Body weight during lactation period was significantly low on days 0 and 4 of lactation in males and day 4 in females in the 100 mg/kg group and on day 4 in males in the 300 mg/kg group, which was the change not associated with the dose.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No abnormal findings considered to be attributable to administration of this compound were observed in dead pups during lactation and pups at scheduled sacrifice.

In the necropsy of dead offspring during the lactation period, pyelectasia was observed in 1 animal in the 100 mg/kg group.
In the necropsy on day 4 of lactation, red patches on the plantar were observed in 15 males and 13 females in the 100 mg/kg group, and the number of occurrences significantly increased in both males and females compared with the control group. However, this finding occurred in litters in 2 broods in both males and females. In addition, dilation of the ureter was observed in 3, 4 and 3 males and 5, 1 and 2 females in the 100, 300 and 1000 mg/kg groups, respectively, and the number of occurrences significantly increased in the male 100 mg/kg group. However, dilation of the ureter in the female 100 mg/kg group was observed in litters in 4 of 5 animals.
Other findings included thymic remnant in the neck in 3, 1, 2 and 3 male animals in the control, 100, 300 and 1000 mg/kg groups and in 1, 2 and 2 female animals in the control, 100 and 300 mg/kg groups, nodes in the liver in 1 animal each in the male and female 1000 mg/kg groups, white patches in the liver in 1 animal in the male 100 mg/kg group, pyelectasia in 3 animals each in the male 100, 300 and 1000 mg/kg groups and in 2 and 1 animal in the female 300 and 1000 mg/kg groups, anophthalmia in 1 animal in the female 300 mg/kg group, cysts in the hindlimbs in 1 animal in the female 100 mg/kg group and polydactyly in 1 animal in the female 300 mg/kg group.

In the external examination in neonates, anophthalmia and polydactyly were observed in 1 animal each in the 300 mg/kg group. These anomalies are considered
to be spontaneous, because the incidences of these anomalies were extremely low and these are of types seen in historical control data.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: n.a.

Reproductive effects observed:

no

Conclusions:

The NOAEL for reproduction/developmental toxicity was considered to be 1000 mg/kg bw/day.

Executive summary:

Method

The study was conducted according to an OECD combined repeated dose toxicity study with the reproduction/developmental toxicity screening test guideline [TG 422] [MHLW, Japan: 2002] under GLP.

During the test Crj: CD (SD) IGS rats (12 animals/sex/dose) were administered with the test article by gavage at doses of 0 (vehicle: distilled water), 100, 300, or 1000 mg/kg bw/day. Males were dosed for 52 days from day 14 before mating and females were dosed from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period.

Observations

No compound-related effects on the estrous cycle, copulation index, fertility index, gestation length, gestation index, number of corpora lutea, or number of implantation sites were found in dams. No compound-related effects on the number, sex ratio, or viability were observed in pups on days 0 and 4 of lactation. Anophthalmia and polydactyly were observed in one pup at 300 mg/kg bw/day. These anomalies are considered to be spontaneous, because the incidences of these anomalies were extremely low and these are of types seen in historical control data. There were no compound-related changes in body weights of pups. No abnormal findings considered to be attributable to administration of this compound were observed in dead pups during lactation and pups at scheduled sacrifice.

Results

Based on these findings, the NOAEL of test item for reproduction/developmental toxicity was considered to be 1000 mg/kg bw/day in rats.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Test material

Test material information

1

Reference substance name:

trisodium (2S)-2,6-bis(3-carboxylatopropanamido)hexanoate

EC Number:

948-778-9

Molecular formula:

C14O8H19N2Na3

IUPAC Name:

trisodium (2S)-2,6-bis(3-carboxylatopropanamido)hexanoate

Test material form:

liquid

Details on test material:

Active ingredient (%): 48.9% dry substance
Purity (%): 95.50 %
Stability: 5 years
Sterilization: None
Solubility: Soluble in water
Storage: Room Temperature

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: n.a.

Results: F1 generation

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: n.a.

Target system / organ toxicity (F1)

Critical effects observed:

no

Overall reproductive toxicity

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

A combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, according to OECD Guideline 422, is available for the source substance, showing that the substance is not toxic for reproduction.
According to the rationale explained in details in the attached justification for read across, it is assumed that target and read-across substance, do share the same toxicological mechanisms and the effects of the target substance are predicted to be equal to the effects of the source substance.
The target substance is not considered toxic for the reproduction.