Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

This section to be updated upon receipt of key study (see accompaying documents)

There is no specific test data available on potential reproductive toxic effect of Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 308062-60-4.  

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28 day (males)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Remarks:

Work performed to OECD guidelines in 2009 and approved by the US Environmental Protection Agency Statement in report claiming the data covers range of alklyimines; specifically, "sodium and potassium salts of N-alkyl (C8-C18)-beta-iminodipropionic acid where the C8-C18 is linear and may be saturated and/or unsaturated, (CAS Reg. Nos. 110676-19-2, 3655-00-3, 61791-56-8, 14960-06-6, 26256-79-1, 90170-43-7, 91696-17-2, and 97862-48-1) [Ref 40 CFR Part 180, Federal Register Volume 76, number 24, 4 February 2011'

Justification for type of information:

Peer-reviewed US Government publication

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:

not specified

Remarks:

Claimed GLP but no detail

Limit test:

no

Species:

rat

Strain:

other: HanRcc:WIST (SPF)

Sex:

male/female

Route of administration:

oral: gavage

Details on mating procedure:

Cohabitation

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Dosing began 14 days before mating and continued for 28 days for males and for day four of lactation for females

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
600 mg/kg/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
160 mg/kg/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
43 mg/kg/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
Control 0 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

10 males and 10 females per group

Control animals:

yes, concurrent no treatment

Positive control:

None

Parental animals: Observations and examinations:

Clinical signs daily (including maternal behaviour)
Functional observation battery (FOB)
Food consumption
Body weights
Blood sampling
Body temperature (during FOB)

Litter observations:

Litter size and viabilty

Postmortem examinations (parental animals):

Yes

Postmortem examinations (offspring):

Yes, macroscopic examinations for malformation

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Taste aversion behaviour

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Yes, intermediate and high dose

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Yes, intermediate and high dose

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Liver and kidney

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Test substance intake: Decrease in top groups pre-mating

Reproductive performance:

no effects observed

Diffuse hypertrophy of the liver in males and females
Tubular degeneration/regeneration and hyaline droplets/granulation of the kidneys in males
Follicular hypertrophy of the thyroid in males and females
Acanthosis of the non-glandular stomach in males and females
Inflammation of the non-glandular stomach in males; and congestion, thrombosis and inflammation of the glandular stomach in females

Dose descriptor:

NOEL

Effect level:

> 43 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Reduced weight gain, adaptive changes to liver and kidneys

Dose descriptor:

NOAEL

Effect level:

ca. 160 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Reduced weight gain, adaptive changes to liver and kidneys

Dose descriptor:

LOAEL

Effect level:

ca. 600 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

No adverse effects on litter size or viability
No abnormalities reported

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 600 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No adverse effects on litter size or viability No malformations reported

Reproductive effects observed:

not specified

No treatment-related effects on litter size or survival were observed. No treatment-related effects on body weight were observed in offspring. Body weight gain was slightly decreased in males and females at 160 and 600 mg/kg/day, but there was no dose response.

No findings were observed on macroscopic examination of the offspring. The reproductive/developmental LOAEL for Sodium coco β-iminodipropionate in rats is not established.

The reproductive/developmental NOAEL is 600 mg/kg bw/day, the highest dose tested, in males and females.

Conclusions:

No treatment-related effects on litter size or survival were observed. No treatment-related effects on body weight were observed in offspring. Body weight gain was slightly decreased in males and females at 160 and 600 mg/kg/day, but there was no dose response.

No findings were observed on macroscopic examination of the offspring. The reproductive/developmental LOAEL for Sodium coco β-iminodipropionate in rats is not established.

The reproductive/developmental NOAEL is 600 mg/kg bw/day, the highest dose tested, in males and females.

Executive summary:

This EPA study is considered valid in terms of grouping of substances. Examination of data on various primary alkylamines show little difference in repeat toxicity effects, including reproduction, suggesting that there is minimal difference in terms of systemic toxicity between the different alklyamines, including branched and linear.

The comparison of sub-acute toxicity between the tested substance and the result of this EPA study are consistent and read-across is considered valid; the EPA study shows slightly more adverse effects than the Key Study (on the registered substance) over 28 days and is therefore considered a suitable surrogate for the reporting of reproductive effects.

The similarity in findings with work on primary amines further justifies read-across to these potential metabolites. This is reviewed in the assessment report attached in Section 13.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

600 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Test data referring to analogue substance as part of a review into this class of material. This is peer reviewed and published by US Government Agencies in support of use in cosmetics.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The US EPA review of Sodium Salts of N-Alkyl (C8-C18)-β-iminodipropionic Acid (SSNA) includes testing of the coco- derivative for reproductive toxicity screening. This shows parental toxicity effects, but no adverse effects on reproductive parameters. The EPA review concludes;

The parental systemic LOAEL for Sodium coco β-iminodipropionate in rats is 160 mg/kg bw/day, based on decreased body weight gain in males and females during the pre-mating period, and an increased incidence of microscopic lesions in the kidneys of males and glandular and acanthosis of the non-glandular stomach of females. The parental systemic NOAEL is 43 mg/kg bw/day.

No treatment-related effects on litter size or survival were observed. No treatment-related effects on body weight were observed in offspring. No findings were observed on macroscopic examination of the offspring.

Short description of key information:

Parental LOAEL= 160 mg/kg bw/day based on decreased body weight gain in males and females during the pre-mating period, and an increased incidence of microscopic lesions in the kidneys of males and acanthosis of the glandular + non-glandular stomachs of females.

Reproductive/ Developmental LOAEL was not observed.

Justification for selection of Effect on fertility via oral route:

Since there is no specific test data on potential reproductive toxic effect of Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, reference is made to a US Government review  on this class of material used as cosmetic ingredients.  In view of primary cosmetic use, it is considered that further animal testing is not appropriate and would be contrary to European principles.

Justification for selection of Effect on fertility via inhalation route:

Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 94441-92-6 is a paste with a low vapour pressure of < 1.5 mPa at 20°C, so it is not considered to be scientifically valid to conduct an inhalation study.

Justification for selection of Effect on fertility via dermal route:

Based on the physicochemical properties of Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 94441-92-6, it is considered very unlikely that dermal absorption would exceed oral absorption, so it is not considered relevant to conduct a dermal study.

Effects on developmental toxicity

Description of key information

There is no specific test data available on potential reproductive toxic effect of Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate

The US EPA review of Sodium Salts of N-Alkyl (C8-C18)-β-iminodipropionic Acid resulted in parental LOAEL= 160 mg/kg bw/day based on decreased body weight gain in males and females during the pre-mating period, and an increased incidence of microscopic lesions in the kidneys of males and acanthosis of the glandular + non-glandular stomachs of females.

Reproductive/ Developmental LOAEL was not observed.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

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

Justification for selection of Effect on developmental toxicity: via oral route:

Since there is no specific test data on potential reproductive toxic effect of Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, [more]

Justification for selection of Effect on developmental toxicity: via inhalation route:

Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 94441-92-6 is a paste with a low vapour pressure of < 1.5 mPa at 20°C, so it is not considered to be scientifically valid to conduct an inhalation study.

Justification for selection of Effect on developmental toxicity: via dermal route:

Based on the physicochemical properties of Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 94441-92-6, it is considered very unlikely that dermal absorption would exceed oral absorption, so it is not considered relevant to conduct a dermal study.

Toxicity to reproduction: other studies

Additional information

The US EPA review of Sodium Salts of N-Alkyl (C8-C18)-β-iminodipropionic Acid (SSNA) includes testing of the coco- derivative for reproductive toxicity screening. This shows parental toxicity effects, but no adverse effects on reproductive parameters. The EPA review concludes;

The parental systemic LOAEL for Sodium coco β-iminodipropionate in rats is 160 mg/kg bw/day, based on decreased body weight gain in males and females during the pre-mating period, and an increased incidence of microscopic lesions in the kidneys of males and glandular and acanthosis of the non-glandular stomach of females. The parental systemic NOAEL is 43 mg/kg bw/day.

No treatment-related effects on litter size or survival were observed. No treatment-related effects on body weight were observed in offspring. No findings were observed on macroscopic examination of the offspring.

Justification for classification or non-classification

No adverse effects were observed in terms of litter size or viability of the young.