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Key value for chemical safety assessment

Effects on fertility

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, 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.

Additional information