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

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Published report by US Government agencies.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl N-acetyl-N-butyl-β-alaninate

EC Number:

257-835-0

EC Name:

Ethyl N-acetyl-N-butyl-β-alaninate

Cas Number:

52304-36-6

IUPAC Name:

ethyl N-acetyl-N-butyl-beta-alaninate

Constituent 2

Reference substance name:

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

IUPAC Name:

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

Details on test material:

Insect Repellent 3535 Technical
(Article Number 111887)
purity: 98.9%

Test animals

Species:

rabbit

Strain:

Himalayan

Administration / exposure

Route of administration:

oral: gavage

Details on exposure:

orally by gavage with 0, 0.1, 0.3 or 1.0 ml/kg/day
equivalent to 0, 100, 300 or 1000 mg/kg/day

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

During gestation day 6 to 19

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 300, 1000
Basis:
actual ingested

No. of animals per sex per dose:

15 mated females

Control animals:

yes, concurrent no treatment

Details on study design:

Range finder performed on non-pregnant animals showing adult toxicity at 1000 mg/kg, but tolerated.

Examinations

Maternal examinations:

Clinical signs, weight, food consumption, histology

Ovaries and uterine content:

Resorptions

Fetal examinations:

Yes - external malformations and histology

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
One female in the 300 mg/kg group died on day 26. Six females in the 1000 mg/kg group died or were euthanized in extremis.
Five of these deaths occurred during the treatment period.
The animals in the high dose group suffered significant weight loss and reduced food consumption between gestation days 6 and 13.
The animals in the 300 mg/kg group demonstrated reduced food consumption during the first week of dosing.
Pathological examination of the decedent animals revealed that three of the does in the 1000 mg/kg group demonstrated multifocal erosion of the stomach. Two of the animals in this group also suffered from tubular degeneration and edema in the Bowman’s capsule of the kidneys.

Effect levels (maternal animals)

1

Dose descriptor:

NOEL

Effect level:

ca. 100 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOEL

Effect level:

ca. 100 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

3

Dose descriptor:

LOAEC

Effect level:

ca. 300 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
In foetal development, there was a significant increase in the number of litters with early resorptions at the 300 mg/kg treatment level
The number of with malformations in the 1000 mg/kg group was greater than the control value (0/63 vs. 6/80). These included open eye (unilateral) (1), anasarca (1), flexed limbs (3), and fused sternabrae (1). In addition, one suffered from multiple malformations. None of these effects targeted a particular organ.

Effect levels (fetuses)

Dose descriptor:

other: There were some foetal effects at levels greater than the negative control, but only at dose levels leading to significant maternal toxicity. There was no pattern in the findings and it is not certain if these effects were significant.

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: See remarks

Remarks on result:

other: There were some foetal effects at levels greater than the negative control, but only at dose levels leading to significant maternal toxicity. There was no pattern in the findings and it is not certain if these effects were significant.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Negative with no foetal development effects at concentrations below that conisdered to be maternally toxic

Executive summary:

There were some foetal effects at levels greater than the negative control, but only at dose levels leading to significant maternal toxicity. There was no pattern in the findings and it is not certain if these effects were significant.

Maternal toxicity was significant at 1000 mg/kg, with clinical signs and histology findings (including liver). At 300 mg/kg, the maternal toxicity was less severe, but still significant.