N-(2-hydroxyethyl)-N-[2-[(1-oxooctyl)amino]ethyl]-β-alanine

Toxicity to reproduction

Administrative data

Endpoint:

reproductive toxicity, other

Remarks:

Repeated Dose 28-Day Oral Toxicity in Rodents

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Version / remarks:

1996

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)

Version / remarks:

1995

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-(2-hydroxyethyl)-N-[2-[(1-oxooctyl)amino]ethyl]-β-alanine

EC Number:

264-761-2

EC Name:

N-(2-hydroxyethyl)-N-[2-[(1-oxooctyl)amino]ethyl]-β-alanine

Cas Number:

64265-45-8

Molecular formula:

C15H30N2O4

IUPAC Name:

N-(2-hydroxyethyl)-N-[2-[(1-oxooctyl)amino]ethyl]-β-alanine

Constituent 2

Reference substance name:

Water

EC Number:

231-791-2

EC Name:

Water

Cas Number:

7732-18-5

Molecular formula:

H2O

IUPAC Name:

water

Test material form:

liquid

Details on test material:

- Analytical purity: 50.6%
- Physical state: liquid

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Approximately 6 weeks.
- Weight at study initiation:
- Fasting period before study: no
- Housing: in groups of 5 per sex in Macrolon cages (M IV type, height 18 cm; during overnight activity monitoring individual housing in
Mlll type; height 15 cm) with sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lilico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): pelleted rodent diet (SM R/M-Z from SSNlFF Spezialdiaten GmbH, Soest, Germany), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.4 - 22.7°C
- Humidity (%): 30 - 74%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test substance was administered undiluted.

Details on mating procedure:

animals were not mated

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once daily, 7 days a week

Details on study schedule:

animals were not mated

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

No. of animals per sex per dose:

5

Control animals:

other: yes, from day 15 onwards Milli-Q water was used

Details on study design:

- Dose selection rationale: The dose levels were selected on the basis of a 5-day dose range finding study
- Rationale for animal assignment: By computer-generated random algorithm according to body weight

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean weekly diet consumption calculated as g food/kg body weight/day

WATER CONSUMPTION: subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.

OTHER: presented in more detail in section "repeated dose toxicty"
HAEMATOLOGY, CLINICAL CHEMISTRY, NEUROBEHAVIOURAL EXAMINATION

Oestrous cyclicity (parental animals):

not examined

Sperm parameters (parental animals):

not examined

Litter observations:

n.a.

Postmortem examinations (parental animals):

GROSS PATHOLOGY: Yes, all animals assigned to the study
ORGAN WEIGHTS: Yes, presented in more detail in section "repeated dose toxicity"
HISTOPATHOLOGY: Yes, presented in more detail in section "repeated dose toxicity"

Postmortem examinations (offspring):

n.a.

Reproductive indices:

n.a.

Offspring viability indices:

n.a.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

There were no clinical signs of toxicity noted over the 28-day observation period.
Salivation as observed among all animals at 1000 mg/kg bw/day and three males at 150 mg/kg bw/day was considered to be of no toxicological significance taking into account the nature and minor severity of this finding. Instead, salivation was considered to be a physiological response to taste and/or irritancy of the test substance upon oral administration.
Alopecia of the forelegs of one male at 50 mg/kg bw/day was a sign within the range of findings encountered in this type of study and was of no toxicological relevance. No clinical signs were noted among control animals, and females at 50 and 150 mg/kg bw/day.

Mortality:

no mortality observed

Description (incidence):

No mortality occurred during the study period.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No toxicologically significant changes in body weights and body weight gain of treated animals were noted.
The slightly lower body weight and body weight gain of males at 1000 mg/kg bw/day in the first week of treatment (achieving a level of statistical significance for body weights) was considered to be of no toxicological significance. The change was of a temporary and slight nature (i.e. within the range considered normal for rats of this age and strain).

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption before or after allowance for body weight was similar between treated and control animals.

Food efficiency:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

There were no microscopic findings recorded which could be attributed to treatment with the test substance.
All microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated rats.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Details on results (P0)

OTHER FINDINGS (PARENTAL ANIMALS)
further results are presented in more detail in section "repeated dose toxicity"

Effect levels (P0)

Dose descriptor:

NOAEL

Remarks:

fertility paramaters

Effect level:

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

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no treatment-related effects up to and including the highest administered dose

Target system / organ toxicity (P0)

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Overall reproductive toxicity

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

On the basis of the results obtained in this study, the dose level of 1000 mg/kg bw/day was considered the NOAEL for general toxicity and for fertility parameters.

Executive summary:

In this Repeated Dose, 28-day Oral Toxicity Study performed according to OECD guideline 407 (1995) and EU Method B.7 (1996) Amphopropionate C8  (50.6 % a.i) was administered to groups of 5 male and 5 female Wistar rats by oral gavage at dose levels of 10, 150 and 1000 mg/kg bw/day for 28 days. The control group animals received MilliQ water from day 15 onwards.

All animals survived to study termination. No test substance-related findings were detected or observed in clinical examinations, body weights, food consumption values, neurobehaviour, haematology, clinical biochemistry and clinical pathology evaluations. During the anatomical pathology examinations, no test substance-related findings were observed or detected during macroscopic examinations, organ weight evaluations or microscopic examinations. In specific, no effects were noted on reproductive organs examined in this study.

There is no evidence for specific target organ toxicity in this study.

The NOAEL is ≥ 1000 mg/kg bw/day in this study.