N-(1-oxooctyl)glycine

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20 November 2007 - 21 January 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: compliant to GLP and testing guideline; adequate coherence between data, comments and conclusions.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

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)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-(1-oxooctyl)glycine

EC Number:

238-122-3

EC Name:

N-(1-oxooctyl)glycine

Cas Number:

14246-53-8

Molecular formula:

C10H19NO3

IUPAC Name:

N-(1-oxooctyl)glycine

Details on test material:

- Name of test material (as cited in study report): LCA07012
- Substance type: mono-constituent
- Physical state: white powder
- Purity: not indicated
- Impurities (identity and concentrations): not indicated
- Purity test date: not indicated
- Lot/batch No.: 0715800012
- Expiration date of the lot/batch: 6 June 2010
- Stability under test conditions: not indicated
- Storage condition of test material: at room temperature, protected from sunlight and humidity

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: breeder
- Age at first treatment: approx. 10 weeks
- Weight at first treatment (mean): M=403 g, F=257 g
- Housing: individually, except during pairing
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Relative humidity: 50 ± 20%
- Light/dark cycle: 12h/12h
- Ventilation: 12 cycles/hour of filtered, non-recycled air.

IN-LIFE DATES: beginning: 27 November 2007 / end: up to 21 January 2008

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
test item was ground, mixed with vehicle heated to 45°C, forming a solution.
The test item dosage forms were prepared at up to 11-day intervals

VEHICLE
- Justification for use and choice of vehicle (if other than water): not indicated
- Concentration in vehicle: 5, 15 and 40 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg/day
- Lot/batch no. (if required): S 35142-236, S 35142-017 and S 39776-337
- Purity: not indicated

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Data awaited from study director

Duration of treatment / exposure:

from 2 weeks before mating until the end of mating (males: total of 37-38 days) or day 5 pp (females: total of 42-55 days)

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25, 75, 200 mg/kg/day (m/f)
Basis:
other: Nominal per gavage

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: in a previous 14-day toxicity study in the rat (see 7.5.1) mortality occured at 1000 mg/kg/day and moderate toxicity (limited to clinical signs and weight gain) occured at 300 mg/kg/day.

- Rationale for animal assignment: computerized stratification procedure (average body weight of each group is similar)

- Satellite and post-exposure recovery period: not performed.

Positive control:

None

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule: day 1 and then weekly; and in F also days 0, 7, 14 and 20 post-coitum and days 1 and 5 post-partum

FOOD CONSUMPTION for each animal: Yes
- Time schedule: weekly (last 7-day consumption period)

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the day of sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5M+5F

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the day of sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5M+5F

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule: at the end of the treatment period for M, on day 5 post-partum for F
- Dose groups that were examined: all
- Battery of functions tested: behavior / reflexes / sensory activity / grip strength / motor activity / rectal temperature

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, adults and pups of all groups
ORGAN WEIGHTS: Yes, adults of all groups
HISTOPATHOLOGY: Yes, adults in control and high-dose

all : see Table 1

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Loud breathing was observed at all dose-levels but no microscopic abnormalities were found in the respiratory organs of the 200 mg/kg/day animals therefore it was considered that this clinical observation did not induce long-term effects. There were no unscheduled deaths at any dose-level.

BODY WEIGHT GAIN:
A minimally lower mean body weight gain during the first 2 weeks of treatment of the males treated at 200 mg/kg/day, with recovery during the second 2 weeks of treatment.

Effect levels

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: NOAEL = highest tested dose, without relevant effects.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Not necessary

Applicant's summary and conclusion

Conclusions:

Based on the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 200 mg/kg/day.

Executive summary:

The test item, LCA07012, was administered daily by oral gavage to male and female Sprague-Dawley rats, for 2 weeks before mating, during mating, gestation and until day 5 post-partum, at dose-levels of 25, 75 or 200 mg/kg/day.

Loud breathing was observed at all dose-levels but no microscopic abnormalities were found in the respiratory organs of the 200 mg/kg/day animals therefore it was considered that this clinical observation did not induce long-term effects. Males treated at 200 mg/kg/day gained minimally less weight during the first 2 weeks of treatment but some of this was recuped during the second 2 weeks and was therefore considered not to represent an effect of treatment. No histopathological lesions considered to be reflective of systemic toxicity were observed.