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Toxicological information

Repeated dose toxicity: other routes

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Administrative data

Endpoint:
short-term repeated dose toxicity: other route
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1980
Report date:
1980

Materials and methods

Principles of method if other than guideline:
- Short description of test conditions: The teratogenic effects of N-acetyl-L-tryptophan was investigated in JCL-ICR mouse.
The test substance was intraperitoneally (i.p.) administered to pregnant mice at doses of 100, 300 and 900 mg/kg bw/day from Day 6 to Day 15 of gestation. In the i.p. administration group, two-third of the mice (F0) were sacrificed for fetal examination on Day 18 of gestation, while the rest of the mice were allowed to deliver naturally for the observation of the offspring (F1) postnatally.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-acetyl-L-tryptophan
EC Number:
214-935-9
EC Name:
N-acetyl-L-tryptophan
Cas Number:
1218-34-4
Molecular formula:
C13H14N2O3
IUPAC Name:
N-acetyl-L-tryptophan
Test material form:
solid

Test animals

Species:
mouse
Strain:
ICR
Remarks:
JCR-ICR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: CLEA Japan, Meguro, Japan
- Age at study initiation: 12 - 13 weeks
- Diet: MF except for gestation and lactation period and NMF for gestation and lactation period, purchased by Oriental Yeast Co., Ltd, Japan, were given ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
water
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
females: 10 days; (from Day 6 to 15 of gestation (GD))
Frequency of treatment:
once a day
Doses / concentrationsopen allclose all
Dose / conc.:
900 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Group 1: 20, 22, 23, and 22 animals in control, 100, 300 and 900 mg/kg bw/day, respectively, sacrifice on
GD 18
Group 2: 13, 11, 12 and 12 animals in control, 100, 300 and 900 mg/kg bw/day, respectively, sacrifice of dams on Day 21 post partum
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were selected based on range-finding tests.
No mortality was observed after i.p. application of 2400 mg/kg bw/day. However, due to technical reasons, 900 mg/kg bw/day was applied as the highest dose for i.p administration.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: every other day

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: every other day

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- sacrifice on GD 18 or day 21 post partum
- Organs examined: brain, pituitary, thymus, heart, lungs, liver, kidneys, spleen, adrenals, ovaries

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on GD 18
- Anaesthetic used for blood collection: Yes, chloroform
- How many animals: 20, 22, 23 and 22 animals in control, 100, 300 and 900 mg/kg bw/day group, respectively
- Parameters checked: red blood cell count (RBC), white blood cell count (WBC), haemoglobin, haematocrit

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on GD 18
- How many animals: 20, 22, 23 and 22 animals in control, 100, 300 and 900 mg/kg bw/day group, respectively
- Parameters checked: total protein, urea N, GOT (glutamate oxaloacetate transaminase), GPT (glutamate pyruvate transaminase)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: No
Statistics:
Wilcoxon test: fetal mortality, number of fetus with external abnormalities, number of fetus with sk
eletal abnormalities except for ossification, number of fetus with visceral abnormallities, number of
offspring with malformation and variation, number of live offspring, and postnatal differentiaion
Chi-squared test: sexratio, copulation ratio, pregnancy rate, delivering rate, and mortality
t test: other items

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Mortality was observed in the control (1 dam died 10 days post partum) and 300 mg/kg bw/day group (1 dam died 20 days post partum). Due to missing pathological findings and the low incidence, the mortality is considered to be incidental.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Food consumption was statistically significantly decreased in the 900 mg/kg bw/day group. As body weights were not altered in any group, this effect is not considered as treatment-related or adverse.
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):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
>= 900 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Remarks on result:
other: no adverse effets observed up to the highest dose applied

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Table 1. Effect of N-acetyl-L-tryptophan on pregnant mice intraperitoneally treated on days 6 to 15 of gestation

 

Control

N-acetyl-L-tryptophan (mg/kg)

100

300

900

No. of pregnant mice

20

22

23

22

Food consumption during pregnancy (g ± S.D.)

139.1 ± 10.3

142.2 ± 15.6

131.9 ± 14.4

129.5 ± 11.6**

**:       significantly different from control at P < 0.01

 

 

Table 2. Effect of N-acetyl-L-tryptophan on dams intraperitoneally treated on days 6 to 15 of gestation

 

Control

N-acetyl-L-tryptophan (mg/kg)

100

300

900

No. of dams

13

11

12

12

Organ weight

Liver

 (g ± S.D.)

2.67 ± 0.28

2.60 ± 0.27

2.91 ± 0.24*

2.79 ± 0.36

*:        significantly different from control at P < 0.05

 

 

Table 3. Organ weights and hematological findings of 91-day aged offspring

 

 

Control

N-acetyl-L-tryptophan (mg/kg)

100

300

900

No. of male offspring sacrificed

13

11

12

12

Organ weight

Adrenals

 (g ± S.D.)

0.0056 ± 0.012

0.0069 ± 0.017*

0.0062 ± 0.0011

0.0066 ± 0.0016

No. of female offspring sacrificed

13

11

12

11

GOT

(mU/mL ± S.D.)

42 ± 3

42 ± 9

46 ± 8

51 ± 10**

*:        significantly different from control at P < 0.05

**:      significantly different from control at P < 0.01

Applicant's summary and conclusion

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