Registration Dossier

Toxicological information

Repeated dose toxicity: other routes

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: other route
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Test procedures in accordance with accepted standard methods, insufficiently documentation, statistical method not described.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1977

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rats were treated with the test substance subcutaneously for 30 days.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 7 weeks old
- Weight at study initiation: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 2 ℃
- Humidity (%): 55 +/- 5 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Route of administration:
subcutaneous
Vehicle:
physiological saline
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
30 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
1 500 mg/kg bw/day
No. of animals per sex per dose:
male and female each 10 rats/group
Control animals:
yes, concurrent vehicle
Details on study design:
In this study, egg albumin was also used as a test substance, but the data of the egg albumin were omitted.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes

FOOD CONSUMPTION: No data

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- How many animals: 5 animals

CLINICAL CHEMISTRY: Yes
- How many animals: 5 animals

URINALYSIS: Yes

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- How many animals: 5 animals

HISTOPATHOLOGY: Yes
- How many animals: 5 animals
Other examinations:
no
Statistics:
Statistics was used, but the method was not descibed in the article.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
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:
No deaths were observed in all groups. At the begining of the dosing period, spontaneous locomotion, respiratory depression and ptosis were observed in both sexes receiving glycine (1500 mg/kg) from ca. 20 minutes after dosing till 3 or 4 hours later. These signs almost disappeared 10 days after dosing. Hardening or necrosis was observed at the injection site of the test substance treated groups and progressed to marked necrosis by the end of the injection period.

BODY WEIGHT AND WEIGHT GAIN: no effects

FOOD CONSUMPTION: The food consumption in the males of the 1500 mg glycine/kg group was temporarily slightly less than in the control group.

FOOD EFFICIENCY: not examined

WATER CONSUMPTION: not examined

OPHTHALMOSCOPIC EXAMINATION: not examined

HAEMATOLOGY:
The number of white blood cells was significantly increased in both sexes of the 1500 mg/kg bw/d dose group. Differential count of neutrophils in females of the high dose group was significantly increased and lymphocytes were significantly decreased when compared to controls. In males of the 100 mg/kg bw/d dose group, differential count of neutrophils was significantly increased and lymphocytes were significantly decreased when compared to controls.

CLINICAL CHEMISTRY: no effects

URINALYSIS: no effects

NEUROBEHAVIOUR: not examined

ORGAN WEIGHTS: Significantly increased weights of spleen were observed in both sexes in the 1500 mg glycine/kg group.

GROSS PATHOLOGY: no effects

HISTOPATHOLOGY: NON-NEOPLASTIC:
Slight cell infiltration in peri-bronchus, liver (glisson's sheath, hepatic lobule) or kidney, bile duct proliferation or sinusoidal dilatation in liver, vacuolation in adrenal gland, extramedullary hematopoiesis in spleen were observed among control and treated groups. No abnormal findings were found in brain, heart, pancreas, stomach, duodenum, rectum, femur, testis and ovary.

HISTOPATHOLOGY: NEOPLASTIC: no effects

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
1 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
100 - 1 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

In both sexes receiving glycine, no deaths were found and the body weight gains were normal compared to the control groups during the dosing period. Necrosis were observed at injection sites in the glycine groups. Especially, in males and/or females received 1500 mg glycine/kg, increased number of white blood cells and of differential count of neutrophils, and increased spleen weight were detected, indicating the non-specific irritation caused by glycine. No histological findings were also detected in the glycine groups. See Tables 1 and 2.

      

Table 1. Hematological examination

Sex Dose(mg/kg) Erythrocyte Leucocyte Hemoglobin Hemogramm %
x 104/mm3 x 102/mm3 Sahli % Neutrophil Lymphocyte
Male Control (saline)   0 1081 +/- 49.9 103 +/- 8.1 99 +/- 3.1 12 87
Glycine  100 1014 +/- 51.4 107 +/- 7.0 95 +/- 1.4 *26 *71
Glycine 1500 1167 +/- 31.0 *184 +/- 14.4 90 +/- 0.5 22 76
Female Control (saline)   0 1119 +/- 51.5 89 +/- 9.5 103 +/- 1.7 11 88
Glycine  100 1060 +/- 28.6 118 +/- 2.0 89 +/- 1.9 11 89
Glycine 1500 1167 +/- 60.0 *181 ± 6.7 100 ± 2.9 *24 *73

*Significant difference from the control (P<0.05)

      

      

Table 2. Ogan weights

Sex Group Dose(mg/kg) Spleen (g)
Male Control (saline)   0 0.78 +/- 0.09
Glycine  100 0.96 +/- 0.30
Glycine 1500 *1.16 +/- 0.18
Female Control (saline)   0 0.63 +/- 0.15
Glycine  100 0.78 +/- 0.25
Glycine 1500 *1.13 +/- 0.25

*Significant difference from the control (P<0.05)

      

      

Applicant's summary and conclusion