Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: other route
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given

Data source

Reference
Reference Type:
publication
Title:
Lithium chloride and dilithium carbamyl phosphate: lithium distribution and toxicity in mice
Author:
Jernigan, H.M., et al.
Year:
1977
Bibliographic source:
Toxicol Appl Pharmacol. 1978 May;44(2):413-21

Materials and methods

Principles of method if other than guideline:
Two groups of 15 mice each were given lithium chloride at 600 mg/kg bw/d twice-daily via ip-injections for 21, 23 or 30 days. Lithium concentrations were measured in blood and tissue samples.
GLP compliance:
no
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Supplier: Mallinckrodt Chemical Works, St. Louis, Missouri, USA
- Analytical purity: no data given

Test animals

Species:
mouse
Strain:
C57BL
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 168 - 180 days
- Diet: Purina Mouse Chow; ad libitum
- Water: water; ad libitum

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
21, 23, 30 days
Frequency of treatment:
twice daily
Doses / concentrations
Remarks:
Doses / Concentrations:
600 mg/kg bw/d
No. of animals per sex per dose:
15 animals
Control animals:
other: Dilithium Carbamyl Phosphate, 1200 mg/kg bw/d

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 2 days prior to dosing, 4-6 h after first dose, on days 2, 7, 14, 21, 23, 30
- Animals fasted: No data
- How many animals: each animal
- Parameters were examined: leukocyte counts, packed cell volume. and random reticulocyte counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 2 days prior to dosing, 4-6 h after first dose, on days 2, 7, 14, 21, 23, 30
- Animals fasted: No data
- How many animals: each animal
- Parameters were examined: lithium content

URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes: Spleen, brain, spinal cord, lumbar spinal nerve, lung, heart, skeletal muscle, parotoid salivary gland, thyroid, adrenal, kidney, urinary bladder, testes, epididymis, ovaries, oviduct, fetuses, lens, eye (lens removed), bone (cranium), skin and hair, liver, gall bladder, stomach, duodenum, ileum, cecum, colon
Other examinations:
Tissue lithium was determined by the modified method of Schou (1958). Lithium analysis of tissue or of blood was done using a Perkin—Elmer Model 290E atomic absorption spectrophotometer.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
3/7 males and 3/8 females of the lithium chloride group, and 7/10males and 1/5 females of the dilithium carbamide phosphate group died during the first 21 days. No spontanous deaths were noted thererafter. No mice died within 17 days after administration of sodium chloride.

BODY WEIGHT AND WEIGHT GAIN
The surviving mice in both groups had a small weight loss in the first week; thereafter they were gradually regaining the lost weight (no further data given).

HAEMATOLOGY
The mean leukocyte counts and the hematocrit of surviving mice in both groups decreased with time. At autopsy, the reticulocyte counts were elevated in both groups (greater than 4%) in all mice examined. Reticulocyte counts were highest (up to 11%) in those individual mice which had the lowest hematocrits.

CLINICAL CHEMISTRY
- The mean lithium concentrations in blood at different time points ranged from 1 to 2 mEq/liter with a mean for each group of 1.7 ± 0.7 mEq/liter averaging all values measured after lithium administration began. At the last routine bleeding before a nonsurvivor died, blood lithium ranged from 1.3 to 12 mEq/liter for lithium chloride and 1.4 to 11 mEq/liter for dilithium carbamide phosphate.
- After normalizing the dose of lithium, there were no significant differences (p > 0.05 using Student’s t-test) in survivors comparing the lithium concentration of each tissue in both groups (see table).

GROSS PATHOLOGY
At autopsy, no infection. inflammation, or hematomas were found at the site of the injections or in the peritoneal cavity.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
< 600 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: mortality and hematological effects
Dose descriptor:
NOAEL
Effect level:
< 1 400 mg/kg bw/day
Based on:
other: silicic acid, lithium salt
Sex:
male/female
Basis for effect level:
other: recalculated value based on the assumption that silicic acid, lithium salt contains 7% lithium (corresponding to MR: 2.8)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Tab. 1: Whole blood lithium concentration (mEy/L; mean ± SD) in mice survived until the end of study:

Days on study
0 2 7 14 21-30
Lithium chloride (n = 6) 0 1.9 ± 1.0 1.9 ± 0.5 1.6 ± 0.4 1.4 ± 0.5
Dilithium carbamide phopshate (n = 8) 0 1.9 ± 1.1 2.0 ± 0.6 1.1 ± 0.3 1.9 ± 0.6

Tab. 2: Lithium distribution in tissues (mEq/kg wet weight):

Surviving 3 weeks Died during 3 weeks
Tissue Lithium chloride Dilithium carbamide phopshate  Lithium chloride Dilithium carbamide phopshate 
Number of animals 3 males, 3 females 7 males, 1 female 4 males, 5 females 3 males, 4 females
Blood (mEq/L) 1.4 ± 0.5 1.9 ± 0.6 - -
Spleen 1.2 ± 0.3 18 ± 0.5 3-13 7-26
Brain 1.2 ± 0.2 1.8 ± 0.5 8-12 6-18
Spinal Cord 1.3 ± 0.4 1.7 ± 0.4 3-12 6-12
Lumbar spinal nerve 2.4 ± 0.7 3.1 ± 1.0 (d) - -
Lung 1.9 ± 0.6 2.6 ± 0.8 11-18 5-13
Heart 1.8 ± 0.5 2.4 ± 0.6 4-18 6-28
Skeletal muscle 2.7 ± 0.9 3.4 ± 0.6 4-20 6-29
Parotoid salivary gland 2.2 ± 0.4 2.9 ± 0.6 10-15 6-24
Thyroid 1.9 ± 1.3 3.7 ± 2.2 13-31 9-50
Adrenal 2.0 ± 1.6 1.8 ± 0.6 4-12 5-23
Kidney (whole) 2.2 ± 0.5 2.7 ± 0.8 4-12 6-22
Kidney (cortex) 2.3 ± 0.6 2.8 ± 0.8 4-14 6-23
Kidney (remainder) 2.3 ± 0.5 3.0 ± 0.7 4-13 6-21
Urinary bladder 2.1 ± 0.7 (d) 4.0 ± 1.3 5-15 8-49
Urine (mEq/L) 8.1 (e) 19.46 (e) - -
Testes 1.4 ± 0.4 1.5 ± 0.5 4-10 5-21
Epididymis 2.2 ± 1.1 4.0 ± 1.6 4-15 7-17
Ovaries 1.5 ± 0.8 1.2 (e) 8 (e) 10 (e)
Oviduct 1.0 ± 0.3 - - 4 (e)
Fetuses - - 4-6 10-15
Lens 1.6 ± 0.4 2.3 ± 0.7 (d) 3-16 9-25
Eyes (lens removed) 2.5 ± 0.5 3.8 ± 1.2 16-21 11-38
Bone (Cranium) 2.5 ± 0.3 3.0 ± 1.0 6-16 6-79
Skin and hair 7.1 ± 2.8 4.5 ± 1.7 8-15 8-18
Liver 0.8 ± 0.3 1.1 ± 0.5 4-12 6-14
Gall bladder 1.9 ± 1.2 2.6 ± 0.7 6-13 2-17
Bile (gall bladder) 10.7 (e) 4.3, 9.5 (e) - -
Stomach tissue 1.2 ± 0.8 2.2 ± 2.1 (d) 4-7 12 (e)
Stomach contents 1.2 ± 0.9 1.2 ± 0.4 (f) 4-7 4-11
Duodenum tissue 1.5 ± 0.4 1.6 ± 0.8 (d) 4-16 9-27
Duodenum contents 2.2 ± 1.2 2.6 ± 0.9 6-16 10-32
Ileum tissue 1.8 ± 0.4 3.1 ± 1.4 (d) 6-20 10-42
Ileum contents 1.9 ± 0.7 5.3 ± 4.2 5-19 9-31
Cecum tissue 3.8 ± 0.4 7.0 ± 2.5 (d) 6-33 14-89
Cecum contents 4.8 ± 1.6 10.1 ± 3.7 7-40 14-97
Colon tissue 3.4 ± 0.8 5.5 ± 2.1 (d) 6-21 10-27
Colon contents 9.1 ± 4.3 15.2 ± 7.0 6-20 23-80
Feces - 25 ± 10 - -

d: one mouse showing very high lithium content in this tissue was not included in the average

e: single sample

f: two mice showing very high lithium content in this tissue were not included in the average

 

Applicant's summary and conclusion