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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Preferred study for this SIDS endpoint. Study predates GLP; however, method was comparable to OECD Guideline 408. The effect of DBT exposure on the thymus of was not assessed in this study. No information on the stability or homogeneity of the test material in the DBTC-prepared diets.

Data source

Reference
Reference Type:
publication
Title:
Acute and Short-term Toxicity Studies on Di-n-butyltin Dichloride in Rats
Author:
Gaunt, I.F., Colley, J., Grasso, P., Creasy, M. and Gangolli, S.D.
Year:
1968
Bibliographic source:
Fd Cosmet. Toxicol. Vol. 6, pp. 599-608. Pergamon Press 1968. Printed in Great Britain

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
not specified
Principles of method if other than guideline:
Groups of 16 male and 16 female weanling rats, housed four per cage, were fed diets containing either 0 (control), 10, 20, 40 or 80 ppm di-n-butyltin dichloride for 90 days. Body weight and food consumption were measured weekly. Haematological investigations were made at week 6 on blood from the tail veins of eight rats of each sex from the 0-, 40- and 80-ppm groups and terminally on blood from the dorsal aorta of all rats. The blood was examined for haemoglobin concentration and haematocrit value and counts were made of erythrocytes, reticulocytes and total and differential leucocytes. Liver function was assessed terminally by measuring the activities of glutamic-oxaloacetic and glutamic-pyruvio transaminases. Amylase activity in the serum was measured terminally in rats from the control and 80-ppm groups as an index of pancreatic damage. Kidney function tests were conducted at wk 6 on six rats of each sex from each level of treatment and on all rats terminally. The urine was examined for colour, pH, microscopic constituents, the content of protein, glucose, bile salts, blood and tin and activity of glutamic-oxaloacetic transaminase. Terminally, measurements were made of serum-urea concentrations. The concentrating ability of the kidney was assessed by measuring the volume and specific gravity of urine produced under conditions of normal hydration, during a 6-hr period of water deprivation, during a 2-hr period after a water load of 25 ml/kg and during a 4-hr period commencing 16 hr after the water load.
Terminally all the rats were killed and subjected to autopsy, during which a careful search was made for gross changes with special reference to the bile duct and pancreas. The brain, pituitary, heart, thyroid, liver, spleen, kidneys, adrenals and gonads were weighed. The duodenal loop with the pancreas and bile duct in situ were fixed flat so as to retain their anatomical relationship. Paraffin-wax sections of these organs, together with salivary gland, trachea, lungs, diaphragm, various lymph nodes, thymus, stomach, ileum, colon, caecum, rectum, urinary bladder, sternum and uterus were stained with haematoxylin and eosin for histopathological examination.
GLP compliance:
no
Remarks:
Pre-dates GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The sample of di-n-butyltin dichloride used in these studies was supplied by Albright & Wilson (Mfg) Ltd., London S.W.1. It was stated to contain 99.7 % di-n-butyltin dichloride and 0.25 % tri-n-butyltin dichloride.

Test animals

Species:
rat
Strain:
other: CFE
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: nda
- Age at study initiation: weanling rats
- Weight at study initiation: Males: 181-189 g; Females: 147-153 g
- Fasting period before study: nda
- Housing: 4 per cage
- Diet (e.g. ad libitum): The basal diet was Spillers' Laboratory Small Animal Diet which was provided ad lib.
- Water (e.g. ad libitum): Water was provided ad lib.
- Acclimation period: nda


ENVIRONMENTAL CONDITIONS
- Temperature (°C): nda
- Humidity (%): nda
- Air changes (per hr): nda
- Photoperiod (hrs dark / hrs light): nda


Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
nda
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
nda
Duration of treatment / exposure:
90 day oral feed study
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
10 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
20 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
40 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
80 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
Groups of 16 male and 16 female weanling rats, housed four per cage, were fed diets containing either 0 (control), 10, 20, 40 or 80 ppm di-n-butyltin dichloride for 90 days.
Control animals:
yes, plain diet
Details on study design:
nda
Positive control:
nda

Examinations

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

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight was measured weekly.

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

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Haematological investigations were made at week 6 on blood from the tail veins of eight rats of each sex from the 0-, 40- and 80-ppm groups and terminally on blood from the dorsal aorta of all rats. The blood was examined for haemoglobin concentration and haematocrit value and counts were made of erythrocytes, reticulocytes and total and differential leucocytes.

URINALYSIS: Yes
- Time schedule for collection of urine: Kidney function tests were conducted at week 6 on six rats of each sex from each level of treatment and on all rats terminally. The urine was examined for colour, pH, microscopic constituents, the content of protein, glucose, bile salts, blood and tin and activity of glutamic-oxaloacetic transaminase.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Terminally all the rats were killed and subjected to autopsy, during which a careful search was made for gross changes with special reference to the bile duct and pancreas. The brain, pituitary, heart, thyroid, liver, spleen, kidneys, adrenals and gonads were weighed. The duodenal loop with the pancreas and bile duct in situ were fixed flat so as to retain their anatomical relationship.


HISTOPATHOLOGY: Yes
Paraffin-wax sections of these organs, together with salivary gland, trachea, lungs, diaphragm, various lymph nodes, thymus, stomach, ileum, colon,caecum, rectum, urinary bladder, sternum and uterus were stained with haematoxylin and eosin for histopathological examination.
Other examinations:
nda
Statistics:
nda

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
no effects observed
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:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no deaths at any level of feeding of di-n-butyltin dichloride (up to 80 ppm) or any effects on the behaviour or condition of the rats.

BODY WEIGHT AND WEIGHT GAIN
There was a slight reduction of growth in both sexes fed 80 ppm but this was statistically significant only in females.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Some reduction in food intake was noted which may have been due to unpalatability since in the preference test, even at 10 ppm, there was a marked preference for the basal diet.

HAEMATOLOGY
In the haematological examination there were decreases in haemoglobin concentrations. These were confined to the highest level of feeding (80 ppm) and seen in females at week 6 and males at week 13. The decreases, although statistically significant were slight and not associated with reductions of other erythrocyte parameters or with a reticulocytosis.

URINALYSIS
There were no deviations from normal in the serum-urea or -enzyme levels or in the urine parameters measured. Tin was not found in any of the urine samples examined.

NEUROBEHAVIOUR
No effects on the behaviour were seen.

ORGAN WEIGHTS
There were, no changes in relative organ weights.

GROSS PATHOLOGY
No abnormalities were seen at autopsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
There were no differences between test and control animals in the findings in any of the tissues examined.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
40 ppm
Sex:
male/female
Basis for effect level:
other: This dietary concentration is equivalent to an intake of 2 mg/kg/day.
Dose descriptor:
LOAEL
Effect level:
80 ppm
Sex:
male/female
Basis for effect level:
other: There was a slight reduction of growth and food intake at this dietary level. The only other finding was a mild anaemia.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

There was a slight reduction of growth and food intake at the highest dietary level. The only other finding was a mild anaemia at the 80 ppm level.

This study has shown that the no-effect level of di-n-butyltin dichloride in the diet of rats for 90 days is 40 ppm, with only very marginal changes at twice this level. This dietary concentration is equivalent to an intake of 2 mg/kg/day. Allowing the usual 100-fold safety factor this would suggest a safe intake for man of 0.02 mg/kg/day, or 1.2 mg/day for a 60-kg adult.

Applicant's summary and conclusion

Conclusions:
This study has shown that the no-effect level of di-n-butyltin dichloride in the diet of rats for 90 days is 40 ppm, with only very marginal changes at twice this level. This dietary concentration is equivalent to an intake of 2 mg/kg/day. Allowing the usual 100-fold safety factor this would suggest a safe intake for man of 0.02 mg/kg/day, or 1.2 mg/day for a 60-kg adult.
Executive summary:

In a 90 day feeding study in male and female rats the no-effect level of di-n-butyltin dichloride is 40 ppm, with only very marginal changes at twice this level. This dietary concentration is equivalent to an intake of 2 mg/kg/day. Allowing the usual 100-fold safety factor this would suggest a safe intake for man of 0.02 mg/kg/day, or 1.2 mg/day for a 60-kg adult.

There were no deaths at any level of feeding of di-n-butyltin dichloride (up to 80 ppm) or any effects on the behaviour or condition of the rats. There was a slight reduction of growth in both sexes fed 80 ppm but this was statistically significant only in females. It was accompanied by some reduction in food intake which may have been due to unpalatability since in the preference test, even at 10 ppm, there was a marked preference for the basal diet. In the haematological examination there were decreases in haemoglobin concentrations. These were confined to the highest level of feeding (80 ppm) and seen in females at week 6 and males at week 13. The decreases, although statistically significant were slight and not associated with reductions of other erythrocyte parameters or with a reticulocytosis. There were no deviations from normal in the serum-urea or -enzyme levels or in the urine parameters measured. Tin was not found in any of the urine samples examined. There were, no changes in relative organ weights and no abnormalities were seen at autopsy. There were no differences between test and control animals in the findings in any of the tissues examined.