Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
data not available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference
Reference Type:
publication
Title:
Short-term toxicity of dimethyl sulfide in the rat
Author:
Butterworth KR, Carpanini FMB, Gaunt IF, Hardy J, Kiss IS and Gangolli
Year:
1975
Bibliographic source:
Fd Cosmet. Toxicol., vol. 13, pp 15-22

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
all the examinations were not performed
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): dimethyl sulphide (DMS)
- Substance type: pure active substance
- Physical state: liquid
- Analytical purity: min. 99%
- Impurities (identity and concentrations): data not available
- Purity test date: data not available
- Lot/batch No.: data not available
- Expiration date of the lot/batch: data not available
- Stability under test conditions: data not available
- Storage condition of test material: data not available

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: A. Tuck & Son, Rayleigh, Essex
- Age at study initiation: data not available
- Weight at study initiation: males were 75 to 90 g and females were 70 to 85 g
- Fasting period before study: data not available
- Housing: data not available
- Diet: ground Spiller's Laboratory Small Animal Diet, ad libitum
- Water: ad libitum
- Acclimation period: data not available

ENVIRONMENTAL CONDITIONS
- Temperature: 21 +/- 1°C
- Humidity: 50 to 60%
- Air changes: data not available
- Photoperiod: data not available

IN-LIFE DATES: data not available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: data not available

VEHICLE
- Amount of vehicle (if gavage): the dosage volume was 5 mL/kg/day
- Justification for use and choice of vehicle, Concentration in vehicle, Lot/batch no., Purity: data not available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
14 weeks
(additional groups were sacrificed after 2 or 6 weeks)
Frequency of treatment:
7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2.5, 25, 250 mg/kg bw/day
Basis:
no data
No. of animals per sex per dose:
15 males and 15 females per group
(only 5 animals/sex in the additional groups sacrificed after 2 and 6 weeks)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: data not available
- Rationale for animal assignment (if not random): data not available
Positive control:
none

Examinations

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


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: the animals were weighed on day 0 and then weekly throughout the test.


FOOD AND WATER CONSUMPTION: was measured over a 24-hr period preceding the day of weighing.


OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the appropriate period of dosing
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: haemoglobin, packed cell volume, red blood cells, reticulocytes, neutrophils, eosinophils, lymphocytes, monocytes


CLINICAL CHEMISTRY: Yes
Serum from all rats was analysed for the activities of glutamic-oxalacetic and glutamic-pyruvic transaminases and lactic dehydrogenase.


URINALYSIS: Yes
- Time schedule for collection of urine: during weeks 2, 6 and 14, urine was collected
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: appearance, microscopic constituents and content of glucose, ketones, bile salts and blood. A concentration and dilution test was carried out on the same animals, involving the measurement of the specific gravity and volume of urine produced in a 6-hr period of water deprivation and in a 2-hr period following a water load of 25 mL/kg. In addition, in the groups examined at week 6 and 14 the same measurements were made on the urine produced between 16 and 20 hr after the water load.


NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: at autopsy, any gross abnormalities were noted (no other information available)

HISTOPATHOLOGY: samples of brain, pituitary, thyroid, heart, liver, stomach, small intestine, caecum, spleen, kidneys, adrenal, gonads, salivary gland, trachea, oesophagus, colon, rectum, lymph nodes, lung, aorta, pancreas, urinary bladder, uterus and skeletal muscle were preserved in 10% buffered formalin. Paraffin-was sections of these tissues were stained with haematoxylin and eosin for microscopic examination. This examination was performed on the tissues from the rats given 250 mg DMS/kg/day for 14 weeks and from half of the control rats. In addition, the tissues from animals in which abnormalities were suspected at autopsy were examined
Other examinations:
none

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
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 examined
Details on results:
CLINICAL SIGNS AND MORTALITY:
All the rats appeared to be in good health throughout the study and no abnormalities in behaviour were observed.

BODY WEIGHT AND WEIGHT GAIN:
There were neither significant differences between the control and test groups of animals nor dose-related variations between the groups in their rate of body-weight gain (see Table 1 in the attached document)

FOOD AND WATER CONSUMPTION:
There were neither significant differences between the control and test groups of animals nor dose-related variations between the groups with respect to their food and water intake (see table 1 in the attache document)

HAEMATOLOGY:
There were no significant differences between the treated and control groups in the results of the haematological examinations (see Table 2 in the attached document)

CLINICAL CHEMISTRY:
There were no significant differences between the treated and control groups in the results of serum enzyme levels

URINALYSIS:
There were no abnormal urinary constituents in any of the animals. Although there were scattered changes in the volume and specific gravity of the urine, these were neither dose-related nor seen consistently in both sexes (see Table 3 in the attached document)

NEUROBEHAVIOUR

ORGAN WEIGHTS:
No statistically significant differences in organ weights were observed after treatment for 2 wk but, when expressed relative to body weight, the brain weight in the group of female rats given 250 mg/kg/day showed a statistically significant increase at this stage compared with those-of the control animals. There was no comparable increase in the brain weights of the male rats. At wk 6 there was a higher splenic weight in the male rats given 25 mg/kg/day and a lower heart weight in the females given 250 mg/kg/day. However, when these weights were expressed relative to body weight, the differences were no longer statistically significant. A reduction in the relative stomach weight in male rats given 25 mg/kg/day was statistically significant. At wk 14 the weight of the small intestine of the male rats was greater than that of the controls at all three dose levels (see Table 4 in the attached document). However, when this weight was expressed relative to body weight. the difference was no longer statistically significant in the rats given 2.5 mg/kg/day (Table 4). The female rats dosed with 250 mg/kg/day had a lower thyroid-gland weight than controls, the decrease being statistically significant (P < 0.01) both for the absolute and relative weight. Conversely, the corresponding male rats had heavier thyroid glands, although this was statistically significant only in respect of the relative organ weight.
The observed difference in organ weight were random, were not dose-related, and were not matched by the results obtained in the comparable group of rats of the opposite sex. They may therefore be assumed to have occurred by chance.

GROSS PATHOLOGY:
At autopsy, occasional pitting of the cortex of the kidneys and pallor of the liver were seen.

HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological examination revealed some degree of fatty degeneration of the liver cells and some chronic inflammation of both the lungs and kidneys. These changes were comparable in incidence and severity in the treated and control animals. No histological abnormalities were observed on the other organs, including the testes and ovaries.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 250 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No treatment-related effects were observed

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

see tables in the attached document

Applicant's summary and conclusion

Conclusions:
No effects on the rate of body-weight gain, intake of food and water, results of haematological examinations, serum-enzyme levels, urinary cell excretion, renal concentration tests, organ weights or histopathological examinations were attributable to the treatment. A NOAEL of 250 mg/kg body weight day was therefore established.
Executive summary:

Groups of male and female rats were given doses of dimethyl sulfide in corn oil by gavage for 2 (5/sex/group), 6 (5/sex/group), or 14 (15/sex/group) weeks at doses of 0, 2.5, 25, or 250 mg/kg bw/day.

No treatment-related effects were observed for body weights, food consumption, water consumption, hematology, and blood chemistry. Organ weights showed statistically significant increase in relative brain weight (to bodyweight) of female rats in the 250 mg/kg bw/day group at the 2-week interval. At 6 weeks, significant decreases in absolute, but not relative, heart weights were noted in these females. At 14 weeks, in male rats, absolute small intestine weights were significantly higher at all dose levels compared to the control group, and the relative small intestine weights were significantly increased at the highest two doses but not at the lowest dose. Females, dosed at 250 mg/kg bw/day, had statistically significant decreased absolute and relative thyroid weights (by 23 percent each). However, in males of this group, the relative thyroid weights were higher (by 19 percent). These organ weight changes could not be correlated with histopathological findings.  Histopathological examination revealed some degree of fatty degeneration of the liver cells and some chronic inflammation of lungs and kidneys. The incidence and severity of these changes were comparable in treated and control animals. No abnormalities were seen in testes and ovaries. The NOAEL was 250 mg/kg bw/day.