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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
p-toluenesulfonic acid
IUPAC Name:
p-toluenesulfonic acid
Constituent 2
Chemical structure
Reference substance name:
Toluene-4-sulphonic acid
EC Number:
203-180-0
EC Name:
Toluene-4-sulphonic acid
Cas Number:
104-15-4
Molecular formula:
C7H8O3S
IUPAC Name:
4-methylbenzene-1-sulfonic acid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Housing: fully air conditioned makrolon cage (Type 4) on softwood granulate
Temperature: 22 ± 3 °C
Relative humidity: 50 ± 20 %
Light period: 12 hours
Acclimatization: 5 days
Food: ad libitum, food for animals Rattendiat Altromin 1324 (Altromin-GmbH, Lage/Lippe), ad libitum except for the time the animals were caged in metabolism
Water: Tap water in plastic drinking bottles, ad libitum except for the time the animals were caged in metabolism
Animals identification: Fur identification with KMn04, numbered ear tags and numbering of the cages

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
one per day, 7 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
males/females, Basis: actual ingested
Dose / conc.:
4 mg/kg bw/day (actual dose received)
Remarks:
males/females,Basis: actual ingested
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Remarks:
males/females, Basis: actual ingested
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
males/females,Basis: actual ingested
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
males/females,Basis: actual ingested
No. of animals per sex per dose:
25 males and 25 females in totale, 5 animals fper sex per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: In a preliminary study to establish the doses for the definitive study, a single dose of 1250 mg.kg bw of the test substance resulted in 40% mortality of female rats. The definitive study high dose was set at 500 mg/kg bw/d.
In an additional preliminary test, rats after daily oral administration of 10, 50 and 200 mg/kg bw showed no signs of intoxication over a period of 14 days. The dissection of the animals at the end of the experiment gave lightening of the liver in places in all dose groups. The histopathological examination of the gastrointestinal tract did not reveal any special features. On the basis of the results of this preliminary test and the acute oral toxicity, the doses of 4, 20, 100 and 500 mg / kg kg / day were determined for the main test.
Positive control:
no

Examinations

Observations and examinations performed and frequency:
The behavior and general state of health of the animals in use was tested twice a day during the experiment and once a day on weekends and public holidays. The rats were examined weekly for neurological disorders, clouding of the eye media, damage to the oral mucosa and disorders of tooth growth.
The body weights of all animals were determined at the beginning of the experiment and twice a week during the experiment.
The feed consumption was determined continuously (2 trolleys per week). The measured values printed out relate to the intervals between the body weight determinations. They are converted as feed consumption per 100 g body weight within 24 hours. The water consumption was determined once a week. It is stated as consumption per 100 g of body weight within 16 hours (3.15 p.m. - 7.15 a.m.).

Hematological examinations
At the end of the experiment, the blood count was examined in all male and female animals without prior feed withdrawal. Blood was drawn from the retro orbital venous plexus. In order to avoid systematic errors, the blood was drawn in accordance with randomization plan No. 641/89 (page 382).
Red blood cell count
Hemoglobin
Hematocrit
White blood cell count
Platelet count
Differential blood count
Reticulocyte count *
Heinz inner body *
Clotting time
* These studies were only carried out on the control group and the 500 mg / kg kg / day group
Furthermore, the values for MCV, MCH and MCHC were calculated.

Hematological examinations
The following parameters were examined:
sodium
potassium
inorg. phosphorus
Uric acid
Total bilirubin
Creatinine
Glucose in the serum
Urea-N (BUN)
Calcium chloride
ASAT (GOT)
ALAT (GPT)
alkaline phosphatase (AP)
gamma-glutamyl transpeptidase (GGT)
Total protein
Albumin and globulin (electrophoresis)

Urinalysis
The urine was obtained on the night of 26/27. Test day (approx. 16 hours) on non-fed and non-impregnated animals in metabolism cages (single urine). The urine analyzes were carried out on all male and female animals and covered the following parameters:
Appearance
colour
pH value
Hemoglobin protein
Glucose
Ketone bodies
Bilirubin
Urobilinogen
Density sediment *
* These parameters were only determined in the control group and the 500 mg / kg kg / day group as well as in animals with hemoglobin in the urine.

Skin, body openings, eyes, teeth, oral mucosa and the internal organs were assessed macroscopically.
The absolute weight of the following organs was recorded:
heart
lung
liver
Kidneys
spleen
Testicles
Adrenal glands



Sacrifice and pathology:
The animals were killed under nembutal anesthesia (injection of approx. 50 mg / kg i.p.) by severing the cranial vena cava and bleeding. In order to avoid systematic errors, the animals were de-activated and bleeded randomly.
The following organs or parts of all animals were placed in fixation fluid:
heart
lung
liver
Kidneys
spleen
stomach
Jejunum
Colon
Thymus
Testicles
Adrenal glands
Bone marrow (femur marrow)
Statistics:
The following parameters were examined for statistically significant differences compared to the controls (p = 0.05):
Body weights for the individual measuring points
Body weight history in the interval -2. until the 29th day of the trial hematological parameters (except for differential blood count)
Clinical-chemical parameters (except GGT)
Albumin and globulin levels
Absolute and relative organ weights
Urine pH and specific gravity
The evaluation was carried out with the help of a program package for evaluating toxicological tests, in accordance with the standard operating procedure of Dr. Passing, Dept. of Practical Mathematics, by Dept. Pharma Research Informatics. The calculation methods used can be found in the respective computer printouts.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In the male animals of the 500 mg / kg body weight group, salivary flow was observed from the 26th to the 28th day of the test after the application. In the other dose groups, behavior and general health were normal throughout the study.
Mortality:
no mortality observed
Description (incidence):
Mortality did not occur.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The body weight remained unaffected by the administration of the test substance.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The absolute and relative feed consumption in the treated group was found to be unchanged by the test substance over the entire duration of the experiment.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
The administration of the test substance was also not found to have any effect on drinking water consumption.
Ophthalmological findings:
not specified
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The hematological examinations in the 4 and 500 mg / kg kg weight groups in the male animals showed statistically significantly lower hemoglobin values. A substance-related effect is unlikely here, since there was no dose dependency and all values were in the normal range of the rat strain used. No other changes were observed. The differential blood count also showed no deviations from the norm.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Inorganic phosphate: statistically significant increases in inorganic phosphate levels in the group tested with 4 and 20 mg / kg bw in both sexes, in male animals tested with 500 mg / kg bw.
Calcium: statistically significant decrease of Calcium levels in the group tested with 4, 20 and 100 mg / kg bw in females
Urea nitrogen levels: decrease of urea nitrogen levels in females of 20 mg/kg bw group and males of the 100 mg/kg bw group.
GPT values: statistically significant increases in GPT values in the group tested 20 mg / kg bw for males.
GOT: statistically significant increases in females of the highest dose group
Alpha globulin: statistically significant increases in alpha-globulin fractions.


Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
Acidic urine in high dose males and females duet to the acidity of the test substance. In the male animals of all dose groups, statistically significant reductions in the specific weight were found. A connection with the administration of the test substance can be ruled out due to the lack of dose dependency. In all test groups, hemoglobin was found sporadically in the urine, but this was only confirmed in 3 animals when the sediments were examined. In all the other animales the sediments were unremarkable.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Behavior and general health were normal throughout the entire trial period.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
In the female animals of the 100 mg / kg body weight group, increases in the relative and absolute adrenal weights occurred. A substance-related effect can be ruled out due to the lack of dose dependency and the lack of histopathological changes.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
One male of the highest dose has a lightened right kidney, one male had liver tjhat is darkened in some areas and one female had a greatly enlarged left kindey.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No organ changes associated with the administration of p-toluenesulfonic acid were observed microscopically
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No organ changes associated with the administration of p-toluenesulfonic acid were observed microscopically

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: slght intolerance irritation (salivation)
Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
clinical signs
mortality

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

In the highest dose group (500 mg/kg bw/day) urine was acidic in both males and females. Also at the highest dose, some of the males had higher salivation production which was considered an irritation reaction. Neither the acidic urine or salivation were considered significant adverse effects (i.e., toxicologically relevant) in this study.  The NOEL would be 100 mg/kg bw/d and the NOAEL 500 mg/kg bw/d. At > 98% purity, the NOAEL based on active ingredient would be nearly the same; > 490 mg/kg bw/d.

Applicant's summary and conclusion

Conclusions:
NOAEL = 500 mg/kg bw/day based on test item concentration
Executive summary:

The repeated oral toxicity of Toluene 4-sulphonic acid was assessed following official guideline OECD 407, Repeated Dose 28-day Oral Toxicity Study in Rodents.
The test was performed on 25 males and 25 females rats with four concentration (4, 20, 100 and 500 mg/kg bw). No mortality were seen and it can be state that the daily administration of the tested item at the highest dosage led to slight intolerance reactions (salivation) in the male animals, which did not occur until the 26th day of the experiment. The excretion of urine with a low pH value in both sexes, on the other hand, is to be regarded as a physiological reaction to the administration of the acidic test substance. No other changes were observed that could be related to the administration of the test substance.