Sodium p-cumenesulphonate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June - September 1983

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:

1984

Report date:

1984

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium p-cumenesulphonate

EC Number:

239-854-6

EC Name:

Sodium p-cumenesulphonate

Cas Number:

15763-76-5

Molecular formula:

C9H12O3S.Na

IUPAC Name:

sodium 4-isopropylbenzenesulfonate

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Bor: WISW (SPF TNO)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Fa. Winkelmann, 4799 Borchen
no further details mentioned

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

13 weeks / 90 days

Frequency of treatment:

daily (7 days/week)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

400 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

800 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

1 200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10, additionally 10 for recovery (control and high dose group)

Control animals:

yes

Details on study design:

- Dose selection rationale: previous range finding test
3 weeks, 4 dosages (0 control group, 400; 800; 1200 mg/kg bw/d) and 1 control group (10 animals)
2 different tests (40 rats, 20 males and 20 females) were divided into 4 groups (5 animals/sex/dose)
a) drinking water
b) food
Body weights, feed and water consumption were calculated weekly. The test substance was applied continuously on all days during the 3-weeks test period.

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Observations: general appearance and behaviour
- Time schedule: a few times/day


DETAILED CLINICAL OBSERVATIONS: a few times/day


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: weekly


OPHTHALMOSCOPIC EXAMINATION: all anminals, before application, weeks 6-7, 12-13, recovery group (17 = 4 weeks later)


HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 6-7, 12-13 and recovery group (17 = 4 weeks later)
- Anaesthetic used for blood collection: ether
- Animals fasted: no
- How many animals: all
- Parameters: WBC, RBC, Hb, Hct, MCH, MCV, MCHC, thrombocytes, differential hemogram, number of reticulocytes


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 6-7, 12-13, recovery group (17 = 4 weeks later)
- Animals fasted: no
- How many animals: all
- Parameters: glucose, kreatinine, urea, total bilirubin, proteine, chloride, phosphate, GOT, GPT, gamm-GT, cholesterine, triglyceride, Na, K


URINALYSIS: Yes
- Time schedule for collection of urine: urinalysis from pooled samples (6 hours)
- Metabolism cages used for collection of urine: yes
- Animals fasted: no data
- Parameters checked: pH, glucose, ketone, urobilinogene, proteine, blood, specific density, native sediment with microscope


NEUROBEHAVIOURAL EXAMINATION: Not mentioned

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Organs examined histologically
Eyes (cornea, iris, retina) (2x)
Adrenal gland
Cerebrum (Ammon's horn)
Peripheral nerve
Cerebellum (stem)
Forestomach
tongue
Drusen stomach (fundus, pylorus)
Salivary gland
Small intestine (3x)
Maxillary lymph nodes
Large intestine (3x)
Esophagus
Mesenteric lymph nodes
Windpipe (trachea)
Uterus (2x)
Lungs (2x)
Ovary (2x)
heart
bladder
Thoracic aorta
Prostate (2x)
liver
Testicles (2x)
spleen
Epididymis (2x)
pancreas
Seminal vesicle (2x)
Cardioid (2x)
Skeletal muscles
thymus
skin
Thyroid gland, parathyroid gland

Other examinations:

Main test: Intermediate examinations (urine, hematology, clinical chemistry) on all animals during the 6th and 7th week of application) Final examinations (urine, hematology, clinical chemistry) on the animals, which are dissected at the end of the application, during the 12th and13th week.
General and eye examinations on all animals are carried out at the beginning of the application, on the occasion of the intermediate examinations, at the end of the application and on the recovery animals at the end of the observation period.
Body weights, food and water consumption (substance intake) are calculated on a weekly basis. Checks of the general condition of the animals are carried out several times a day.
The blood is taken from the retroorbital venous plexus of the test animals
under ether anesthesia (Ether pro narcosi, Hoechst).

The following parameters are determined:

a) clin. chemistry
Glucose, creatinine, urea, total bilirubin, total protein, chloride, phosphate, GOT, SPT, y-GT, cholesterol and triglycerides with RA-1000 system (Tech "-
nicon) as well as Na and K ion-selective with the Electrolyte Analyzer 980 (AVL).

b) hematology
All blood tests were performed on non-fasting animals. The blood was drawn from the infraorbital plexus under light atheric anesthesia.
The rats were placed in metabolism cages for 6 hours for urine testing. The microscopic examination was carried out on the native sediment, other investigations using Combur-6 test strips (Boehringer, Mannheim).
The parameters checked are: WBC, RBC, Hb, Hct, MCH, MCV, MCHC and platelets with the Counter S plus (from Coulter) as well
Differential blood count and reticulocyte count microscopically.

To collect urine, the animals are placed in metabolism cages for 6 hours. Test strips (Boehringer) are used to determine the pH, glucose, ketone, urobilinogen, protein and blood in the urine. The specific weight is determined by weighing.
The native sediment is assessed microscopically.

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:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

In hematology, there were no treatment-dependent trends in reductions after an initial review:

IV group
males: RBC, HB, HCT signif. lowered, but within the normal range
females: segment nuclear signif. increased, but within the normal range
Lymphocytes signif. lowered (3/20 fall just outside the normal range)

III
males: RBC (not signif.), HB, HCT signif. lowered, but within the normal range
Final examination In the 12./13. Appl. week

VI
males: monocytes signif. decreased, but within the normal range
females: reticocytes signif. decreased, but within the normal range

III group
males: WBC signif. decreased, but within the normal range. females: segment nuclear signif. increased, but within the standard range

II group
males: WBC signif. decreased, but within the normal range of lymphocytes significant. increased but within the normal range
Segmented nuclei and monocytes signif. decreased, but within the normal range

Recovery examination in the 4th week of follow-up
IV group
males: Eosinophils signif. increased but within the normal range
females: reticulocytes signif. decreased, but within the normal range

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Interim examination
IV group
males: BUN (urea), signif. elevated
GPT, total protein and triglycerides
signif. decreased, but within the normal range
females: K signif. decreased (but only 1/20 outside the normal range Phosphorus and GPT, significantly decreased, but within the normal range

III group
males: BUN signif. elevated
Cholesterol and GPT signif. decreased, but within the normal range

II group
males: GOT signif. decreased, but within the normal range
females GOT and creatinine
signif. decreased, but within the normal range

Final examination
IV group
males: BUN signif. elevated
Cholesterol signif. decreased, but within the normal range
females: cholesterol signif. decreased, but within the normal range

Ill group
males: cholesterol signif. decreased (but only 1/10 outside the normal range)
GPT and Phosphorus signif. humiliated
but within the normal range

II group
males: cholesterol and phosphorus signif. decreased, but within the normal range

Recovery investigation
IV group
Na signif. humiliated

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

Other effects:

not specified

Details on results:

Results of the dose range findings
The dose-tange finding show no substance specific effects (body weight gain, pathological, histopathological effects, clinical signs, behaviour)
There were no significant differences between dose and control groups in either experiment. In the female animals, however, there seems to be a dose-dependency in the feed conversion.In the behavior of the animals and in the final examination before the dissection, no substance-dependent observations could be made.
The macroscopic assessment did not reveal any evidence of pathological changes that could be substance-dependent. According to Henkel's autopsy protocol, there were no histological changes in the organ assessed, whIch would indicate the effect of the substance.

Main test
The pathological-anatomical examinations of the animals in the main study do not show any indications of changes caused by the test substance.
For the main test OW 90d-003, the dosages of the previous tests were therefore retained. The substance administration via drinking water was chosen as the form of administration.
The substance is administered 7 days a week. 120 Wistar rats were used for the experiment; from the control and the highest dose group (20 males and 20 females animals), after the end of the dose, half of the animals remain in a 4-week observation period. The pathological-anatomical examination does not give any indications of changes caused by the test substance.
Some pathological-histological findings (salivary gland, pancreas) indicate the presence of virus-related sialodacryoadenitis.
The findings of the fore and glandular stomach are low overall and cannot be assigned to a defined clinical picture. However, they are represented in Groups I and IV.
The slight to moderate loss of the external granular layer in the retina of the eyes is posture-related (exposure to light) and mainly affects the female and male animals of group I.
Another spontaneous finding concerns a large number of urinary bladders in the animals of the main and "recovery" groups. Morphologically, the diapedesis of erythrocytes and / or plasma components from the wall vessels through the transitional epithelin of the urinary bladder lumen can be observed. Sometimes this material has pushed the epithelial structure apart. This results in moderate to high-grade circumscribed epithelial proliferation with low-grade, chronically inflammatory infiltrates in the submucosa. There are no signs of bacterial infection, which is usually the cause of cystitis in rats.
In conclusion there are no pathological or histological indications of changes due to the test substance.

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

1 200 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

NOAEL = 1200 mg/kg bw day (highest dose tested) based on active ingredient

Executive summary:

The repeated oral toxicity of Sodium p-cumenesulphonate was assessed following official guideline OECD 408, Repeated Dose 90-Day Oral Toxicity Study in Rodents. The tested substance showed very low order of toxicity. The pathological-anatomical examinations of the animals in the main study do not show any indications of changes caused by the test substance.