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Description of key information

There are a total of 8 oral and 6 dermal repeated dose toxicity studies on the hydrotrope category substances. Most of these studies were conducted on Sodium xylene sulphonate, one reliable subchronic study was conducted on sodium cumene sulphonate and one reliable subacute study exists on Sodium toluene sulphonate.

The key oral study is the 90 day sub-chronic study, conducted in 1968, which is generally comparable to the OECD 408 guideline study. In that study, the highest dose for female rats - 4092 mg active ingredient (a.i.) per kilogram body weight - resulted in a loss in relative weight of the spleen. The 2nd highest dose for females - 763 mg a.i. per kilogram body weight - had no measureable adverse effects and therefore establishes the repeat dose oral NOAEL for the substance. The highest oral dose for male rats - 3534 mg a.i. per kilogram body weight - had no measurable adverse effects. No adverse effects were reported in the 90 day sub-chronic mouse study.

The key dermal study is the two year chronic/carcinogenicity study in the rat, which was generally comparable to the OECD 453 guideline study. There were no treatment related incidences of mononuclear cell leukaemia, neoplasms, or non-neoplastic lesions of the skin and other organs. In that study the NOAEL for females is 60 mg a.i./kg/day based on epidermal hyperplasia. This value was then used for the NOAEL for local dermal effects.No systemic toxicity was observed in this or any of the other repeat dose dermal studies.

There is no need for repeat dose data by the inhalation route since the two important routes of exposure have been addressed.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline not specified, but with detailed documentation
Justification for type of information:
Please see Category Approach
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
no functional observations or ophthalmoscopy
Principles of method if other than guideline:
Groups of 30 young rats (15 males and 15 females) were exposed by diet for 90 days to three concentrations. A control group was included. Observations were made of behavior, appearance, growth, food and water intake and a number of haematological factors. At the end of the experiment (during week 14) ten organs of each surviving rat were weighed and examined histologically for pathological changes. Liver enxyme activities were also determined.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: CIVO-colony- Age at study initiation: newly weaned - Weight at study initiation: 41-60 g- Fasting period before study: no data- Housing: metal wire screen cages (5 to a cage)- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: no dataENVIRONMENTAL CONDITIONS- Temperature (°C): 24 degrees centigrade- Humidity (%): no data- Air changes (per hr): no data - Photoperiod (hrs dark / hrs light): no dataIN-LIFE DATES: From: To: no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: test chemical mixed directly with stock diet DIET PREPARATION- Rate of preparation of diet (frequency): once a fortnight- Mixing appropriate amounts with (Type of food): stock diet consisting of 28% yellow maize, 26% whole wheat, 10% rolled oats, 10% soybean oil meal, 8% fish meal and <5% each of meat scraps, dried whey, soybean oil, grass meal, minerals, sodium chloride and vitamin preparation.- Storage temperature of food: room temperatureVEHICLE- Justification for use and choice of vehicle (if other than water): no vehicle
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks / 90 days
Frequency of treatment:
in ad libitum diet
Remarks:
Doses / Concentrations:0.2%, 1.0% and 5.0%Basis:nominal in diet
No. of animals per sex per dose:
15
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: previous range finding test- Rationale for animal assignment (if not random): according to body weight
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes- Observations: general appearance and behaviour- Time schedule: no dataDETAILED CLINICAL OBSERVATIONS: No dataBODY WEIGHT: Yes- Time schedule for examinations: weeklyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: NoFOOD EFFICIENCY:- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: YesWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes - Time schedule for examinations: weekly for the first week onlyOPHTHALMOSCOPIC EXAMINATION: NoHAEMATOLOGY: Yes- Time schedule for collection of blood: week 6 and week 12- Anaesthetic used for blood collection: No data- Animals fasted: No- How many animals: 10 males and 10 females from each dose group- Parameters checked in table [No.4] were examined.CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: terminally- Animals fasted: No data- How many animals: 10 males and 10 females from each dose group- Parameters checked in table [No.5 and No.6] were examined.URINALYSIS: Yes - Time schedule for collection of urine: urinalysis from pooled samples from 10 males and 10 females from each dose group in 7th week.- Metabolism cages used for collection of urine: No data- Animals fasted: No data- Parameters checked in table [No.7 and No.8] were examined.NEUROBEHAVIOURAL EXAMINATION: NoOTHER: kidney funcion from samples of 10 males and 10 females in 13th week. Serum protein electrophoresis of 10 males and 10 females of control and high dose groups at 13 weeks. Liver enzyme activity at termination.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table No.10) HISTOPATHOLOGY: Yes (see table No.11)
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:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
> 763 - < 3 534 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Conclusions:
Test compound possesses a very low order of toxicity. 1% in the diet (corrresponding to a daily intake of 763 mg a.i./kg bw) was a no toxic effect level. At 5% in the diet (corresponding to 4092 mg a.i./kg bw) there were slight indications of deleterious effecs.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
763 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Sufficient to meet requirements
System:
other: cardiovascular / hematological
Organ:
spleen

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
The two important routes of exposure have been addressed. Hence no need for inhalation repeated dose.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The database of available repeat dose dermal studies includes two sub-chronic 90 day studies as well as two chronic/carcinogenicity studies, conducted in both rats and mice. These studies were limited in design such that not all important endpoints were investigated. These studies found only local effects and no systemic toxicity. So for the purpose of calculating a DNEL value for systemic effects, the oral NOAEL has been used together with information on relative absorption by the oral and dermal routes.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
0.48 mg/cm²
Study duration:
chronic
Species:
rat
Quality of whole database:
Sufficient to meet requirements. The study with the lowest NOAEL for local effects (hyperplasia of the epidermis) is the 2 year dermal carcinogenicity study in the rat, where the NOAEL for females was 60 mg/kg. Taking a mean body weight figure for the female rats in the 60 mg/kg dose group of 0.2kg (stated range = 0.107 to 0.288 kg) and assuming a surface area of dosing of 25 cm2, gives a NOAEL of 0.48 mg/cm2.

Additional information

A 28-day oral repeat dose toxicity study was conducted in male and female Wistar rats employing p-toluene sulphonic acid (Hoeschst, 1990). Whilst this is not a hydrotropes category member it does share the same organic anion as sodium toluene sulphonate. This study followed the OECD Guideline 407 with no reported deviations to the study plan and was conducted to GLP. Rats (10/sex/dose) were orally administered 0, 4, 20, 100 or 500 mg/kg bw/day of the substance. The top dose for this study was selected on the basis of a preliminary study in which a single dose of 1250 mg/kg bw resulted in 40% mortality in females. Some of the males displayed salivation at the top dose and urinalysis showed that the urine was acidic in both males and females. The salivation was considered to be a sign of irritation by the study authors and both effects were not considered to be toxicologically relevant (non-adverse). Thus, the NOEL is 100 mg/kg bw/day and the NOAEL is 500 mg/kg bw/day (nominal concentration) or >490 mg/kg bw/day (actual concentration).

Reference:

Hoeschst , A.G. (1990). Subakute orale toxizitat (29 Applikationen in 29 Tagen an SPF-Winstar-Ratten.

Justification for classification or non-classification

Based on the reported findings from a variety of repeat dose studies by both the oral and dermal routes, there is no justification for hazard classification.