Reaction mass of 4-hydroxybenzene-1,3-disulphonic acid and 4-hydroxybenzenesulphonic acid and sulphuric acid and water

Endpoint summary

Description of key information

NOAEL oral =  500 mg/kg bw/day.

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:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study 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 or test system 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 data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 degrees centigrade
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-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 temperature


VEHICLE
- 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 data


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD 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: No


FOOD 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: Yes


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


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: 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: No


OTHER: 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

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

500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A GLP guideline study with p-toluenesulphonic acid (CAS No. 104-15-4) reported no adverse effects to male and female rats exposed orally for 28 days. The highest dose was 500 mg/kg bw/day (>490 mg/kg bw/day based on >98% active ingredient). Therefore the NOAEL was set at 500 mg/kg bw/day.

The NOAEL in the definitive 28 -day oral study of toluene-4-sulphonic acid is 500 mg/kg bw/day. A preliminary dose-finding study indicated mortality of females at 1250 mg/kg bw. And while this is a valid study there were no adverse effects observed at the highest dose tested. Therefore a read-across is included to view a derived NOAEL for a related substance. Hydrotropes are the salt form of the sulphonic acids.

The studies with the salts (hydrotropes) provide valid read-across for the acids. The specific cation is not expected to have an appreciable effect on fate, ecotoxicity or mammalian toxicity and therefore the dataset for the entire hydrotropes category can be applied broadly. 

The aromatic sulphonic acids are almost completely ionized in watery environments even at low pH. The salts of these acids are the hydrotropes (or “sulphonates”) which include ammonium, calcium, potassium and sodium cations. In principle the salts get dissociated when in contact with water, so forming back to the acids. Because of their close chemical similarities and because much of the production of the aromatic sulphonic acids goes to manufacturing the salts, the extensive dataset for the hydrotropes can also be used as a source of read-across for endpoints in an aromatic sulphonic acid dossier. This is particularly relevant for studies that are conducted in water (e.g., ecotoxicity and biodegradation) as well as for mammalian toxicity studies where the relatively high acidity of the acid form has an immediate and harsh local effect, whereas the salt form provides an indication of potential systemic toxicity beyond the site of application or initial contac

There are a total of 6 oral repeated dose studies for the hydrotrope sodium xylene sulphonate (CAS No. 1300-72-7). The key study is a 90-day oral study, conducted in 1968, 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 test 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 a 90 day mouse study with the same substance.

Justification for classification or non-classification

Classification for STOT is relevant where significant toxic effects are seen from single or repeated dose studies. No such significant toxicity is seen in all available studies

No classification for STOT is warrented at present under 67/548/EEC or Regulation 1272/2008.