Disodium oxybis[methylbenzenesulphonate]

Endpoint summary

Description of key information

There is no sub-chronic study available. In the subacute oral study in rats no hazard was identified resulting in a NOEL of 1000 mg/kg bw/day. It is assumed that prolongation of treatment time does not provide additional information on toxic effects.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study and GLP

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Age at study initiation: 7 to 8 weeks
- Weight at study initiation: males 153-173 g, females 133-151 g
- Housing: individually
- Diet ad libitum
- Water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 55
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

All animals were treated with the test item or vehicle for 7 days per week for a period of 28 days.
The test item formulation or vehicle was administered at a single dose to the animals by oral gavage.
For each animal the individual dosing volume was calculated on the basis of the body weight most recently measured.
The application volume for all groups was 5 ml/kg bw .

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Determination of the nominal concentration in dosing formulations including stability and and homogenicity.

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily on 7 days per week

Remarks:

Doses / Concentrations:
0, 100, 300 and 1000 mg/kg bw/day
Basis:

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

The test item was administered 7 days per week in graduated doses to 3 groups of male and 3 groups of fmale rats.
Animals of an additional control group were handeled identically.
All animals were observed daily for clinical signs.
Body weight and food conclumption was measured twice weekly.
Determination of hematology values and clinical chemistry values was done at termination of the treatment.
Sacrifice of surviving animals and organ weight determination.
Gross pathological examination and histopathological examination when adverse effects were observed.

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS:
Yes, daily.

DETAILED CLINICAL OBSERVATIONS:
Yes, daily.

BODY WEIGHT:
Yes, twice per week.

FOOD CONSUMPTION:
Yes, twice per week.

OPHTHALMOSCOPIC EXAMINATION:
Yes, all animals before the first administration and in the last week of the treatment period.

HAEMATOLOGY:
Yes, one day after the last administration after overnight fasting.
haematocrit value (Hct), haemoglobin content (Hb), red blood cell count (RBC), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), reticulocytes (Re), platelet count (PLT), white blood cells (WBC). neutrophils (Neu), lymphocytes (Lym), monocytes (Mono), eosinophils (Eos), basophils (Baso), prothrombin time (PT), activated partial thromboplastin time (aPTT)

CLINICAL CHEMISTRY:
Yes, one day after the last administration after overnight fasting.
alanine aminotransferase (ALAT), aspartate-aminotransferase (ASAT), alkaline phosphatase (AP), creatinine (Crea), total protein (TP), albumin (Alb), urea, total bilirubin (TBIL), total bile acids (TBA), total cholesterol (Chol), glucose (Gluc), sodium (Na), potassium (K)

URINALYSIS:
Yes, from all animals prior to sacrifice.
specific gravity, nitrite, pH-value (pH), protein, glucose, ketone bodies (Ket), urobilinogen (UBG), bilirubin (BIL), erythroctes (Ery), leukocytes (Leu)

NEUROBEHAVIOURAL EXAMINATION:
Yes, once before the first exposure and one in the fourth week of exposure.

Sacrifice and pathology:

Yes, after four weeks of treatment.

Organ weights:
Tissue/Organ:
liver, kidneys, adrenals, testes, epididymides, prostate, seminal vesicles and coagulating glands, ovaries, uterus with cervix, thymus, thyroid/parathyroid glands, spleen, brain, pituitary gland, heart


Preserved and examined tissues:

Gross pathology
All gross lesions macroscopically identified were examined microscopically.
Tissue/organ:
brain (cerebrum, cerebellum and pons), spinal cord, pituitary, thyroid/parathyroid glands, thymus, oesophagus, salivary glands, stomach, small and large intestines (including Peyer's patches), liver, pancreas, kidneys, adrenal glands, spleen, heart, lung, trachea, aorta, uterus with cervix (females), ovaries (females), vagina (females), testes (males), epididymides (males), prostate with seminal vesicles with coagulating glands as a whole (males), mammary gland, urinary bladder, lymph nodes (mesenteric and axillary), peripheral nerve (e.g. sciatic nerve) with skeletal muscle
bone with bone marrow (sternum), eyes, skin

Histopathology
A histopathological evaluation was carried out on all animals of the control and high dose groups (of the main study) which are sacrificed at the end of the treatment period. Histopathological examinations were not extended to animals of the other dose groups, as no treatment-related changes were observed in the high dose group.

Statistics:

A statistical assessment of the results of the body weight, food consumption, parameters of haematology, blood coagulation and clinical biochemistry and absolute and relative organ weights was performed for each gender by comparing values of dosed with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Statistical analysis of paired organs was performed on total weight of the particular paired organ. These statistics were performed with GraphPad Prism V.5.01 software (p<0.05 is considered as statistically significant).

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality occurred in the control or any of the dose groups during the treatment period of this study.
No test item related clinical signs were observed in male and female animals during the entire study period. During the weekly detailed clinical observation, no significant changes or differences between the groups were found.

BODY WEIGHT AND WEIGHT GAIN, FOOD CONSUMPTION
In both males and females, no test item related effect was observed on body weight and body weight change and food consumption in treatment groups during the entire study period.

OPHTHALMOSCOPIC EXAMINATION
There were no ophthalmoscopic findings in any of the animals of this study.

HAEMATOLOGY
In males and females, no effect on haematological and coagulation parameters was observed in treated groups except statistically significant increase in group mean WBC count was observed in male MD group when compared with controls.

CLINICAL CHEMISTRY
In males, the statistical analysis of clinical biochemistry data revealed significant decrease in alkaline phosphatase in HD group when compared with controls. In females, a statistically significant decrease in ALAT was observed in LD and MD dose groups when compared with controls. Other clinical biochemistry parameters analysed in male and females remained unaffected in all treated groups when compared with controls.

URINALYSIS
All urinary parameters were in the normal range of variation and no evident differences between dose groups and control group were observed.

NEUROBEHAVIOUR
No relevant effects were observed in any of the parameters of the functional observation battery before and at the end of the treatment period.
There were no biologically relevant differences in body temperature between the groups.

ORGAN WEIGHTS
In males and females, absolute and relative organ weights remained unaffected due to treatment with the test item and all group mean and individual values were comparable with controls.

GROSS PATHOLOGY, HISTOPATHOLOGY: NON-NEOPLASTIC
No test item-related macroscopic or histopathological organ changes were observed in this study and observed changes were considered to be incidental in origin and/or within the range of expected changes for rats of this age and strain kept under laboratory conditions.

OTHER FINDINGS
In males and females, few specific gross pathological findings were observed in control and treated group animals. These findings are assumed to be spontaneous findings in this strain and not considered to be treatment related.

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Conclusions:

Based on the data generated from this study, no significant toxicological effects of ditolylether disulfonic acid disodium salt, isomer mixture were found up to 1000 mg/kg bw/day. Therefore the NOEL (No Observed Effect Level) is considered to be 1000 mg/kg bw/day.

Executive summary:

In a subacute toxicity study according to OECD TG 407 ditolylether disulfonic acid disodium salt, isomer mixture dissolved in water was administered 7 days per week in graduated doses (100, 300, 1000 mg/kg bw/day) to 3 groups of male and 3 groups of female rats. Animals of an additional control group were handled identically. All animals were observed daily for clinical signs and mortality. Body weight and food consumption was measured twice weekly. Determination of hematology values and clinical chemistry values was done at termination of the treatment. After termination of the treatment surviving animals were sacrificed and organ weight determination, gross pathological examination and histopathological examination when adverse effects were observed, was done.

 

Based on the data generated from this study, no significant toxicological effects of ditolylether disulfonic acid disodium salt, isomer mixture were found up to 1000 mg/kg bw/day. Therefore the NOEL (No Observed Effect Level) is considered to be 1000 mg/kg bw/day.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

There is no sub-chronic study available as required by regulation (EC) No.1907/2006 (REACH) ANNEX IX, section 8.6. In the available 28-day stud
y (OECD TG 407) male and female rats were given daily doses up to and including 1000 mg/kg bw/day (limit dose). Based on the data generated from this study no effects of ditolylether disulfonic acid disodium salt, isomer mixture were found up to and including 1000 mg/kg bw/day. Therefore the NOEL (NoObserved Effect Level) of ditolylether disulfonic acid disodium salt, isomer mixture is considered to be 1000 mg/kg bw/day. Furthermore, as no evidence of toxicological effects up to the limit dose of 1000 mg/kg bw/day are reported it can be assumed that prolongation of treatment time does not provide additional information on toxic effects.
Overall, no hazard (NOEL 1000 mg/kg corresponding to the limit dose and no LOEL identified) was identified in a comprehensive sub-acute toxicity study. It is unlikely that additional sub-chronic toxicity testing will reveal significant toxicity and further testing is of low priority and should be omitted based also on animal welfare reasons.

Additional information

There is no sub-chronic study available as required by regulation (EC) No.1907/2006 (REACH) ANNEX IX, section 8.6. A reliable short-term study (28 days) is available.

In the available 28-day study (OECD TG 407) male and female rats were given daily doses up to and including 1000 mg/kg bw/day (limit dose). Based on the data generated from this study no effects of ditolylether disulfonic acid disodium salt, isomer mixture were found up to and including 1000 mg/kg bw/day. Therefore the NOEL (NoObserved Effect Level) of ditolylether disulfonic acid disodium salt, isomer mixture is considered to be 1000 mg/kg bw/day. Furthermore, as no evidence of toxicological effects up to the limit dose of 1000 mg/kg bw/day are reported it can be assumed that prolongation of treatment time does not provide additional information on toxic effects. Thus, the requirements REACH Regulation are fulfilled.

Overall, no hazard (NOEL 1000 mg/kg corresponding to the limit dose and no LOEL identified) was identified in a comprehensive sub-acute toxicity study. It is unlikely that additional sub-chronic toxicity testing will reveal significant toxicity and further testing is of low priority and should be omitted based also on animal welfare reasons.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This only available study is conducted according to OECD TG 407 under GLP conditions and evaluated with Klimisch score 1.

Justification for classification or non-classification

Based on the available data no classification/labelling is required.