Sodium dimethyl 5-sulphonatoisophthalate

Endpoint summary

Description of key information

Sodium Sulfo Dimehtylisophtalate has a NOAEL of 1000 mg/kg bw/d for repeated dose toxicity (oral). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2012-08-14 to 2012-09-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented guideline and GLP compliant study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: OPPTS 870.3050 Repeated Dose 28-Day Oral Toxicity Study in Rodents, EPA Health Effects Test Guideline, June 2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Toxi-Coop Zrt. Cserkesz u. 90. H-1103 Budapest, Hungary
- Age at study initiation:
Male animals: 39 – 41 days old; Female animals: 39 – 41 days old
- Weight at study initiation: Male animals: 130 – 143 g Female animals: 102 – 118 g
- Housing: 2 or 3 animals of the sex/ cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 8 – 12 air exchanges / hour by central air-condition system.
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Route of administration:

oral: gavage

Vehicle:

other: 0.5% Methylcellulose

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The test item was formulated in the vehicle (0.5 % Methylcellulose) in concentrations of 200, 50 and 12.5 mg/mL. The application volume was 5 mL/kg bw.

VEHICLE:
- Justification for use and choice of vehicle (if other than water): 0.5 % aqueous methylcellulose was a suitable vehicle to facilitate formulation analysis for the test item.
- Lot/batch no.:N83746634

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Five samples were taken (from different places) from each concentration and measured on 2 occasions. Similarly, one sample was taken from the control solution and analyzed. All formulations proved to be homogeneous. Measured concentrations varied between 100 and 110 % of the nominal concentrations.
The suitability of the chosen vehicle and sufficient stability for the test item at the intended concentrations were analytically verified up front. SIM-Ester was stable for 4 hours at room temperature (recovery: 99 % and 108 % of nominal concentrations of ca. 1 mg/mL and ca. 200 mg/mL, respectively) and for three days in refrigerator (recovery: 98 % and 104 % of nominal concentrations of ca. 1 mg/mL and ca. 200 mg/mL, respectively).

Duration of treatment / exposure:

28 days

Frequency of treatment:

The test item was administered in a single dose by oral gavage on a 7 days/week basis, every day at a similar time (+/- 2 hours). Concurrent control animals were handled (only vehicle) in an identical manner to the test groups.

Remarks:

Doses / Concentrations:
62.5, 250 and 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

Group 1 (control): 10 (including 5 recovery animals) per sex
Group 2 (62.5 mg/kg bw/day): 5 per sex
Group 3 (250 mg/kg bw/day): 5 per sex
Group 4 (1000 mg/kg bw/day): 10 (including 5 recovery animals) per sex

Control animals:

yes, concurrent vehicle

Details on study design:

- Post-exposure recovery period in satellite groups: 14 days

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once a day, after treatment at approximately the same time.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each day). Detailed clinical observations were made on all animals outside the home cage in a standard arena once, prior to the first exposure and once weekly thereafter.

SENSORY REACTIVITY: Yes
- During the last exposure week.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed in the treatment period with an accuracy of 1 g on Days 0, 7, 14, 21 and 27. Furthermore, body weight was recorded during the recovery period with same accuracy on Days 34 and 41.

FOOD CONSUMPTION: Yes
- The food consumption was determined in the treatment phase with an accuracy of 1 g on Days 7, 14, 21 and 27 by reweighing the non-consumed diet, and it was determined by the same way during the recovery period on Days 34 and 41.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: One day after the last treatment and on recovery animals at the end of recovery period.
- Anaesthetic used for blood collection: Yes (Isofluran anesthesia)
- Animals fasted: Yes, animals were food deprived for approximately 16 hours prior to blood collection.
- Hematology parameters:
WBC: White Blood Cell (leukocyte) count,
RBC: Red Blood Cell (erythrocyte) count,
HGB: Hemoglobin concentration,
HCT: Hematocrit (relative volume of erythrocytes),
MCV: Mean Corpuscular (erythrocyte) Volume,
MCH: Mean Corpuscular (erythrocyte) Hemoglobin,
MCHC:Mean Corpuscular (erythrocyte) Hemoglobin Concentration,
RET: Reticulocytes,
PLT: Platelet (thrombocyte) count,
NEU: Neutrophil,
LYM: Lymphocyte,
EOS: Eosinophil,
MONO: Monocyte,
BASO: Basophil.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: One day after the last treatment and on recovery animals at the end of recovery period.
- Animals fasted: Yes, animals were food deprived for approximately 16 hours prior to blood collection.
- Blood coagulation parameters:
APTT: Activated partial Thromboplastin Time,
PT: Prothrombin Time,
ALT: Alanine Aminotransferase activity,
AST: Aspartate Aminotransferase activity,
GGT: Gamma Glutamyltransferase activity,
ALP: Alkaline Phosphatase activity,
TBIL: Total Bilirubin concentration,
CREA: Creatinine concentration,
UREA: Urea concentration,
GLUC: Glucose concentration,
CHOL: Cholesterol concentration,
BAC: Bile acids,
Ca++: Calcium concentration,
Na+: Sodium concentration,
K+: Potassium concentration,
Cl-: Chloride concentration,
ALB: Albumin concentration,
TPROT: Total Protein concentration,
A/G: Albumin/globulin ratio.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during the last exposure week
- Dose groups that were examined: all animals of all groups
- Battery of functions tested: Sensory reactivity to different types of stimuli (e.g. auditory, visual and proprioceptive), grip strength and motor activity

ESTRUS CYCLE: Yes
- Time schedule for examinations: Prior to necropsy, the estrus cycle of all females were determined by taking vaginal smears.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, on each animal one day after the last treatment or termination of the recovery period. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed, and any abnormality was recorded with details of the location, color, shape and size.

ORGAN WEIGHT: YES, recorded prior to preservation (wet weight).
liver, kidneys, testes, epididymides, uterus, thymus, spleen, brain and heart, prostate and seminal vesicles with coagulating glands as a whole, adrenals, ovaries. Paired organs were measured together.

HISTOPATHOLOGY: Yes (see table)

Statistics:

Statistical analysis was done for the following data:
- body weight,
- food consumption,
- hematology,
- blood coagulation- clinical chemistry,
- organ weight data.
The heterogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant Duncan Multiple Range test was used to access the significance of inter-group differences. Where significant heterogeneity was found, the normal distribution of data by Kolmogorov-Smirnov test was examined. In case of not normal distribution, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was applied. If there was a positive result, the inter-group comparisons were performed using Mann-Whitney U-test. The frequency of clinical signs, pathology and histopathology findings were calculated.
Results were evaluated in comparison with values of control group (i.e. control value).

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality occurred. There were no toxic signs related to the test item effect at the daily clinical observations. The behavior and physical condition of animals were considered to be normal at each dose level during the treatment and recovery periods. Grey color of stool was noted for male and female animals at 1000 and 250 mg/kg bw/day at the daily and detailed weekly clinical observations from Days 14, 15 or 21 up to the end of the treatment period and for three days in the recovery period.

BODY WEIGHT AND WEIGHT GAIN
There were no statistically or biologically significant differences between the control and test item treated groups in the mean body weight and body weight gain during the entire observation period (treatment and recovery periods).

FOOD CONSUMPTION
The daily mean food consumption was similar in the control and test item treated groups during the treatment and recovery periods.

HAEMATOLOGY
Hematological investigations did not reveal any test item related changes in the examined parameters.

CLINICAL CHEMISTRY
Clinical pathology examinations did not reveal any pathologic changes in the examined blood coagulation or clinical chemistry parameters.

FUNCTIONAL OBSERVATION BATTERY
Functional observation battery did not demonstrate treatment-related differences with respect to the controls in the behavior or in reactions to different type of stimuli at the end of the treatment period.

ORGAN WEIGHTS
There were no test item related changes in the examined organ weights at any dose level.

GROSS PATHOLOGY
Necropsy observations did not reveal any test item related macroscopic findings in male or female animals, at any dose level tested.

HISTOPATHOLOGY
Histological examination did not reveal any toxic or test item related lesions in the investigated organs.

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No signs of toxicity were noted.

Critical effects observed:

not specified

Conclusions:

Under the conditions of the present study, Sodium dimethyl 5-sulphonatoisophthalate (SIM-Ester) caused no signs of toxicity in male or female Wistar rats after 28-days oral (gavage) administration at 1000mg/kg bw/day, 250 mg/kg bw/day or 62.5 mg/kg bw/day.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2000-11-7

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data for Dimethyl terephthalate (DMT) are published in a SIDS Initial Assessment Report for SIAM 11

Justification for type of information:

The sub-chronic toxicity of SIM-Ester (CAS No. 3965-55-7) can be reliably assessed taking into account the results of the OECD 421 and OECD 407 guideline studies. SIM-Ester is acutely non-toxic and did not induce adverse effects in the OECD 407 and OECD 421 guideline study when administered at dose levels up to 1000 mg/kg bw/d by oral gavage. In an weight of evidence approach (Roth T. et al, 2013, Section 13 of this IUCLID), toxicity data on the structurally related compounds isophthalic acid (CAS No. 121-91-5, IPA), dimethyl terephthalate (CAS No. 120-61-6, DMT) and terephthalic acid (CAS No. 100-21-0, TPA) are used for assessment of sub-chronic toxicity of SIM-Ester. Hydrolysis of SIM-Ester to the monomethylester and finally to 5-sulfoisophthalic acid with subsequent urinary excretion has been identified as the main metabolic and excretory pathway (see toxicokinetic section).
Toxicologically extensively investigated substances which are structurally closely related to SIM-Ester and its final metabolite 5 -sulfoisophthalic acid are isophthalic acid (CAS No. 121-91-5), dimethyl terephthalate (CAS No. 120-61-6, IPA) and terephthalic acid (CAS No. 100-21-0). The substances show a toxicological profile comparable to SIM-Ester, i.e. low acute toxicity (LD50 (rat, oral and dermal) > 2000 mg/kg bw; LC50 (rat, inhalation) > 5 mg/L), no sensitization and no genotoxic/mutagenic potential as well as a similar toxicokinetic behavior (OECD, 2001a, 2001b and 2002, Roth T. et al 2013). Dimethyl terephthalate is the closest structural analogue for SIM-Ester as it is also a dimethylester. These similarities justify the read-across from the structural analogues to SIM-Ester regarding repeated dose toxicity.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

other: No information on any Guideline used, but basic principles of an OECD 408 study are considered.

Version / remarks:

n.a.; The study was performed prior to the adoption of the test guideline specified

Deviations:

yes

Remarks:

Only males used. The study is reported in an SIDS initial assessment report for SIAM 11 and thus, information is only presented as brief summary.

GLP compliance:

no

Remarks:

Study was conducted in 1973 prior to implementation of GLP

Limit test:

no

Specific details on test material used for the study:

DMT (Eastman Organic Chemicals, Cat. No. 6580)

Species:

rat

Strain:

Long-Evans

Sex:

male

Details on test animals or test system and environmental conditions:

Weanling rats (30/group) were exposed to DMT in a basal diet. Ten animals from each group were
sacrificed after 96-days. The remaining animals were placed back onto control diet for observation of potential long-term effects over the rest of their life.

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

96 days

Frequency of treatment:

7-days/week

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control diet

Dose / conc.:

152 mg/kg bw/day (nominal)

Remarks:

i.e. 0.25 %

Dose / conc.:

313 mg/kg bw/day (nominal)

Remarks:

i.e. 0.5 %

Dose / conc.:

636 mg/kg bw/day (nominal)

Remarks:

i.e. 1.0 %

No. of animals per sex per dose:

30 males/group

Control animals:

yes, plain diet

Details on study design:

Weanling rats (30/group) were exposed to DMT in a basal diet. Ten animals from each group were sacrificed after 96-days, and tissue samples from all major organ systems were removed for histologic examination. Livers and kidneys were weighed for organ weight comparisons.
Hematology and serum biochemistry’s were conducted on Days 55 and 90. The remaining animals were placed back onto control diet for observation of potential long-term effects over the rest of their life.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Not specified

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: n.a.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

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: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: Not specified

HAEMATOLOGY: Yes
- Parameters examined: hematocrit, hemoglobin, white blood cell or differential counts
- Blood sampling: Days 55 and 90

CLINICAL CHEMISTRY: Yes
- Parameters examined: BUN, SGOT, OCT, SAP, blood glucose, serum protein
- Blood sampling: Days 55 and 90

NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Clinical signs:

not specified

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The only toxicological effect seen in the study was a reduced weight gain in the high dose animals.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No dose-related changes were seen in BUN, SGOT, OCT, SAP, blood glucose, or serum protein values

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Average body and relative and absolute liver and kidney weights of the experimental groups did not differ significantly from control weights.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Microscopic
examination of tissues from all organ systems
revealed no morphologic evidence of any
abnormalities that could be attributed to compound
exposure

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOEL

Effect level:

313 mg/kg bw/day (nominal)

Based on:

not specified

Sex:

male

Basis for effect level:

body weight and weight gain

Key result

Critical effects observed:

no

Conclusions:

Data interpretation of this study cannot be evaluated due to lack of primary reference, and is limited by lack of details. A NOEL of 0.5 % equivalent to 313 mg/kg was reported by authors of SIDS document based on a reduced weight gain in the high dose animals. No other effect of toxicological significance is described.

Executive summary:

A sub-chronic oral feeding study with DMT was performed in Long Evans Hooded rats at dose levels of 0, 0.25, 0.5 and 1.0% (equivalent to 152, 313, 636 mg/kg). Weanling rats (30/group) were exposed to DMT in a basal diet. Ten animals from each group were sacrificed after 96-days, and tissue samples from all major organ systems were removed for histologic examination. Livers and kidneys were weighed for organ weight comparisons. Hematology and serum biochemistry’s were conducted on Days 55 and 90. The remaining animals were placed back onto control diet for observation of potential long-term effects over the rest of their life.
The only toxicological effect seen in the study was a reduced weight gain in the high dose animals. No toxicological effects on hematocrit, hemoglobin, white blood cell or differential counts were seen in any group. No dose-related changes were seen in BUN, SGOT, OCT, SAP, blood glucose, or serum protein values. Average body and relative and absolute liver and kidney weights of the experimental groups did not differ significantly from control weights. Microscopic examination of tissues from all organ systems revealed no morphologic evidence of any abnormalities that could be attributed to compound exposure. A no observed effect level (NOEL) is reported to be 0.5 % or 313 mg/kg.

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:

reliable

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Remarks:

Repeated Sublethal Testing

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1959

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study without detailed documentation

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats were exposed 4 h per day for 9 days within a 14-day period to a single concentration (32 mg/L) of the test substance (whole body exposure). The study predates OECD guidelines.

GLP compliance:

no

Remarks:

study was performed prior to implentation of GLP

Limit test:

yes

Species:

rat

Strain:

other: ChR-CD

Sex:

not specified

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

> 75 % of particles were < 3 µm in diam.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

4 hours exposures, 9 during 2-week period.

Frequency of treatment:

see above

Dose / conc.:

32 mg/L air (analytical)

Remarks:

Basis:
analytical conc.

No. of animals per sex per dose:

6 animals per dose

Control animals:

no

Details on study design:

- Dose selection rationale: based on result of acute inhalation study

Positive control:

none

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: No data

FOOD CONSUMPTION: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY and CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (no further data)
HISTOPATHOLOGY: Yes (no further data)

Statistics:

none

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

discomfort

Mortality:

mortality observed, treatment-related

Description (incidence):

discomfort

Details on results:

Pathological Changes:
1 rat killed day of 9th treatment - slight emphysema
1 rat killed 11 days after 9th treatment - bronchopneumonia possibly aggravated by exposure

Key result

Dose descriptor:

conc. level:

Effect level:

ca. 32 mg/L air

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: Only one dose level tested; Discomfort; effects in lung noted in 2/6 animals (pulmonal irritation but no systemic effects).

Remarks on result:

other: Repeated inhalation of massive amounts of dust may be a source of pulmonary irritation.

Key result

Critical effects observed:

not specified

Conclusions:

Repeated inhalation of an extremely high concentration of SIM-Ester in its dust form (32 mg/L) resulted in adverse effects in the respiratory tract.

Executive summary:

In a repeated dose inhalation toxicity study (Haskell Laboratory for Toxicology and Industrial Medicine, 1959) 6 ChR-CD rats were whole body exposed to SIM-Ester dust 4 hours per day for 9 days during a period of two weeks. The test concentration was 32 mg/L (+/- 20%); 75% of the particles had a diameter below or equal to 3 µm. Amimals showed discomfort. Treatment related effects were limited to a slight emphysema seen in one animal (sacrificed on the 9th treatment day) and bronchopneumonia observed in another animal (sacrificed 11 days after the 9th treatment). No further pathologcial changes were reported. The authors concluded that repeated inhalation of massive amouts of SIM-Ester in its dust form may be a source of pulmonary irritation. This is most likely due to the dust overload effect and not related to the intrinsic properties of the substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

32 000 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Poorly documented study

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Remarks:

Repeated Sublethal Testing

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1959

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study without detailed documentation

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats were exposed 4 h per day for 9 days within a 14-day period to a single concentration (32 mg/L) of the test substance (whole body exposure). The study predates OECD guidelines.

GLP compliance:

no

Remarks:

study was performed prior to implentation of GLP

Limit test:

yes

Species:

rat

Strain:

other: ChR-CD

Sex:

not specified

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

> 75 % of particles were < 3 µm in diam.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

4 hours exposures, 9 during 2-week period.

Frequency of treatment:

see above

Dose / conc.:

32 mg/L air (analytical)

Remarks:

Basis:
analytical conc.

No. of animals per sex per dose:

6 animals per dose

Control animals:

no

Details on study design:

- Dose selection rationale: based on result of acute inhalation study

Positive control:

none

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: No data

FOOD CONSUMPTION: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY and CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (no further data)
HISTOPATHOLOGY: Yes (no further data)

Statistics:

none

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

discomfort

Mortality:

mortality observed, treatment-related

Description (incidence):

discomfort

Details on results:

Pathological Changes:
1 rat killed day of 9th treatment - slight emphysema
1 rat killed 11 days after 9th treatment - bronchopneumonia possibly aggravated by exposure

Key result

Dose descriptor:

conc. level:

Effect level:

ca. 32 mg/L air

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: Only one dose level tested; Discomfort; effects in lung noted in 2/6 animals (pulmonal irritation but no systemic effects).

Remarks on result:

other: Repeated inhalation of massive amounts of dust may be a source of pulmonary irritation.

Key result

Critical effects observed:

not specified

Conclusions:

Repeated inhalation of an extremely high concentration of SIM-Ester in its dust form (32 mg/L) resulted in adverse effects in the respiratory tract.

Executive summary:

In a repeated dose inhalation toxicity study (Haskell Laboratory for Toxicology and Industrial Medicine, 1959) 6 ChR-CD rats were whole body exposed to SIM-Ester dust 4 hours per day for 9 days during a period of two weeks. The test concentration was 32 mg/L (+/- 20%); 75% of the particles had a diameter below or equal to 3 µm. Amimals showed discomfort. Treatment related effects were limited to a slight emphysema seen in one animal (sacrificed on the 9th treatment day) and bronchopneumonia observed in another animal (sacrificed 11 days after the 9th treatment). No further pathologcial changes were reported. The authors concluded that repeated inhalation of massive amouts of SIM-Ester in its dust form may be a source of pulmonary irritation. This is most likely due to the dust overload effect and not related to the intrinsic properties of the substance.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

32 000 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Poorly documented study

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

Subacute

In a repeated dose toxicity study (Toxi-Coop Zrt. (e) 2012) Sodium dimethyl sulphonatoisophthalate (SIM-Ester) was administered orally (by gavage) to Wistar rats once a day at 0 (vehicle control; n=10/sex), 1000 (n=10/sex), 250 (n=5/sex) and 62.5 mg/kg bw/day (n=5/sex) doses corresponding to concentrations of 0, 200, 50 and 12.5 mg/mL, applied in a dose volume of 5 mL/kg bw for 28 days. Five animals per sex in the control and high dose group were observed for another 14-day recovery period following termination of the 28-day dosing period. A sufficient stability of SIM-Ester in the chosen vehicle was verified. Animals were observed for mortality twice a day in the course of the study. Daily general clinical observations and weekly detailed clinical observations were performed. A functional observation battery was conducted in the last week of treatment. The body weight and food consumption were measured and evaluated weekly. Animals assigned to the recovery group were observed identically for 14 days after the termination of the treatment. Clinical pathology examinations including hematology and clinical chemistry were conducted one day after the last treatment and on recovery animals at the end of recovery period. Gross pathology was performed on animals on the day following the last treatment and on recovery animals at the end of recovery period. The absolute and relative weights of selected organs were determined. Full histopathology was performed on the preserved organs or tissues of the animals of the control and high dose groups including recovery groups. The results of study were interpreted comparing test item treated groups with respect to controls, which were administered concurrently with vehicle (0.5 % aqueous methylcellulose) only.

No mortality occurred during the observation period. Toxic signs related to the test item were not found at any dose level at the daily and detailed weekly clinical observations and in the course of functional observation battery. Grey color of stool was noted for male and female animals at 1000 and 250 mg/kg bw/day starting at days 14 and lasting up to the end of the treatment period and for three days in the recovery period. The body weight development was undisturbed in male and female animals at each dose level in the course of the entire study. The mean daily food consumption was not influenced by the test item. Clinical pathology examinations did not reveal any test item related changes in the examined hematology, blood coagulation or clinical chemistry parameters. Neurobehavioral examinations revelated no effects. Specific macroscopic alterations related to the test item were not found during the necropsy. There were no test item related changes in the examined organ weights at any dose level. Histological examination did not detect any toxic or test item related lesions in the examined organs. Under the conditions of the present study, the test item caused no signs of toxicity in male or female Wistar rats after 28-days oral (gavage) administration at 1000 mg/kg bw/day, 250 mg/kg bw/day or 62.5 mg/kg bw/day. Based on the observations made in this toxicity study the No Observed Adverse Effect Level (NOAEL) was determined to be 1000 mg/kg bw/day.

In a repeated dose inhalation toxicity study (Haskell Laboratory for Toxicology and Industrial Medicine (c), 1959) 6 ChR-CD rats were whole body exposed to SIM-Ester dust 4 hours per day for 9 days during a period of two weeks. The test concentration was 32 mg/L (+/- 20%); 75% of the particles had a diameter below or equal to 3 µm. Amimals showed discomfort. Treatment related effects were limited to a slight emphysema seen in one animal (sacrificed on the 9th treatment day) and bronchopneumonia observed in another animal (sacrificed 11 days after the 9th treatment). No further pathologcial changes were reported. The authors concluded that repeated inhalation of massive amouts of SIM-Ester in its dust form may be a source of pulmonary irritation. This is most likely due to the dust overload effect and not related to the intrinsic properties of the substance. The outcome of the study is not relevant for classification and labelling as the test concentration of 32 mg/L exceeds by far the maximum concentration of 5 mg/L for aerosols according OECD guideline 412.

Subchronic

The subchronic toxicity of SIM-Ester can be reliably assessed taking into account the existing data on repeated dose toxicity and the subchronic toxicity data of structurally related compounds. This is further elucidated below.

SIM-Ester is acutely non-toxic and did not induce adverse effects in the OECD 407 and OECD 421 guideline study when administered at dose levels up to 1000 mg/kg bw/d by oral gavage. Based on this data, SIM-Ester does not raise a concern regarding repeated dose toxicity. Hydrolysis of SIM-Ester to the monomethylester and finally to 5-sulfoisophthalic acid with subsequent urinary excretion has been identified as the main metabolic and excretory pathway (see toxicokinetic section). Toxicologically extensively investigated substances which are structurally closely related to SIM-Ester and its final metabolite 5 -sulfoisophthalic acid are isophthalic acid, dimethyl terephthalate and terephthalic acid. The substances show a toxicological profile comparable to SIM-Ester, i.e. low acute toxicity (LD50(rat, oral and dermal) > 2000 mg/kg bw; LC50(rat, inhalation) > 5 mg/L), no sensitization and no genotoxic/mutagenic potential as well as a similar toxicokinetic behavior (OECD, 2001a, 2001b and 2002). These similarities justify the read-across from the structural analogues to SIM-Ester regarding repeated dose toxicity.

The toxicities of the three structural analogues are very similar with the formation of urinary calculi and subsequent inflammatory changes of the urinary tract being the only notable effect after subacute and subchronic repeated oral ingestion (OECD, 2001a, 2001b and 2002). The calculi are composed primarily of a calcium-terephthalate or -isophthalate complex and do not occur unless the solubility of Ca++ and the respective phthalate is exceeded. The effects were observed at high dose levels only. Dimethyl terephthalate, which is the closest structural analogue for SIM-Ester as it is also a dimethylester, caused urinary tract effects only at dose levels above 1000 mg/kg bw/d in a 14-day feeding study. No effects were seen in a 96-day feeding study up to 636 mg/kg bw/d which was the highest dose tested (OECD 2001a). Due to the higher water solubility of SIM-ester (31 g/L) in comparison to dimethyl terephthalate (19 mg/L) similar effects in the urinary tract are expected to occur only at even higher dose levels. This is in line with the outcome of the 28-day repeated dose toxicity study with SIM-Ester, where no substance related effects were found up to the limit dose of 1000 mg/kg bw/d.

In conclusion, based on the available toxicity data on SIM-Ester and the repeated dose toxicity data of structurally related compounds, it can be reliable estimated that SIM-Ester will not cause adverse effects relevant for classification and labelling in a subchronic toxicity study. Thus, the performance of a respective study is scientifically not necessary and moreover, should be omitted considering animal welfare reasons.  

 

References:

OECD (2001a). Dimethyl terephthalate (CAS No. 120-61-6) – SIDS Initial assessment report for SIAM 11. United States, January 23-26, 2001.

OECD (2001b). Terephthalic Acid (TPA) (CAS No. 100-21-0) – SIDS Initial assessment report for 12th SIAM. Paris, France, June 2001.

OECD (2002). Isophthalic acid (CAS No. 121-91 -5) – SIDS Initial assessment report for 14th SIAM. Paris, France, March 2002.

Roth T. et al (2013) Assessment of Sub-chronic and Developmental Toxicity of Sodium-dimethyl-5-sulphonatoisophthalate in a Weight of evidence Approach (Poster presented at EUROTOX 49th Annual Meeting)

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Well dcoumented and reliable study (Klimisch score = 1, GLP compliant).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Only one study available

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Only one study available

Justification for classification or non-classification

Based on the result of the repeated dose toxicity testing, SIM-Ester does not need to be classified and labelled for danger of serious damage to health by prolonged exposure (R48) according to Directive 67/548/EEC (DSD) and for specific target organ toxicity after repeated exposure (STOT RE) according to Regulation (EC) No 1272/2008 (CLP).