Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 mg/m³
DNEL related information
Overall assessment factor (AF):
375
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
1 500
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

The substance is of low acute toxicity following oral and dermal exposure, with LD50 values determined to be greater than the limit dose of 2000 mg/kg bw. No data are available on acute inhalation toxicity however, this route of exposure is unlikely to occur on the basis of the vapour pressure of the substance and the unlikely possibility to generate aerosol, particles or droplets of an inhalable size.

In vivo animal studies showed that the substance is corrosive to the skin and irritating to the eyes and requires labelling with R34 – causes burns and R41 - risk of serious damage to eyes. The substance was also found to possess sensitising potential in a Buhler test, and requires labelling with R43 – May cause sensitisation by skin contact. The substance appears a potent sensitiser, with the great majority of tested animals developing a dermal response; no NOAEL for sensitisation was determined, hence no DNEL can be estimated for local effects on the skin.

Base on a fully compliant genotoxicity package, consisting of two in vitro studies investigating the ability to induce gene mutation in bacterial cells and chromosome aberrationsin cultured human lymphocytes, and one in vivo micronucleus study, the substance is considered not genotoxic.

Two repeated oral toxicity studies have been performed, administering the substance by oral gavage for 28 consecutive days up to the limit dose of 1000 mg/kg bw/day (corrected for purity). Although fully GLP-compliant, the first study was not considered reliable because the dosing suspensions in corn oil were prepared weekly and were found to not be stable, with analytically determined concentrations much lower than nominal values. The NOAEL of this study was set at the nominal dosage of 60 mg/kg bw/day but the study was repeated, using propylene glycol 400 as the vehicle, preparing the dosing solutions daily and administering them within 4 hrs of preparation. Homogeneity, stability for 4 hrs as well as appropriate concentrations in samples taken weekly during the study were confirmed using a HPLC method. This second study is therefore fully compliant, and appropriate to evaluate the repeated toxicity of the substance.

The substance was administered at dosages of 60, 250 and 1000 mg/kg bw/day (corrected for purity). Treatment did not affect mortality, body weight, food consumption, food efficiency, water consumption. Clinical signs were limited to increased salivation post dosing in male rats treated at 1000 mg/kg bw/day, a single observation of staining around the mouth in one male, and an isolated incident of respiratory pattern changes in one female of this group during the final week of treatment. These signs are commonly observed following the oral administration of an irritant substance and actually no clinical signs were noted during the recovery period. FOBs and motor activity assessment, as well as urinalysis, did not reveal any difference compared to the control group. Haematology showed statistically significant increases of haemoglobin, erythrocyte count and haematocrit in males, but not females, treated at 1000 mg/kg bw/day, disappearing at the end of the recovery period. Clinical chemistry investigations revealed significant increases in aspartate aminotransferase and alanine aminotransferase, together with reductions in cholesterol and tryglicerides levels in animals of both sexes treated at 1000 mg/kg bw/day. Males of this group also showed a statistically significant increase in the A/G ratio, with the effect extending to the recovery males. Alanine aminostransferase levels were also elevated in animals of both sexes treated at 250 mg/kg bw/day, and significant reductions in cholesterol and triglycerides levels were recorded in females of this group. Effects at 60 mg/kg bw/day were limited to an increase in alanine aminotransferase for females only. At necropsy, one male treated at 1000 mg/kg bw/day had sloughing of the glandular region of the stomach. Analysis of organ weight data did not show any toxicologically significant change. Histopathology revealed treatment-related changes in the stomach, pancreas and the mesenteric lymph node. Minimal to moderate acanthosis and hyperkeratosis were noted in the forestomach of animals of both sexes treated at 1000 mg/kg bw/day. Low severity grades of acanthosis, within one instance of associated minimal hyperkeratosis, were seen for two recovery females following completion of the recovery period suggesting regression of these changes. Minimal acanthosis was also seen in males treated at 250 mg/kg bw/day and one female of this group showed minimal hyperkeratosis. These epithelial changes in the forestomach were considered a consequence of a portal-of-entry irritating effect of the substance given as a bolus by gavage and considered adaptive rather than toxic in nature. In the pancreas, excess accumulation of zymogen granules was seen in exocrine pancreatic cells of animals treated at 1000 mg/kg bw/day and in 3 females treated at 250 mg/kg bw/day. Complete regression of this change was observed in recovery animals. In the mesenteric lymph node, lymphoid depletion was observed in animals of both sexes treated at 1000 mg/kg bw/day and hysticytosis was noted in 3 females of this group. Although two recovery females demonstrated lymphoid depletion of the mesenteric lymph node, the condition was considered as having generally regressed following completion of the recovery period.

The NOAEL (No Adverse Effect Level) of the study was established at 60 mg/kg bw/day, because the elevated alanine aminotransferase noted for females only was not considered to be adverse. This dose level corresponds to the NOEL (No Effect Level) for male rats.

The toxicological endpoint from this study is considered appropriate for long-term DNELs setting. An additional assessment factor of 5 was used to account for the lack of any study investigating carcinogenicity or the reproductive and developmental toxicity of the substance.  

No ADME or toxicokinetic data are available for the substance but, in view of the systemic effects observed following oral administration in the repeated 28-day oral gavage study, as well as the clinical signs and reductions in the PCE/NCE ratios in mice injected intraperitoneum in the micronucleus study, the substance is considered to be absorbed. Based on the high molecular weight (>452<508) and the high Log POW(>7.4) a default value of 10% for dermal absorption is considered appropriate.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

DNELs for the general population are not required because of the lack of exposure to the general population from the uses of toluene sulfonic acid.