4-poly(propyl), benzene sulfonic acid

Endpoint summary

Description of key information

The following information is available for the repeated dose toxicity endpoints:
Dunster et al. (2009) AS305BD Twenty-Eight Day Repeated Dose Oral (Gavage) Toxicity Study in the Rat. Testing laboratory: Harlan Laboratories Limited.  Report no.: 0703-0423. Owner company: Chevron Energy Technology Company. Report date: 2009-06-25.
Dhinsa, N.K. (2008) AS305BD Twenty-eight day repeated dose oral (gavage) study in the rat. Testing laboratory: Harlan Laboratories Limited.  Report no.: 0703-0382. Owner company: Chevron Energy Technology Company. Report date: 2009-06-10.
The first study has been rated as 1 under the Klimisch scoring system while the second one was rated as 3 (not reliable) because dosing solution were found to not be stable and results therefore were considered only supportive. The first study is considered to be sufficient to address this endpoint.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

60 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Two repeated-dose toxicity studies (28-day, oral gavage) were performed with the substance.

In a first study, dosing suspensions in corn oil were prepared weekly. Although analysis confirmed a homogeneous distribution of the substance, it was found that the substance was not stable in corn oil, and concentrations were far below the nominal values. Results obtained in this study allowed to set the NOAEL at the nominal dosage of 60 mg/kg bw/day and were consistent with those obtained in the repeated study, for which polyethylene glycol 400 was used as the vehicle, the dosing solutions were prepared daily, and were administered within 4 hrs from preparation. Homogeneity, stability for 4 hrs and content within +/- 10% of target concentrations were confirmed by a HPLC method. In this fully compliant study, dosages of 60, 250 and 1000 mg/kg bw/day (corrected for 90% purity) were administered daily, by oral gavage to groups of 5 male and 5 female Sprague-Dawley rats. A concurrent vehicle control group received the vehicle, polyethylene glycol 400, at 4 mL/kg bw/day. Additional similar sized groups of animals for the control and the high dose groups were treated for 28 consecutive days and then maintained without treatment for a further 14 days.

There were no unscheduled deaths during the study. Incidents of increased salivation were noted following dosing in males treated at 1000 mg/kg bw/day, with one of them also showing staining around the mouth on a single day. An isolated incident of respiratory pattern changes was evident 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. Body weight, food consumption, food efficiency and water consumption were not affected by treatment. 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 the following treatment-related changes:

-         Minimal to moderate acanthosis and hyperkeratosis 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.

-         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.