Sulphophthalic acid derivatives reaction products of fatty alcohol C12-C14 and sodium hydroxide

Endpoint summary

Description of key information

NOAEL = 1000 mg/kg bw/day

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

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 study available

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

The objective of this study was to obtain initial information on the toxic potential of test item and on the possible effects of the test item on reproduction and developmentwhen repeatedly administered orally (by gavage) to rats at doses of 100, 300 and 1000 mg/kg bw/day (calculated by active ingredient) compared to control animals according to OECD 422.

As a screening test, it was intended to provide initial informationon the possible health hazards likely to arise from repeated exposure over a relatively limited period of time and on the possible effects onmale and female reproductive performance such as gonadal function, mating behavior, conception, pregnancy, parturition as well as on development of the F1 offspring from conception to day 13 post-partum associated with administration of repeated maternal doses

The test item wasadministered orally (by gavage) once daily at 0 (vehicle only), 100, 300 and 1000 mg/kg body weight (mg/kg bw/day) doses to four groups ofHan:WIST ratsconsisting of 12 animals per sex per groupin concentrations of 20, 60 and 200 mg/mL (calculated by active ingredient)corresponding to a 5 mL/kg bw dosing volume.A group of vehicle (distilled water) treated animals (n= 12/sex) served as a control.

The suitability of the chosen vehicle for the test item at the intended concentrations was analytically verified up front.The test itemwasstable inthe vehiclein concentrations of 1 mg/mL and 400 mg/mL at room temperature and in a refrigerator (at 5 ± 3 °C) for three days.

The concentration of the test item in the dosing formulations administered to the animals was checked two times during the study. Test item concentrations in the dosing formulations varied within the rangeof 100 % and 106 % (in comparison to the nominal values)and confirming the proper preparation of the dosing formulations.

All animals of the parent (P) generation were dosed prior to mating (14 days) and throughout mating. In addition, males received the test item or vehicle after mating up to the day before the necropsy (altogether for 41 days). Dams were additionally exposed through the gestation period and up to lactationdays 13-16,i.e. up to the day before necropsy (altogether for 51, 54 or 67 days). One dam for which no living pups remained was administered for 44 days.

Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of offspring.

Blood samples were collected for possible determination of serum levels of thyroid hormones (FT3, FT4 and TSH) from all dams.

Five dams and their male mating partners were randomly selected from each group to examine further signs of toxicity such as functional observations, hematology and blood coagulation, clinical chemistry, gross necropsy, organ weighing and histopathologic examinations.

All parental animals were subjected to gross pathology one day after the last treatment. The body weight, brain weight and weight of the testes and epididymides and prostate and seminal vesicles with coagulating glands as a whole of adult male animals were determined. In addition, for five males and females randomly selected from each group, adrenals, brain, heart, kidneys, liver, spleen and thymus were weighed.

Thyroid gland was preserved from all adult males and females for the intended subsequent histopathological examination.

Full histopathology examinations were performed on the preserved organs and tissues of the randomly selected animals in the control and high dose groups. Additionally, full histopathological examinations were performed for organs and tissues of one dam with severe clinical signs and macroscopic findings at 1000 mg/kg bw/day.

In addition, organs showing macroscopic findings at the necropsy (kidneys, skin and thymus) were processed and examined histologically in some animals of low and mid dose groups.

 

The results of this study were summarized – indicating only the doses of 100, 300 and 1000 mg/kg bw/day by active ingredient – as follows:

Mortality

There was no mortality in any group of control, 100, 300 or 1000 mg/kg bw/day.

 

Clinical and functional observation

Clinical signs of systemic toxicity related to the test item were not detected at any dose level, neither at the daily nor at the detailed weekly clinical observations or at the functional observations. The behavior and physical condition of the animals was not impaired at any dose level (100, 300 or 1000 mg/kg bw/day) during the entire treatment period.

 

Body weight and body weight gain

The body weight development was not affected by the test item in male or in female animals at 100, 300 or 1000 mg/kg bw/day during the entire treatment period (pre-mating and post-mating period for male animals; pre-mating, gestation and lactation periods for female animals).

Food consumption

The mean daily food consumption was similar in male or female animals in control and at 100, 300 and 1000 mg/kg bw/day during the entire study.

Hematology and blood coagulation

Hematologicaland blood coagulation investigation did not reveal test item related changes in the examined parameters at 100, 300 or 1000 mg/kg bw/day.

 

Clinical chemistry

There were no test item related effects on the examined clinical chemistry parameters at 100, 300 or 1000 mg/kg bw/day (male or female).

 

Serum thyroid hormones

Therewereno test item related changes in the serum thyroid hormone (FT3, FT4 and TSH) levels at any dose (parental male or 13-day offspring).

 

Necropsy

Macroscopic findings related to the effect of the test item were not found in male and female animals at 100, 300 or 1000 mg/kg bw/day.

 

Organ weight

There were no test item related changes in the weights (absolute and relative to body or brain weights) of brain, testes and epididymides,prostate and seminal vesicles with coagulating glands as a wholeof male animals at any dose level.

The weights of organs of selected animals were comparable in the control and test item treated groups (male and female).

 

Histopathology

There were no toxic or other test item related lesions detectable by histological examination in the investigated reproductive organs (ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland) in male or female animals administered with 1000 mg/kg bw/day.

Histopathological examinations did not indicate any toxic or other test item related lesions in the investigated organs of selected male and female animals at 1000 mg/kg bw/day.

Under the conditions of the present study,no signs of systemic toxicity in selected male or female animals at 100, 300 or 1000 mg/kg bw/day were found.

Based on these observations the No Observed Adverse Effect Levels (NOAEL) by active ingredient was found to be1000 mg/kg bw/day

 

Data obtained in the Dose Range Finding Test, used as supporting study, show no effects after repeated exposure via oral route and the extrapolated NOAEL is 1000 mg/kg bw/day.

Justification for classification or non-classification

According to the CLP Regulation (EC) No. 1272/2008, substances are classified as specific target organ toxicants following repeated exposure, and are placed in one of two categories, depending on the nature and severity of the effect(s) observed. Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure, are classified in Category 1 for target organ toxicity (repeat exposure). Classification in Category 1 is applicable when significant toxic effects are observed in a 90-day repeated-dose animal study at low concentrations (< 10 mg/kg bw/day in oral studies, and < 20 mg/kg bw/day in dermal studies) (CLP Regulation (EC) No. 1272/2008: Annex 1, Part 3, Table 3.9.2).

Substances which can be presumed to have the potential to be harmful to human health following repeated exposure, based on evidence from animal studies, are classified in Category 2. Classification in Category 2 is applicable when significant toxic effects are observed in a 90-day repeated-dose animal study at generally moderate exposure concentrations (10 to 100 mg/kg bw/day in oral studies, and 20 to 200 mg/kg bw/day in dermal studies) (CLP Regulation (EC) No. 1272/2008: Annex 1, Part 3, Table 3.9.3).

Equivalent guidance values for an equivalent 28-day study period raises the concentration values for classification by three-fold: classification in category 1 is applicable at low concentrations (< 30 mg/kg bw/day in oral studies; < 60 mg/kg bw/day in dermal studies) and in Category 2 at generally moderate concentrations (30 to 300 mg/kg bw/day in oral studies, 60 to 600 mg/kg bw/day in dermal studies).

Based on the short-term, repeated dose toxicity study (combined with reproductive and developmental toxicity) according to the OECD Guildeline 422 (2016), the test item did not produce adverse toxicity in male or female rats when administered at 1000 mg/kg bw/day. Therefore, no classification of the test item is warranted for specific target organ toxicity – repeated exposure according to the CLP Regulation (EC) No. 1272/2008.