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

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

NOAEL = 1000 mg/kg bw/day

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

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 was administered 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 rats consisting of 12 animals per sex per group in 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 item wasstable 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. The 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. Estrous cycle was monitored by examining vaginal smears before the treatmentfor two weeks and for two weeks from the beginning of the treatment period and during the mating period until evidence of copulation. Vaginal smears were prepared on the day of the necropsy for each female animal.

The dams were allowed to litter and rear their offspring up to day 13 post-partum. Litters were weighed and offspring were observed for possible abnormalities and were euthanized on post-natal day 13 or shortly thereafter.

Blood samples were collected for possible determination of serum levels of thyroid hormones (FT3, FT4 and TSH) from 2-7 pups per litter (in litters more than 9 pups) on post-natal day 4, from all dams and from 3-7 pups per litter at termination on post‑partum/post-natal day 13 and from all parent male animals at termination. FT3, FT4 and TSH was determined in the samples of parental male animals and PN 13 offspring.

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 and one male and one female pup per litter for the intended subsequent histopathological examination.

Offspring found dead and one male and one female pup per litter (from which thyroid glands were preserved) were subjected to necropsy and organs (kidneys) with macroscopic findings were preserved, processed and evaluated histologically.

Histopathologyexamination was performed onovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating glandin the control and high dose groups (male or female).

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.

 

Estrous cycle

A test item influence on the estrous cycle was not found at any dose level (100, 300 and 1000 mg/kg bw/day).

 

Reproductive performance

The examined parameters of delivery data of dams and reproductive performance were not adversely affected by the test item at 100, 300 or 1000 mg/kg bw/day in male or female animals.

 

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.

Offspring

The offspring’s development was undisturbed at 100, 300 and 1000 mg/kg bw/dayfrom birth to post-natal day 13.No effect on the mortality, clinical signs, body weight development, anogenital distance (male and female) or nipple retention (male) were detected.

 

Conclusion 

Under the conditions of the present study, the test substance did not adversely influence the reproductive performance (gonad function, mating behavior, conception, parturition) in parental male and female Han:WIST rats after oral (by gavage) administration at 100, 300 or 1000 mg/kg bw/day. 

There were no signs of systemic toxicity in selected male or female animals at 100, 300 or 1000 mg/kg bw/day. 

The development of the F1 offspring was not impaired from birth to post-natal day 13 after repeated oral administration of dams at 100, 300 or 1000 mg/kg bw/day.

Based on these observations the No Observed Adverse Effect Levels (NOAEL) by active ingredient were determined as follows:

 

NOAEL for reproductive performance of male/ female rats =1000 mg/kg bw/day

NOAEL for F1 Offspring =1000 mg/kg bw/day

 

Effects on developmental toxicity

Description of key information

NOAEL = 1000 mg/kg bw/day

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Preliminary data on the developmental toxicity derive from the test before described and carried out according to the OECD guideline 422.

Under the conditions the test substance did not adversely influence the development of the F1 offspring that resulted not impaired from birth to post-natal day 13 after repeated oral administration of dams at 100, 300 or 1000 mg/kg bw/day.

Based on these observations the No Observed Adverse Effect Levels (NOAEL) by active ingredient were determined as follows:

NOAEL for F1 Offspring =1000 mg/kg bw/day

Justification for classification or non-classification

According to CLP Regulation (EC) No 1272/2008, reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.

For the purpose of classification for reproductive toxicity, substances may be allocated to one of two categories. Within each category, effects on sexual function and fertility, and on development, are considered separately.

- Category 1: Known or presumed human reproductive toxicant. Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

- Category 2: Suspected human reproductive toxicant. Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1.

Based on the available information, no effect on fertility and development was observed therefore no calssification is warrented according to the CLP Regulation (EC No 1272/2008).