Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.4 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

17.7 mg/m³

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Acute/short-term exposure - systemic effects

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, 4,4'-sulphonyldiphenol displays low acute toxicity as evidenced by an LD50 value of 2830 mg/kg bw determined in rats for the oral route. A weight of evidence for the dermal route of exposure is indicating a similar low acute toxicity with a LD50 value well above 2000 mg/kg bw. No experimental data for the inhalation route is available.

Therefore, 4,4'-sulphonyldiphenol is not subject to classification for acute toxicity according to Regulation No 1272/2008, and consequently the derivation of worker DNELs for acute/short-term exposure - systemic effects is not required.

Acute/short-term and long-term exposure - local effects

Based on the available toxicological information, 4,4'-sulphonyldiphenol is not subject to classification for skin, eye and/or respiratory irritation and no worker DNEL for local effects following acute/short-term or long-term exposure is derived. In addition, no skin sensitizing properties were observed.

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health".

Long-term exposure - systemic effects

Selection of the relevant dose descriptor (starting point):

Data on 4,4´-sulphonyldiphenol is available on repeated dose toxicity, toxicity to reproduction as well as developmental toxicity and used for the derivation of the respective DNELs.

In an OECD 408 4,4´-sulphonyldiphenol was administered by gavage to groups of 10 male and 10 female Wistar rats at dose levels of 0, 100, 300 and 1000 mg/kg bw/d (BASF SE, 2014) over a period of three months. Due to a severely impaired body weight development in male animals of the high dose group, i.e. -20% on study day 63, the male animals were treated at a dose level of 600 mg/kg bw/d from study day 70 onwards. Female animals were continuously treated at the limit dose. Drinking water containing 1% carboxymethylcellulose served as vehicle.

Under the conditions of the study, an increase in relative liver weights (correlated with histopathological lesions), histopathological changes in the uterus and a regenerative anemia was observed at 1000 mg/kg bw/d in female rats. Therefore, the NOAEL for systemic toxicity in female rats is 300 mg/kg bw/d. 100 mg/kg bw is identified as the NOAEL in males based on an adverse decrease in male body weights and histopathological lesions in the mammary gland observed in male animals of the mid dose group (300 mg/kg bw).

An Extended One Generation Reproductive Toxicity Study in Sprague-Dawley rats, oral route, according to test method OECD 443, with the developmental neurotoxicity and immunotoxicity (DNT/DIT) cohorts and with the conditional extension of Cohort 1B to mate the F1 animals to produce an F2 generation has been conducted (BASF, 2019). The test substance 4,4´-sulphonyldiphenol was administered to groups of 24 male and 24 female healthy young Sprague-Dawley rats as an aqueous preparation by stomach tube at dosages of 0, 20, 60 and 180 mg/kg bw/d. F0 animals were treated at least for 10 weeks prior to mating to produce a litter (F1 generation). Pups of the F1 litter were selected (F1 rearing animals) and assigned to 5 different cohorts which were subjected to specific postweaning examinations. Cohort 1B (= F1 generation parental animals) were selected to produce F2 pups. F1 animals selected for breeding were continued in the same dose group as their parents. Groups of 24 males and 24 females, selected from F1 pups to become F1 parental generation, were offered an aqueous preparation by stomach tube at different dosages (0, 20, 60 and 180 mg/kg bw/d) of the test substance post weaning, and the breeding program was repeated to produce a F2 litter. The study was terminated with the terminal sacrifice of the F2 weanlings and F1 parental animals. Administration period for F0 parental animals was four months in total, F1B parental animals approximately four months, cohort F1A two months, cohort 2A one and a half months, and cohort 3 just over one month in total. Control animals were dosed daily with the vehicle (0.5% Sodium carboxymethyl cellulose [CMC] suspension in drinking water).

Under the conditions of the present modified extended 1-generation reproduction toxicity study the NOAEL for general, systemic toxicity is 60 mg/kg bw/d for the F0 and F1 parental as well as adolescent animals, based on evidence for kidney toxicity, as well as corresponding effects on clinical-pathological parameters, which were observed at the LOAEL of 180 mg/kg bw/d. The NOAEL for fertility and reproductive performance for the F0 and F1 parental rats is 180 mg/kg bw/d, the highest dose tested. Based on increased postimplantation loss in the F1 progeny, the NOAEL for developmental toxicity in the F1 and F2 progeny is considered to be 20 mg/kg bw/d. The NOAEL for developmental neurotoxicity and developmental immunotoxicity for the F1 progeny is 180 mg/kg bw/d, the highest dose tested.

4,4´-sulphonyldiphenol was tested for its prenatal developmental toxicity in Wistar rats (BASF, 2014). The test substance was administered as an aqueous suspension to groups of 25 time-mated female Wistar rats by gavage at doses of 30, 100, and 300 mg/kg bw/d on gestation days (GD) 6 through 19. The control group, consisting of 25 females, was dosed with the vehicle (1% Carboxymethylcellulose in drinking water (1% CMC)) in parallel.

Under the conditions of this prenatal developmental toxicity study, the oral administration of 4,4´-sulphonyldiphenol to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 300 mg/kg bw/d caused evidence of maternal toxicity, such as reduced food consumption and (net) body weight gain. In conclusion, the NOAEL for maternal toxicity is 100 mg/kg bw/d. There were no toxicologically relevant adverse fetal findings evident. Thus, the NOAEL for prenatal developmental toxicity is 300 mg/kg bw/d.

Studies with the longest exposure (90-day repeated dose toxicity study and extended one generation reproductive toxicity study) are regarded as the most relevant studies to derive a point of departure (NOAEL) for human health risk assessment.

Adaptation of the starting point - inhalation:

Investigations on the absorption, distribution, elimination and plasma kinetics of ¹⁴C- 4,4'-sulphonyldiphenol were performed in male and female Wistar rats according to OECD 417 (BASF, 2019).

As a result, ¹⁴C-4,4'-sulphonyldiphenol was rapidly absorbed from the gastrointestinal tract. Calculations based on the bile excretion experiments showed that about 93 and 96% of the administered dose were absorbed at a dose level of 300 mg/kg bw for male and female rats, respectively, whereas about 95% of the administered dose were absorbed for males and 87% of the administered dose were absorbed for females at a dose level of 30 mg/kg.

After daily administration for 14 days with unlabelled 4,4'-sulphonyldiphenol followed by one oral dose of the labelled substance at 30 mg/kg bw, excretion via urine and feces predominantly occurs within the first 48 hours post exposure (>40%). The total amounts of excreted radioactivity after 7 days reflected more than 90% of the administered dose for both genders. Plasma kinetics confirmed high oral absorption and demonstrated potential enterohepatic recirculation and fast excretion. However, no information on systemic oral bioavailability in rats is available.

In a human clinical study, six female volunteers were orally exposed to a single dose of 0.1 mg/kg bw deuterated 4,4’-sulphonyldiphenol-d8. Blood samples were taken prior to dosing and over the course of 48h. Urine samples were collected pre-exposure and throughout 72h after treatment at multiple time-points. High oral absorption was observed, with a small plasma peak concentration around 4-10h after application, indicating enterohepatic recirculation. The fraction of 4,4’-sulphonyldiphenol-d8 reaching systemic circulation unchanged was 62 ± 5%, reflecting the oral systemic bioavailability (Khmiri et al., 2020). Although there are known species-to-species differences concerning glucuronidation, Gayrard et al. (2019) showed comparable results on toxicokinetics in piglets. In pigs, on average 57.4% of the orally administered 4,4’-sulfonyldiphenol reached the systemic circulation in the unconjugated form.

It is not expected, that the oral systemic bioavailability of 4,4’-sulphonyldiphenol in rats differs essentially from the oral systemic bioavailability observed in humans and pigs. Thus, 50% oral bioavailability in rats is considered a reasonable assumption.

Therefore, in the absence of route-specific information, it is proposed to include a default factor of 2 in the case of oral-to-inhalation extrapolation, assuming 50% oral bioavailability in rats and 100% inhalation bioavailability in humans of 4,4'-sulphonyldiphenol.

The lowest worker DNEL for inhalative exposure to 4,4'-sulfonyldiphenol is derived from the developmental toxicity NOAEL from the OECD 443 study.

The oral NOAEL is converted into an inhalation NOAEC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL x (1/sRV(rat)) x (ABS oral (rat)/ABS inhal (human)) x (sRV (human)/wRV (human))

inhalation NO(A)EC = 20 mg/kg bw/d x 1/0.38 m³/kg bw x 50%/100% x 6.7 m³/10 m³ = 17.7 mg/m³

Assessment factors:

Allometric scaling: 1 (default factor)
Remaining differences: 2.5 (default factor)
Intraspecies (worker): 5 (default factor)
Exposure duration: 1 (duration of pregnancy covered; As the experimental exposure of a study according to OECD 443 adequately covered the pregnancy of the species under investigation over 2 generations an AF for exposure duration is not necessary.)
Dose response: 1 (default factor)
Quality of database: 1 (GLP guideline study)

The resulting lowest worker DNEL for inhalation exposure is:

DNEL (long-term systemic, inhalation) = 1.4 mg/m³

This value of 1.4 mg/m³ will be used for further risk characterization.

As indicated this DNEL is referring to the systemic toxicity of 4,4'-sulfonyldiphenol. Since the neat substance is a granular solid a potential impairment of the respiratory tract due to exposure to the dust additionally needs to be taken into account. E.g. the German Committee for Dangerous Substances derived a general limit value for low soluble dusts of 1.5 mg/m³ for the alveolar and 10 mg/m³ for the inhalable fraction.

Adaptation of the starting point - dermal:

Dermal absorption of 4,4'-sulfonyldiphenol was examined ex vivo (European Thermal Paper Association, 2017). The test substance was applied at 102 µg/cm² or 1 µg/cm² to human split-thickness skin membranes mounted into static diffusion cells and the cells were left open to the atmosphere. Percutaneous absorption was assessed by collecting receptor fluid samples prior to dosing and at 1, 2, 4, 8, 12 and 24 h post dose. At 8 h post dose, the exposure period was terminated by removing the applied test preparation from the skin surface (where applicable) and washing the skin surface. At 24 h post dose, the skin was removed from the static cells, the stratum corneum tape stripped and the skin divided into epidermis, dermis and unexposed skin samples. All samples were analyzed by liquid scintillation counting.

Following topical application of 102 µg/cm² test substance to human skin, the potentially absorbed dose was 1.80 +/- 0.38% (1.84 +/- 0.39 µg eqiv./cm²) of the applied dose.

Following topical application of 1 µg/cm² test substance to human skin, the potentially absorbed dose was 8.79 +/- 3.24% (90.8 +/- 33.4 ng equiv./cm²) of the applied dose.

In a human study the toxicokinetics of 4,4’-sulfonyldiphenol was examined after dermal exposure. The study showed a very low dermal absorption. The recovered plasma concentration was below the lower limit of quantification (LLOQ) (Khmiri et al, 2020).

Therefore, in order to derive a worker DNEL a worst-case dermal absorption rate of 10% is assumed for 4,4'-sulfonyldiphenol.

The lowest worker DNEL for dermal exposure to 4,4'-sulfonyldiphenol is derived from the developmental toxicity NOAEL from the OECD 443 study.

The oral NOAEL is converted into a dermal NOAEL according to the following formula:

dermal NOAEL = oral NOAEL x (ABS oral(rat)/ ABS dermal (human))

dermal NOAEL = 20 mg/kg bw/d x 50%/10% = 100 mg/kg bw/d

Assessment factors:

Allometric scaling: 4 (default factor)
Remaining differences: 2.5 (default factor)
Intraspecies (worker): 5 (default factor)
Exposure duration: 1 (duration of pregnancy covered; As the experimental exposure of a study according to OECD 443 adequately covered the pregnancy of the species under investigation over 2 generations an AF for exposure duration is not necessary.)
Dose response: 1
Quality of database: 1 (GLP guideline study)

The resulting lowest worker DNEL for dermal exposure is:

DNEL (long-term systemic, dermal) = 2 mg/kg bw/d

This value of 2 mg/kg bw/d will be used for further risk characterization.

Standard assessment factors are in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health".

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.4 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

8.7 mg/m³

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

20 mg/kg bw/day