Sodium cumenesulphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a reproductive and developmental toxicity screening test in rats [OECD TG 421], test substance was administered orally by gavage at doses of 0, 100, 300 and 1000 mg/kg bw/day. Then both the reproductive performance of parental animals and the development and growth of F1 offspring were examined. There was no significant effect of test substance on the numbers of total offspring and live offspring, sex ratio, live birth index, viability index or body weight, and no compound-related abnormality was found in external features, clinical signs or autopsy findings of offspring up to 1000 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (diarrhea, soft feces, etc.) were observed at 1000 mg/kg bw/day. Thus the NOAEL for reproductive and developmental toxicity was considered to be 1000 mg/kg bw/day in rats.

The 91-day oral rat feeding study with sodium cumene sulfonate, included examination of sex organs such as the prostate, testes and ovaries. There is no evidence from this repeat dose study to suggest that the chemical would have an adverse effect on reproductive organs.

Non-ER binder due to non-cyclic molecular structure.Sodium cumenesulphonate  have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore sodium cumenesulphonate  does not cause reproductive toxicity.

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

Ten-week-old male and female rats were used. Twelve male and twelve female animals were used for each dose of 0, 100, 300 and 1000 mg/kg bw/day.

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Test substance was administered orally by gavage. Male animals were dosed from 14 days before mating to the day before scheduled sacrifice through the mating period and thereafter (total 46 days). Female animals were dosed from 14 days before mating to 3 days after delivery through the mating and gestation periods.

Details on mating procedure:

For mating, one male to one female mating was used. A female rat was placed together with a male rat until copulation was confirmed. Day 0 of gestation (GD 0) was defined as the day when a vaginal plug or sperm was found. Pregnant female animals were delivered and maintained until 4 days after parturition (PND 4).

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Exposure period: Males: 14 days before mating until sacrifice (pre-mating, mating and post-mating periods: 46 days total)
Females: 14 days before mating until the third day after delivery (pre-mating, mating, gestation and lactation periods)
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: Male: 47 days; Female: 40-44 days

Frequency of treatment:

daily

Details on study schedule:

Once daily by oral gavage for 46 days from day 14 before the start of mating for males and once daily for 14 days before the start of mating, during the mating period up to the day of successful copulation, and during the gestation period up to day 3 of lactation for the females that had successful copulation.

Remarks:

Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
Basis: nominal conc.

No. of animals per sex per dose:

12/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Dose selection rationale: no-effect dose level in a previous 28-day repeated oral dose toxicity study was 1000 mg/kg, the high dose level was set at 1000 mg/kg and the middle dose level and the low dose level at 300 and 100 mg/kg, respectively, using a common ratio of approximately 3.
Sex: male/female Duration of test: Male: 47 days; Female: 40-44 days

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes - Time schedule: least twice daily from day 1 of administration, counting the day administration started as day 1 of administration, to the day of necropsy, the day following day 46 of administration. On the day of necropsy, they were observed once in the morning. - Cage side observations checked in table [No.?] were included. BODY WEIGHT: Yes - Time schedule for examinations:on days 1, 2, 5, 7, 10 and 14 of administration and every 7 days thereafter before dosing of the day, on the last day of administration and the day of necropsy.

Oestrous cyclicity (parental animals):

Vaginal smear specimens were prepared by Giemsa staining every day from 10 days before the start of administration to the day of successful copulation and observed under a light microscope for the stage of estrous cycle (proestrus, estrus, metestrus, and diestrus).

Litter observations:

All live pups were weighed on days 0, 1 and 4 of lactation. All live pups were checked for survival and death and observed for general condition and external appearance once a day from day 0 of lactation to day 4 of lactation.

Postmortem examinations (parental animals):

SACRIFICE - Male animals: All surviving animals were subject to necropsy on the day following day 46 of dosing. - Maternal animals: All surviving animals were subject to necropsy on the day following day 46 of dosing. GROSS NECROPSY - Gross necropsy consisted of external and internal examinations including the brain (cerebrum, cerebellum), pituitary, thymus, thyroid glands (including parathyroid glands), adrenals, spleen, heart, thoracic aorta, tongue, esophagus, stomach (forestomach and glandular stomach), liver, pancreas, duodenum, jejunum, ileum (including Peyer’s patches), cecum, colon, rectum, larynx, trachea, lungs (including bronchi), kidneys, urinary bladder, testes, epididymides, prostate, seminal vesicles with coagulating glands, eyeballs and Harderian glands, skin (right abdominal region, in principle), sternal and femoral bones (including bone marrow, right), spinal cord (cervical region), mesenteric lymph node, submandibular lymph node, submandibular gland, sublingual gland, parotid gland, skeletal muscles (gastrocnemius muscle, right), and sciatic nerve (right), ovaries, uterus (uterine horn and uterine cervix), vagina, mammary glands and skin (right abdominal region, in principle). HISTOPATHOLOGY / ORGAN WEIGHTSFor all males, the testes and epididymides. For all animals the following were examined microscopically: males - forestomach, stomach (limiting ridge), glandular stomach, liver and heart. Females - ovaries, lungs and trachea

Postmortem examinations (offspring):

The pups that died were subjected to necropsy immediately after it was found dead and its whole body fixed and preserved.The pups that survived were euthanized after external observation (including the inside of the oral cavity) on day 4 of lactation, and organs/tissue in the whole body observed macroscopically. For the pups that had abnormalities, the whole body was fixed and preserved.

Reproductive indices:

Copulation index (%) Fertility index (%)

Offspring viability indices:

Gestation index (%) Live birth index (%) Sex ratioDelivery index (%)Implantation index (%)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

There were no treatment-related changes in precoital time, mating index, fertility index and pregnancy index.Results for F0- Precoital time, fertility and mating data: There were no statistically significant differences compared with the controls.- Gross findings: There were no chemical- related findings in all treatment groups.- Histopathological findings: There were no chemical- related findings in all treatment groups.

Dose descriptor:

NOAEL

Remarks:

parental toxicity

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

gross pathology

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

not examined

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Other effects:

not examined

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

In a reproductive and developmental toxicity screening test in rats [OECD TG 421], sodium p-toluenesulfonate was administered orally by gavage at doses of 0, 100, 300 and 1000 mg/kg bw/day. Then both the reproductive performance of parental animals and the development and growth of F1 offspring were examined. There was no significant effect of sodium p-toluenesulfonate on the numbers of total offspring and live offspring, sex ratio, live birth index, viability index or body weight, and no compound-related abnormality was found in external features, clinical signs or autopsy findings of offspring up to 1000 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (diarrhea, soft feces, etc.) were observed at 1000 mg/kg bw/day. Thus the NOAEL for reproductive and developmental toxicity was considered to be 1000 mg/kg bw/day in rats.

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive and developmental toxicity.

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

sexual maturation

clinical signs

body weight and weight gain

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other effects:

not examined

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Reproductive effects observed:

not specified

Observations: offspring

Remarks on results including tables and figures

With regard to systemic general toxicity, diarrhea or soft feces was observed in all animals at 1000 mg/kg bw/day with frequency of 2 to 19 times. Diarrhea or soft feces was also observed in two females at 100 mg/kg bw/day and in one male at 300 mg/kg bw/day. Diarrhea and soft feces observed at 1000 mg/kg bw/day were considered to be dose related because they were observed at high frequency (up to 19 times). The treatment did not affect body weight gain or food intake in either sex. Macroscopic findings for males in the 1000 mmg/kg bw/day group included thickening of the stomach limiting ridge (seven out of 12 males). There were no treatment-related changes in absolute and relative organ weights in either sex. Histopathological examination revealed inflammatory cellular infiltration of lamina propria and squamous cell hyperplasia in the stomach limiting ridge in the male group at 1000 mg/kg bwmg/kg bw/day. These changes were significantly different from the controls.   Thickening of the stomach limiting ridge and histopathological changes in the stomach limiting ridge were not observed in females; however, these effects were considered to be toxicologically significant. These changes in the stomach limiting ridge were considered due to stimulation by alkaline property of sodium toluenesulfonate (pH 9.93).   Table1. Histopathological findings of male rats ================================================================================ Dose(mg/kg)                                             0   100   300   1000 -------------------------------------------------------------------------------- No. of animals examined                                 12   12    12    12 GradeStomach, limiting ridge Cellular infiltration, inflammatory cell,              +    0    0     0     7** lamina propria Squamous cell hyperplasia                        +    0    0     0     9** Cyst, squamous cell                              +    0    0     0     1 ================================================================================ Values are number of animals with findings.Grade; +: slight change. **: Significantly different from the 0 mg/kg group at p<0.01   There were no treatment-related histopathological findings for the testis, epididymis or ovary. Male and female reproduction were not affected by test-substance administration. The substance showed no effect on the following parental reproductive parameters: estrous cycle length, mating index, fertility index, numbers of corpora lutea and implantations, implantation index, delivery index, gestation index, gestation length, and parturition and maternal behaviour. Based on these results, NOAELs for general toxicity and reproductive toxicity in rats were considered to be 300 mg/kg bw/day and 1000 mg/kg bw/day, respectively.

Conclusions:

Parental toxicity was observed at the top dose of 1000 mg/kg bw/day. There were no adverse effects reported for reproductive or developmental parameters. A NOAEL of 300 mg/kg bw/day for parental toxicity and 1000 mg/kg bw/day for reproductive and developmental toxicity.

Executive summary:

In a reproductive and developmental toxicity screening test in rats [OECD TG 421], test substance was administered orally by gavage at doses of 0, 100, 300 and 1000 mg/kg bw/day. Then both the reproductive performance of parental animals and the development and growth of F1 offspring were examined. There was no significant effect of test substance on the numbers of total offspring and live offspring, sex ratio, live birth index, viability index or body weight, and no compound-related abnormality was found in external features, clinical signs or autopsy findings of offspring up to 1000 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (diarrhea, soft feces, etc.) were observed at 1000 mg/kg bw/day. Thus the NOAEL for reproductive and developmental toxicity was considered to be 1000 mg/kg bw/day in rats.

Reference 2

Endpoint:

two-generation reproductive toxicity

Remarks:

QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction: Accepted Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.

Qualifier:

according to guideline

Guideline:

other: QSAR Toolbox Version 3.3.5.17

Principles of method if other than guideline:

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

GLP compliance:

no

Remarks:

not applicable. QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.

Limit test:

no

Species:

other: fish (trout) and mammals.

Strain:

other: QSAR model

Sex:

not specified

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Details on exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Parental animals: Observations and examinations:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

Sodium cumenesulphonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore sodium cumenesulphonate does not cause reproductive toxicity.
1.1. CAS number:
28348-53-0
1.2. Other regulatory numbers:
Not reported
1.3. Chemical name(s):
benzenesulfonic acid, (1-methylethyl)-, sodium salt
sodium cumenesulphonate
sodium 2-(propan-2-yl)benzenesulfonate
1.4. Structure codes:
a. SMILES:
CC(C)c1ccccc1S(=O)(=O)O{-}.[Na]{+}
1.6. Profiling results:
DNA binding by OECD
No alert found
Est rogen Receptor Binding
Non binder, without OH or NH2 group
OECD HPV Chemical Categories
Hydrotrope surfactants
Linear alkylbenzene sulfonates
Protein binding by OECD
No alert found
Protein binding potency
Not possible to classify according to these rules (GSH)
Superfragments
No superfragment
Toxic hazard classification by Cramer (original)
High (Class III)
US-EPA New Chemical Categories
Not categorized

Dose descriptor:

other: Relative ERBA (Estrogen Receptor Binding Affinity)

Effect level:

< -3 other: Log RBA(Relative Binding Affinities )

Based on:

other: Estrogen receptor (ER) binding

Sex:

not specified

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Generation: QSAR model

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Sodium cumenesulphonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore sodium cumenesulphonate does not cause reproductive toxicity.
1.1. CAS number:
28348-53-0
1.2. Other regulatory numbers:
Not reported
1.3. Chemical name(s):
benzenesulfonic acid, (1-methylethyl)-, sodium salt
sodium cumenesulphonate
sodium 2-(propan-2-yl)benzenesulfonate
1.4. Structure codes:
a. SMILES:
CC(C)c1ccccc1S(=O)(=O)O{-}.[Na]{+}
1.6. Profiling results:
DNA binding by OECD
No alert found
Est rogen Receptor Binding
Non binder, without OH or NH2 group
OECD HPV Chemical Categories
Hydrotrope surfactants
Linear alkylbenzene sulfonates
Protein binding by OECD
No alert found
Protein binding potency
Not possible to classify according to these rules (GSH)
Superfragments
No superfragment
Toxic hazard classification by Cramer (original)
High (Class III)
US-EPA New Chemical Categories
Not categorized

Dose descriptor:

other: Relative ERBA (Estrogen Receptor Binding Affinity)

Generation:

F1

Effect level:

< -3 other: Log RBA(Relative Binding Affinities

Based on:

other: Estrogen receptor (ER) binding

Sex:

not specified

Basis for effect level:

other: Non-ER binder due to non-cyclic molecular structure.

Remarks on result:

other: Generation: QSAR model

Reproductive effects observed:

not specified

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

 

Non-binder, impaired OH or NH2 group

Non-binder without OH or NH2 group

Non-binder, non-cyclic structure

Non-binder, MW > 500

Non-binder, non-cyclic structure– chemicals without cycles and MW =<500

Non-ER binder due to non-cyclic molecular structure.

 

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Popular among these are the “four phase” assessment that includes Comparative Molecular Field Analysis (CoMFA) and the Common Reactivity Pattern Approach (COREPA)

Since the RE-binding is a receptor mediated event, particular organic functional groups, size and shape are critical to binding potency.

Sodium cumenesulphonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore sodium cumenesulphonate does not cause reproductive toxicity.

Conclusions:

Non-ER binder due to non-cyclic molecular structure.Sodium cumenesulphonate  have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore sodium cumenesulphonate  does not cause reproductive toxicity.

Executive summary:

Sodium cumenesulphonate  have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore sodium cumenesulphonate  does not cause reproductive toxicity.

1.1. CAS number:

28348-53-0

1.2. Other regulatory numbers:

Not reported

1.3. Chemical name(s):

benzenesulfonic acid, (1-methylethyl)-, sodium salt

sodium cumenesulphonate

sodium 2-(propan-2-yl)benzenesulfonate

1.4. Structure codes:

a. SMILES:

CC(C)c1ccccc1S(=O)(=O)O{-}.[Na]{+}

1.6. Profiling results:

DNA binding by OECD

No alert found

Est rogen Receptor Binding

Non binder, without OH or NH2 group

OECD HPV Chemical Categories

Hydrotrope surfactants

Linear alkylbenzene sulfonates

Protein binding by OECD

No alert found

Protein binding potency

Not possible to classify according to these rules (GSH)

Superfragments

No superfragment

Toxic hazard classification by Cramer (original)

High (Class III)

US-EPA New Chemical Categories

Not categorized

Reference 3

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available reproductive study was fully documented and conducted in accordance with GLP. In this study the NOAEL for reproductive toxicity was considered to be 1000 mg/kg bw/day in rats.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

With regard to systemic general toxicity, diarrhea or soft feces was observed in male and female groups at 1000 mg/kg bw/day.

Histopathological examination revealed inflammatory cellular infiltration of lamina propria and squamous cell hyperplasia in the stomach limiting ridge in the male group at 1000 mg/kg bw/day.

These changes were significantly different from the controls. Male and female reproduction were not affected by test-substance administration. Test substance showed no effect on the following parental reproductive parameters:

estrous cycle length, mating index, fertility index, numbers of corpora lutea and implantations, implantation index, delivery index, gestation index, gestation length, and parturition and maternal behavior. In examination of neonates, there was no effect of sodium p-toluenesulfonate on the numbers of total offspring and live offspring, sex ratio, live birth index, viability index or body weight.

No compound-related abnormality was found in external features, clinical signs or autopsy findings of offspring.

Based on these results, the NOAEL for developmental toxicity was considered to be 1000 mg/kg bw/day in rats.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction:Accepted DART QSAR method for chemicals properties assessment.. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals.

Qualifier:

according to guideline

Guideline:

other: QSAR Toolbox Version 3.3.5.17

Principles of method if other than guideline:

This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals.

GLP compliance:

no

Remarks:

not applicable DART QSAR method for chemicals properties assessment..

Limit test:

no

Species:

rat

Strain:

other: QSAR model

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Details on exposure:

This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 929 chemicals that have been evaluated for their DART potential. These chemicals were grouped into 54 different categories, and 76 sub-categories, based on defined receptor binding and chemical properties, and when known, their MOA. Data is separated into two types of endpoints: developmental and reproductive toxicity. Detailed information for the effect associated with observed data is available in the metadata information of the database.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

QSAR model

Duration of treatment / exposure:

QSAR model

Frequency of treatment:

QSAR model

Duration of test:

QSAR model

Control animals:

other: QSAR model

Maternal examinations:

This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 929 chemicals that have been evaluated for their DART potential. These chemicals were grouped into 54 different categories, and 76 sub-categories, based on defined receptor binding and chemical properties, and when known, their MOA. Data is separated into two types of endpoints: developmental and reproductive toxicity. Detailed information for the effect associated with observed data is available in the metadata information of the database.

Fetal examinations:

This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 929 chemicals that have been evaluated for their DART potential. These chemicals were grouped into 54 different categories, and 76 sub-categories, based on defined receptor binding and chemical properties, and when known, their MOA. Data is separated into two types of endpoints: developmental and reproductive toxicity. Detailed information for the effect associated with observed data is available in the metadata information of the database.

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
No adverse effects on the highest dose tested according the DART QSAR method for chemicals properties assessment..
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 929 chemicals that have been evaluated for their DART potential.

Dose descriptor:

NOAEL

Effect level:

3 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Fetal body weight changes:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Basis for effect level:

other: Embryotoxic / teratogenic effects:no effects

Remarks on result:

other: No adverse effects on the highest dose tested according the DART QSAR method for chemicals properties assessment.. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals.

Abnormalities:

not specified

Developmental effects observed:

not specified

See attached QSAR study report

Conclusions:

NOAEL for developmental toxicity was 3000 mg/kg bw/day (No adverse effects on the highest dose tested) for sodium cumenesulphonate and does not cause developmental toxicity.
Developmental & Reproductive Toxicity (DART): Not known precedent reproductive and developmental toxic potential (DART scheme v.1.0)

Executive summary:

Profiling results:

DNA binding by OECD: No alert found

Est rogen Receptor Binding: Non binder, without OH or NH2 group

OECD HPV Chemical Categories: Hydrotrope surfactants, Linear alkylbenzene sulfonates

Protein binding by OECD: No alert found

Protein binding potency: Not possible to classify according to these rules (GSH)

Superfragments: No superfragment

Toxic hazard classification by Cramer (original): High (Class III)

US-EPA New Chemical Categories: Not categorized

Developmental & Reproductive Toxicity (DART): Not known precedent reproductive and developmental toxic potential (DART scheme v.1.0)

Reference 2

Endpoint:

developmental toxicity

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

according to guideline

Guideline:

other: EPA TSCA, 1985

Principles of method if other than guideline:

Female rats were mated with untreated males (1/1) from the same strain. The day of observation of a copulatory plug was defined as day 0 of gestation. Mortality was checked twice daily. Clinical symptoms of dams were noted daily from day 6 to 20. Body weight and food consumption were recorded on day 0, 6, 9, 12, 16 and 20. All females were subjected to macroscopic examination on day 20 or on day of death. The uteri were removed, weighed and examined for number of corpora lutea, implantation sites and the number and location of foetuses and resorptions. Foetuses were inspected on total number, sex, weight and external, visceral (1/2 of foetuses) and skeletal (1/2 of foetuses) defects.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Michigan
- Age at study initiation: 12.5 weeks
- Weight at study initiation: 243-312g
- Fasting period before study: no data
- Housing: individually in suspended stainless steel wire mesh cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 71-71 degrees F
- Humidity (%): 48-59%
- Air changes (per hr): controlled
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:


DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Purina Certified Rodent Chow #5002
- Storage temperature of food: room temperature


VEHICLE
- Justification for use and choice of vehicle (if other than water): vehicle used but no data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

no data

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: until evidence of copulatory plug (7 days maximum)
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug
- Any other deviations from standard protocol: no data

Duration of treatment / exposure:

On gestation days 6-15

Frequency of treatment:

Daily

Duration of test:

Until gestation day 20

Remarks:

Doses:150, 1500 and 3000 mg/kg bw (vehicle: water, dosing volume 10 mL/kg);
solutions were prepared weekly.

No. of animals per sex per dose:

30 females

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: prior range finding study (study 715-001)
- Rationale for animal assignment (if not random): random block
- Other:

Maternal examinations:

Animals were observed twice daily for mortality and signs of overt toxicity. Clinical observations were made from gestation days - 20. Individual body weights were recorded on gestation days 0, 6, 9, 12, 16 and 20. Individual food consumption was recorded concurrent with the body weighing days. Food consumption was calculated. On gestation day 20 all surviving animals were euthanized and immediately examined by cesarean section.

Ovaries and uterine content:

The uterus and overies were exposed and examined. The uterus was weighed. The location of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The abdominal and thoracic cavities and organs were examined for grossly evident morphological changes. Uteri from nongravid females were placed in 10% ammonium sulfide solution for detection of implantations.

Fetal examinations:

Individual fetuses were weighed, sexed, and examined for external malformations and variations. Approximately one-half of the fetuses were placed in Bouin's solution for subsequent soft-tissue examination using hte Wilson razor-blade sectioning technique. The remainder of the fetuses were prepared for skeletal examination. All gross, visceral and skeletal alterations observed were classified as malformations or developmental variations.

Statistics:

Treatment and control groups were subjected to appropriate statistical comparison. Dunnett t-test for body wight, food consumption, numbers of corpora lutea, total implantations, live fetuses and mean fetal body weights. Chi-square or Fishers test for male to female sex ratios and proportion of litters with malformations and developmental variations. Kruskal-Wallis test for the proportion of resorbed and dead fetuses and postimplantation losses

Indices:

see "Statistics" above

Clinical signs:

no effects observed

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
One death occurred at the 1500 mg/kg/day dose but it was considered a gavage injury. No clinical observations or necropsy findings. No effects on body weight or body weight gain. There was a significant increase in food consumption for the 3000 mg/kg/day during gestation interval 12-16 but this was considered normal biological variation and not a direct effect of the test substance.

Dose descriptor:

NOAEL

Effect level:

> 3 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Dose descriptor:

NOAEL

Effect level:

> 936 mg/kg bw/day

Based on:

act. ingr.

Basis for effect level:

other: developmental toxicity

Fetal body weight changes:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No indications of developmental toxicity including teratogenesis. All indices were comaparable to the corresponding controls.

Dose descriptor:

NOAEL

Effect level:

> 3 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Teratogenicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

not specified

Developmental effects observed:

not specified

Results

NOAELMaternal:3000 mg/kg bw/day (equivalent to 936 mg active ingredient (a.i.)/kg using 31%purity)

NOAELTeratogenicity: 3000 mg/kg bw/day (equivalent to 936 mg a.i./kg using 31% purity)

Results:Mean measured concentration: 96-98% of nominal; stability over 10 daysconfirmed

 

Dose (mg/kg bw/day)	0	150	1500	3000	DR
Maternal data
Mortality	0/30	0/30	1/30	0/30
Clinical signs(A)	No treatment related effects
Body weight /body weight gain	No treatment related effects
Food intake _NC day 12-16				ic
Uterus weight	No treatment related effects
Necropsy	No treatment related effects
Number of pregnant females	27/30	29/30	25/30	25/30
Number of corpora lutea and implantation sites /dam	No treatment related effects
Pre-implantation loss	No treatment related effects
Post-implantation loss/ resorptions	No treatment related effects
Embryonic / foetal resorptions	No treatment related effects
Number of live foetuses/ dam	No treatment related effects
Foetal data
Number of litters included in evaluations	27	28	25	25
Foetal weight	No treatment related effects
External examination / sex	No treatment related effects
Anomalies: visceral/ skeletal(B)	No treatment related effects

 

Conclusions:

The test substance did not induce developmental or teratogenic effects at doses up to 3000 mg/kg/day test material, equivalent to 936 mg/kg active ingredient.

Reference 3

Endpoint:

developmental toxicity

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

other: OECD Test Guide-line 421

Principles of method if other than guideline:

The test was conducted according to OECD guide-line 421. The test substance was administered orally to twelve male and twelve female rats through pre-mating, mating, gestation and lactation periods starting from 14 days before mating until postnatal Day 3 (PND 3).
Dams delivered naturally and were kept until PND 4. All live pups were weighed on PND 0, 1 and 4.
All dams and live pups were sacrificed and necropsied on PND 4

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

Ten-week-old male and female rats were used. Twelve male and twelve female animals were used for each dose of 0, 100, 300 and 1000 mg/kg bw/day.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Test substance was administered orally by gavage. Male animals were dosed from 14 days before mating to the day before scheduled sacrifice through the mating period and thereafter (total 46 days). Female animals were dosed from 14 days before mating to 3 days after delivery through the mating and gestation periods.

For mating, one male to one female mating was used. A female rat was placed together with a male rat until copulation was confirmed. Day 0 of gestation (GD 0) was defined as the day when a vaginal plug or sperm was found. Pregnant female animals were delivered and maintained until 4 days after parturition (PND 4).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

no data

Details on mating procedure:

For mating, one male to one female mating was used. A female rat was placed together with a male rat until copulation was confirmed. Day 0 of gestation (GD 0) was defined as the day when a vaginal plug or sperm was found. Pregnant female animals were delivered and maintained until 4 days after parturition (PND 4).

Duration of treatment / exposure:

Males: 14 days before mating until sacrifice (pre-mating, mating and post-mating periods: 46 days total) Females: 14 days before mating until the third day after delivery (pre-mating, mating, gestation and lactation periods)

Frequency of treatment:

Daily

Duration of test:

Sex: male/female Duration of test: Male: 47 days; Female: 40-44 days

Remarks:

Doses:0, 100, 300, 1000 mg/kg bw/day

No. of animals per sex per dose:

12/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Dose selection rationale: no-effect dose level in a previous 28-day repeated oral dose toxicity study was 1000 mg/kg, the high dose level was set at 1000 mg/kg and the middle dose level and the low dose level at 300 and 100 mg/kg, respectively, using a common ratio of approximately 3.
Sex: male/female Duration of test: Male: 47 days; Female: 40-44 days

Maternal examinations:

Time schedule: least twice daily from day 1 of administration, counting the day administration started as day 1 of administration, to the day of necropsy, the day following day 46 of administration. On the day of necropsy, they were observed once in the morning. - Cage side observations checked in table [No.?] were included. BODY WEIGHT: Yes - Time schedule for examinations:on days 1, 2, 5, 7, 10 and 14 of administration and every 7 days thereafter before dosing of the day, on the last day of administration and the day of necropsy.

Ovaries and uterine content:

Vaginal smear specimens were prepared by Giemsa staining every day from 10 days before the start of administration to the day of successful copulation and observed under a light microscope for the stage of estrous cycle (proestrus, estrus, metestrus, and diestrus).

Fetal examinations:

All live pups were weighed on days 0, 1 and 4 of lactation. All live pups were checked for survival and death and observed for general condition and external appearance once a day from day 0 of lactation to day 4 of lactation.

Indices:

Copulation index (%) Fertility index (%)
Gestation index (%) Live birth index (%) Sex ratioDelivery index (%)Implantation index (%)

Clinical signs:

no effects observed

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
With regard to systemic general toxicity, diarrhea or soft feces was observed in male and female groups at 1000 mg/kg bw/day.
Histopathological examination revealed inflammatory cellular infiltration of lamina propria and squamous cell hyperplasia in the stomach limiting ridge in the male group at 1000 mg/kg bw/day.
These changes were significantly different from the controls. Male and female reproduction were not affected by test-substance administration. Test substance showed no effect on the following parental reproductive parameters:
estrous cycle length, mating index, fertility index, numbers of corpora lutea and implantations, implantation index, delivery index, gestation index, gestation length, and parturition and maternal behavior. In examination of neonates, there was no effect of sodium p-toluenesulfonate on the numbers of total offspring and live offspring, sex ratio, live birth index, viability index or body weight.
No compound-related abnormality was found in external features, clinical signs or autopsy findings of offspring.
Based on these results, the NOAEL for developmental toxicity was considered to be 1000 mg/kg bw/day in rats.

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

1 000 mg/kg bw/day

Based on:

act. ingr.

Basis for effect level:

other: maternal toxicity

Fetal body weight changes:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No indications of developmental toxicity including teratogenesis. All indices were comaparable to the corresponding controls.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

Based on these results, the NOAEL for developmental toxicity was considered to be 1000 mg/kg bw/day in rats.

Executive summary:

With regard to systemic general toxicity, diarrhea or soft feces was observed in male and female groups at 1000 mg/kg bw/day.

Histopathological examination revealed inflammatory cellular infiltration of lamina propria and squamous cell hyperplasia in the stomach limiting ridge in the male group at 1000 mg/kg bw/day.

These changes were significantly different from the controls. Male and female reproduction were not affected by test-substance administration. Test substance showed no effect on the following parental reproductive parameters:

estrous cycle length, mating index, fertility index, numbers of corpora lutea and implantations, implantation index, delivery index, gestation index, gestation length, and parturition and maternal behavior. In examination of neonates, there was no effect of sodium p-toluenesulfonate on the numbers of total offspring and live offspring, sex ratio, live birth index, viability index or body weight.

No compound-related abnormality was found in external features, clinical signs or autopsy findings of offspring.

Based on these results, the NOAEL for developmental toxicity was considered to be 1000 mg/kg bw/day in rats.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available developmental study was fully documented and conducted in accordance with GLP. Based on these results, the NOAEL for developmental toxicity was considered to be 1000 mg/kg bw/day in rats.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the hazard assessment of Sodium cumenesulphonate in section 2.1 and 2.2. in IUCLID 6., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health” andaccording to the criteria described in Directive 67/548 and in the CLP Regulation:

 

Directive 67/548	Toxicity to reproduction/development Repr. Cat. 1; R61 May cause harm to the unborn child. Repr. Cat. 2; R61 May cause harm to the unborn child. Repr. Cat. 3; R63 Possible risk of harm to the unborn child. Toxicity to reproduction/fertility  Repr. Cat. 1; R60 May impair fertility. Repr. Cat. 2; R60 May impair fertility. Repr. Cat. 3; R62 Possible risk of impaired fertility
CLP	Reproductive toxicity Repr. 1A Repr. 1B Repr. 2 H360: May damage fertility or the unborn child <state specific effect if known > <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>. H361: Suspected of damaging fertility or the unborn child <state specific effect if known>

 

 

It is concluded that the Sodium cumenesulphonate does not meet the criteria to be classified for human health hazards for Reproductive toxicity.