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Key value for chemical safety assessment

Effects on fertility

Description of key information

In the key one-generation reproduction study (OECD 415), a calcium sulfonate read across source substance, (CAS 115733-09-0), was administered in corn oil via oral gavage to 28 Sprague-Dawley rats/sex at dose levels of 0, 50, 167 and 500 mg/kg bw/day (Bjorn, 2004). All F0 males were dosed for 70 days prior to mating, mating (maximum 3 weeks) and through the completion of parturition. All F0 females were dosed for up to 70 days (14 days prior to mating, during mating and gestation and through day 20 of lactation). No substance related effects occurred in treated animals, except for the observation of post dosing salivation and dark material around the nose in the mid and high dose groups in F0 males and the negative ammonium sulfide staining in two high dose and one mid dose F0 female.

The animals were observed twice daily for appearance and behavior, and a detailed clinical observation was performed weekly and daily for females during gestation. Cage site observations were performed daily approximately 30 to 120-minutes post dosing. In addition, the bodyweights were determined weekly and on the day of euthanasia for males. Females were weighed after evidence of mating on gestational days 0, 7, 14 and 21. Food consumption was recorded on the same days as body weights except during the mating period. Animals were paired 1:1 for mating, after successful mating each pregnant female was caged individually. Positive evidence of mating was confirmed by the presence of sperm or a vaginal copulatory plug (day 0 of gestation). If evidence of mating was not present after three weeks, mating was discontinued. All of the surviving F0 females were allowed to deliver and rear their pups to lactation day 21. Detailed pup examinations and pup sex were performed on lactation days 0. Pups that were stillborn, cannibalized or found dead were subjected to a gross necropsy with emphasis on developmental morphology. Pups culled on day 4 were subjected to an abbreviated gross necropsy with emphasis on the reproductive system. All internal gross lesions were preserved for possible future microscopic examination. Gross necropsies (consisting of external and internal examinations including the cervical, thoracic and abdominal viscera) were performed on death, organ weights and microscopic examinations were performed on termination. The surviving F0 dams were necropsied on lactation day 21, following a minimum of 60 days of dosing. The surviving F0 males were necropsied at the conclusion of parturition following a minimum of 96 days of dosing. F0 females that failed to deliver were necropsied on post-mating day 25 (with evidence of mating) or 25 days following the termination of the mating period (with no evidence of mating). Organ weights were determined and microscopic examinations were conducted for all surviving control and high dose F0 animals. Tissues examined microscopically included the liver, kidney, brain, right epididymides, cervix, coagulation gland, ovaries, pituitary, prostrate, seminal vesicles, testes, uterus, vagina and gross lesions. F0 animals from all groups found dead or sacrificed early were subjected to a gross necropsy and the microscopic evaluation of all tissues. Sperm was collected from all surviving F0 males and evaluated for sperm count, concentration, motility and morphology assessment. The parameters examined in P males included: testis weight, epididymis weight, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm motility and sperm morphology. The F1 offsprings were examined for number and sex of pups, stillbirths, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioral abnormalities. Moreover, a gross examination of dead pups was conducted for external and internal abnormalities. So the possible cause of death of pups born or found dead was evaluated.

No substance related effects occurred in treated animals, except for the observation of post dosing salivation and dark material around the nose in the mid and high dose groups in F0 males and the negative ammonium sulfide staining in two high dose and one mid dose F0-female. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21). Based on the results of this study it is concluded that the 500 mg/kg/day dose level, the highest dose tested, is the no observed adverse effect level (NOAEL) for parental F0 and F1 pup toxicity.


Short description of key information:
The reproductive toxicity profile of benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts (read across target substance) was not determined by actual toxicity testing. Instead, a read across source substance was used to predict the reproductive toxicity behaviour of the registered substance.

Justification for selection of Effect on fertility via oral route:
In a 1-generation reproduction study on the read across source substance, benzenesulfonic acid, C14-C24 branched and linear alkyl derivatives was administered to 28 Sprague-Dawley rats/sex/via gavage at dose levels of 0, 50, 167 and 500 mg/kg bw/day. No substance related effects occurred in treated animals. As no effects occurred at the highest dose, a NOAEL cannot be identified, and is greater than 500 mg/kg bw/day for reproductive toxicity.
  
This study is acceptable, and satisfies the guideline requirement for a 1-generation reproductive study; OECD 415 in rats. 

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
The study meets the criteria for Klimisch code 1, as it is conducted to OECD guidelines and to GLP. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Justification for type of information:
REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Benzenesulfonic acid C14-C24 branched and linear alkyl derivative, calcium salt
3. CATEGORY APPROACH JUSTIFICATION
Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR
Qualifier:
according to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
no
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: (P) males 5 wks, females 7 weeks; (F1) x wks
- Weight at study initiation: (P) Males: 154-197 g; Females: 139-184 g;
- Housing: Suspended wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26°C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15 changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Corn oil was added to the test substance to achieve the desired volume and then stirred for 30 minutes.


VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation:
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged individually
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
F0 males - 70 days premating; mating period through completion of parturition
F0 females - 14 days premating; mating; 25 days of gestation and 20 days of lactation.
F1 pups - gestation through day 20 of lactation
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 50, 167, 500 mg/kg bw
Basis:
other: gavage
No. of animals per sex per dose:
28 F0 rats/sex/group in control, low, mid and high dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results of a 28 day oral gavage study.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly and daily for females during gestation


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly and on the day on euthanasia for males. After evidence of mating, females were weighed on gestational days 0, 7, 14 and 21 and on lactation days 1, 4, 7, 14 and 21.
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm motility, sperm morphology.
Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities.


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead.
Postmortem examinations (parental animals):
gross necroscopy on death, organ weights and microscopic examination on termination
SACRIFICE
- Male animals: All surviving animals after completion of female parturition.
- Maternal animals: All surviving animals that delivered on lactation day 21; females that failed to deliver were sacrificed on gestation day 25.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

Postmortem examinations (offspring):
SACRIFICE
- These animals were subjected to macroscopic postmortem examinations


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

Statistics:
ANOVA for body weights, changes, food consumption, semen parameters, organ weights.
Reproductive indices:
yes
Offspring viability indices:
yes
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not specified
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
There were no remarkable findings in F0 males, with the exception of post dosing salivation.
in F0 females, there were no remarkable findings with the exception of negative ammonium sulfide staining in two high dose and one mid dose animal.
Dose descriptor:
NOAEL
Effect level:
> 500 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No significant adverse effects occurred at 500 mg/kg/bwt (highest dose tested).
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
There were no remarkable observations in F1 animals.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 500 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No adverse effects occurred in animals in the top dose group, therefore a NOAEL cannot be identified from this study.
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Key result
Reproductive effects observed:
no
Conclusions:
Adverse effects did not occur in parental animals or offspring at doses up to 500 mg/kg bw/day, therefore NOAELs cannot be identified from this study.
Executive summary:

In a 1-generation reproduction study, benzenesulfonic acid, C14-C24 branched and linear alkyl derivatives was administered to 28 Sprague-Dawley rats/sex/via gavage at dose levels of 0, 50, 167 and 500 mg/kg bw/day.

 

No substance related effects occurred in treated animals. As no effects occurred at the highest dose, a NOAEL cannot be identified, and is greater than 500 mg/kg bw/day for reproductive and developmental toxicity.

  

This study is acceptable, and satisfies the guideline requirement for a 1-generation reproductive study; OECD 415 in rats. 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study meets the criteria for Klimisch code 1, as it is conducted to OECD guidelines and to GLP. However as this study is used in the context of a read across, Klimisch 2 is assigned.
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

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
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

In the one-generation study conducted on read-across source substance, no substance related adverse effects occurred in treated animals, except for the observation of post-dosing salivation and dark material around the nose in the mid and high dose groups in F0 males and the negative ammonium sulfide staining in two high dose and one mid dose F0-female. No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21). Based on the results of this study it is concluded that the 500 mg/kg/day dose level is the no observed adverse effect level (NOAEL) for parental F0 and F1 pup toxicity (no significant adverse effects occurred at this dose level). Consequently, as neither reproductive effects nor toxicologically significant systemic effects were found in maternal organisms and in pups at the highest dose level test, the benzenesulfonic acid, di-C10-14-alkyl dervis, sodium salts is not expected to be a reproductive or developmental toxicant. The substance does not meet the criteria for classification and labelling in accordance with European regulation (EC) No. 1272/2008