Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a reproductive and developmental toxicity screening study (OECD 421) Sodium toluene sulphonate was administered to male and female Sprague-Dawley rats by oral gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day on a total of 46 days before the start of mating, during the mating period and after the end of mating to male rats and before the start of mating, during the mating and gestation periods up to day 3 of lactation to female rats. Males and females in the 1000 mg/kg bw/day group showed diarrhoea or soft faeces, and males showed mild inflammatory cell infiltration of the lamina propria and squamous cell hyperplasia in the limiting ridge of the stomach. There were no effects from administration of the substance on the reproductive function or development and growth of the next generation in any dose group. Therefore, it was considered that the NOAEL for parental toxicity was 300 mg/kg bw/day and the NOAEL for reproductive and developmental toxicity was 1000 mg/kg bw/day.

The 90-day oral rat and oral mouse studies and the 2-year chronic dermal rat and mouse studies conducted on sodium xylene sulfonate included examination of sex organs of both sexes. No treatment related effects on reproductive organs were reported in any study.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
GLP compliance:
not specified
Specific details on test material used for the study:
Purity: 94.9%, containing unknown compounds as impurity (inorganic compounds 4.7%, and loss on drying 0.4%)],
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
SPF Crl:CD
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
5 hours duration
Frequency of treatment:
Once 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.
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
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.
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
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Males in the 1000 mg/kg group showed thickening of the limiting ridge of the stomach. Repeated administration of the test article might have caused minimal irritation in the limiting ridge of the stomach following repeated administration of the substance of pH 9.93.
Neuropathological findings:
not examined
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
Key result
Dose descriptor:
NOAEL
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
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
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
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 study the substance was administered to male and female Sprague-Dawley rats 12 animals/sex/dose by oral gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day. Males and females in the 1000 mg/kg bw/day group showed diarrhea or soft feces, and males showed mild inflammatory cell infiltration of the lamina propria and squamous cell hyperplasia in the limiting ridge of the stomach. There were no effects from administration of the substance in the reproductive function or development and growth of the next generation in any dose group. Therefore, it was considered that the no observed adverse effect level (NOAEL) of sodium p-toluenesulfonate under the conditions of this study was 300 mg/kg bw/day, and the NOAEL on the reproductive functions of parent animals and on the development and growth of the next generation were both 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
Quality of whole database:
Sufficient to meet requirements.
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

In the developmental toxicity study on calcium xylene sulphonate, thirty (30) female rats received 0, 150, 1500 or 3000 mg test substance/kg bw/day by oral gavage on days 6 to 15 of gestation. Clinical symptoms were noted daily through day 20. Body weight and food consumption were recorded every three days through day 20. All females were macroscopically examined on day 20. The uteri were removed, weighed and examined for number of corpora lutea, implant sites, and number, and location of foetuses and resorptions. Foetuses were inspected on total number, sex, weight and external, visceral (one-half) and skeletal (one-half) defects. One death occurred at the 1500 mg/kg bw/day dose but it was considered a gavage injury. There were no abnormal clinical observations or necropsy findings. There were no effects on body weight or body weight gain. There was a siginifcant increase in food consumption for the 3000 mg/kg bw/day dose during gestation interval (day) 12 -16, but this was considered normal biological variation and not a direct effect of the substance. All indices were comparable to the corresponding controls. The NOAEL based on active ingredient of the test substance is 936 mg/kg bw/day.

A 2nd study was also performed to OECD Guideline 414 to assess the influence of Sodium Xylene Sulphonate on on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the New Zealand White Rabbit. Three groups of 22 females received Sodium Xylene Sulphonate at doses of 100, 300 or1000 mg/kg/day by oral gavage administration at a volume-dose of 5 mL/kg body weight from Day 6 to Day 28 after mating, inclusive. A similarly constituted Control group received the vehicle, purified water, at the same dose volume and for the same duration as those receiving the test item. Based o

n the results obtained in this study of embryo-fetal development, it was concluded that the

dose level of 1000 mg/kg/day represented the No Observed Adverse Effect Level (NOAEL) for maternal toxicity and for embryo-fetal survival, growth and development.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 2016 to March 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Specific details on test material used for the study:
The required amount of test item was weighed and approximately 50% of the final volume of vehicle added. This was magnetically stirred until uniformly mixed, and then made up to final volume with vehicle. The formulation was magnetically stirred until homogenous.

A series of formulations at the required concentrations were prepared by dilution of individual weighings of the test item.
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Number of animals: 96 females.

Duration of acclimatization: 19 days.

Age of the animals at the start of the study (Day 0 of gestation): Approximately 19 to 23 weeks old.

Weight range of the animals at the start of the study (Day 0 of gestation): 2.64 to 4.28 kg.
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical procedure was successfully validated with respect to specificity of chromatographic analysis, limits of detection and quantification, linearity of detector response, repeatability, method accuracy and precision.

The homogeneity and stability was confirmed for Sodium Xylene Sulphonate in Vehicle formulations at nominal concentrations of 1 mg/mL and 200 mg/mL during distribution between the bottles, during magnetic stirring for 4 hours, ambient temperature (+15 to +25°C) storage for 1 day and refrigerated storage (+2 to +8°C) for up to 15 days. Stability of discrete samples was confirmed for 15 days refrigerated storage

The mean concentrations of Sodium Xylene Sulphonate in test formulations analyzed for the study were within ±10% of nominal concentrations, confirming accurate formulation.
Details on mating procedure:
Male/female ratio: 1:1 using identified stock New Zealand White bucks.

Checks: Natural mating observed.

After mating: Each female was injected intravenously with 25 i.u. luteinizing hormone.

Day 0 of gestation: On the day of mating.

A colony of stud males was maintained specifically for the purpose of mating; these animals were not part of the study and were maintained as stock animals.
Duration of treatment / exposure:
Females were treated from Day 6 to Day 28 (inclusive) after mating
Frequency of treatment:
Once daily at approximately the same time each day
Duration of test:
28 days
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Three groups of 22 females received Sodium Xylene Sulphonate at doses of 100, 300 or 1000 mg/kg/day by oral gavage administration at a volume-dose of 5 mL/kg body weight from Day 6 to Day 28 after mating, inclusive.
Control animals:
yes, concurrent vehicle
Ovaries and uterine content:
For females surviving to term, the following was recorded:

Uterus: Gravid uterine weight (including cervix and ovaries).

The following were recorded for all animals including those prematurely sacrificed, where possible:

For each ovary/uterine horn: Number of: Corpora lutea, Implantation sites, Resorption sites (classified as early or late), Fetuses (live and dead).

Apparently non-pregnant animals and for apparently empty uterine horns: The absence or number of uterine implantation sites was confirmed.
Fetal examinations:
Examination of all viable fetuses and placentae: Dissected from the uterus, individually weighed and identified within the litter using a coding system based on
their position in the uterus. Examined externally with abnormalities recorded, sampled as appropriate and retained in appropriate fixative. All fetuses were subject to a gross internal examination of the viscera of the neck, thorax and abdominal cavities and the sex of each fetus was also recorded.

Fixation: Nominally one half of eviscerated fetuses were decapitated; heads were initially stored in Bouin’s fluid. Remaining eviscerated fetuses and torsos were fixed in Industrial Methylated Spirit.

Processing: Bouin’s fixed fetal heads were subject to free-hand serial sectioning. Industrial Methylated Spirit fixed fetuses and torsos were processed and stained with Alizarin Red.

Bouin’s fixed heads: Serial sections were examined for soft tissue abnormalities.

Alizarin Red stained fetuses and torsos: Assessed for skeletal development and abnormalities.
Statistics:
The following data types were analyzed at each timepoint separately:
Body weight, using gains over appropriate study periods
Gravid uterine weight and adjusted body weight
Food consumption, over appropriate study periods
Litter size and survival indices
Fetal, placental and litter weight

The following comparisons were performed:
Group 1 vs 2, 3 and 4

A sequence of statistical tests was used for body weight, gravid uterus weight, food consumption, corpora lutea, implantations, live young, fetal, placental and litter weight data.

For litter size and survival indices and fetal, placental and litter weight and gravid uterine weight data, if 75% of the data (across all groups) were the same value, for example c, Fisher’s exact tests (Fisher 1973) were performed. Treatment groups were compared using pairwise comparisons of each dose group against the control both for i) values c, as applicable.

Pre/post implantation loss and sex ratio were analyzed by generalized mixed linear model with binomial errors, a logit link function and litter as a random effect (Lipsitz 1991). Each treated group was compared to control using a Wald chi-square test. For pre implantation loss, the numerator was number of corpora lutea - number of implantations, the denominator was Number of corpora lutea. For post-implantation loss, the numerator was number of implantations - number of live fetuses, the denominator was number of implantations. For sex ratio, the numerator was number of males; the denominator was number of live fetuses.

For resorptions, each treated group was compared to control by exact Wilcoxon rank sum test (Wilcoxon 1945).

Significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level.
Clinical signs:
no effects observed
Description (incidence and severity):
Among females surviving to scheduled termination, there were no signs observed at routine physical examination or in relation to dose administration that were clearly attributable to Sodium Xylene Sulphonate administration.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
There were three premature deaths during the course of the study, none of which were considered to be related to Sodium Xylene Sulphonate administration.

On Day 14 of gestation, Female No. 69 receiving 1000 mg/kg/day was killed for reasons of animal welfare. This animal had shown noisy respiration (rales) since Day 12 of gestation and due to this sign was not able to be dosed on Day 12 or 13 of gestation; the animal was despatched to necropsy due to severe respiratory impairment. Other clinical signs observed between Day 12 and Day 14 of gestation included low hay and water intake, thin build, reduced faecal and urine output and small faecal pellets; no signs had been observed in relation to dose administration. Low food consumption was evident from Day 9 of gestation along with weight loss of 0.21 kg from Day 8 of gestation. Macroscopic examination revealed poorly defined dark areas on the lungs, aerated fluid adjacent to the salivary glands and the capsule above the salivary glands was slightly distended with air; there was no evidence of any trauma to the trachea or oesophagus (i.e. no evidence of mis-dosing). The
uterus contained ten grossly normal embryos.

On Day 19 of gestation, Female No. 54 receiving 300 mg/kg/day was found dead shortly after dose administration. This female had previously shown normal food consumption and body weight performance, no ante-mortem clinical signs had been observed during the study, post-dosing observations were limited to difficulty in achieving intubation of the catheter on Day 12 of gestation and signs at despatch to necropsy were limited to abnormally coloured coat staining on the muzzle. There were no significant abnormalities detected at macroscopic examination; the uterus contained six grossly normal embryos and one early resorption.

On Day 22 of gestation, Control Female No. 8 died shortly after dose administration having experienced a prolonged convulsion. On two occasions (Days 16 and 19 of gestation) difficulty in achieving intubation of the catheter had occurred, and the female had shown clinical signs of noisy/irregular respiration on Days 16-17 of gestation. Normal body weight performance and levels of food consumption had been observed throughout the study.

Macroscopic examination revealed a perforation in the lower section of the trachea, indicating that the female had been mis-dosed; the uterus contained three grossly normal fetuses.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The body weight performance of pregnant females surviving to scheduled termination was unaffected by Sodium Xylene Administration at doses up to and including 1000 mg/kg/day. The mean gravid uterine weight on Day 29 of gestation was similar in all groups. When overall mean body weight gain was adjusted for the contribution of the gravid uterus, net mean body weight loss was recorded in all groups of females and no effect of treatment with Sodium Xylene Sulphonate was inferred.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The body weight performance of pregnant females surviving to scheduled termination was unaffected by Sodium Xylene Administration at doses up to and including 1000 mg/kg/day.

The mean gravid uterine weight on Day 29 of gestation was similar in all groups. When overall mean body weight gain was adjusted for the contribution of the gravid uterus, net mean body weight loss was recorded in all groups of females and no effect of treatment with Sodium Xylene Sulphonate was inferred.
Food efficiency:
no effects observed
Description (incidence and severity):
Mean food consumption during Days 1-29 of gestation was similar in all groups and unaffected by the administration of Sodium Xylene Sulphonate.
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:
no effects observed
Description (incidence and severity):
There were no test item-related macroscopic abnormalities detected among the females at scheduled termination on Day 29 after mating.

The incidence of major and minor fetal abnormalities and skeletal variants showed no relationship to maternal treatment with Sodium Xylene Sulphonate.

Across the treated groups there was a slightly increased incidence of short supernumerary cervical rib and 7th costal cartilage not connected to sternum compared to concurrent control. There was, however, no dose response apparent and all fetal and litter incidences were within the Historical Control Data range, therefore these slight increases were considered were considered to be fortuitous and not adverse.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Litter Responses: At scheduled termination on Day 29 after mating, three Control females (No’s. 5, 12 and 15), three low dose group females (No’s. 32, 40 and 41), two intermediate dose group females (No’s. 45 and 46) and five high dose females (No’s 70, 71, 73, 75 and 82) were found not to be pregnant. Therefore, a total of 18, 19, 19 and 16 litters were available for assessment at 0, 100, 300 and 1000 mg/kg/day, respectively.

Placental, Litter and Fetal Weights: There was no effect of maternal treatment on mean placental, litter or fetal weights at any dose level investigated.
Number of abortions:
no effects observed
Description (incidence and severity):
There was no evidence that maternal treatment with Sodium Xylene Sulphonate at doses up to and including 1000 mg/kg/day had any adverse effect on litter data, as assessed by the mean numbers of implantations, resorptions, live young and pre- and post-implantation losses, at any of the doses investigated. Sex ratio, as assessed by the percentage of males per litter, was in line with expectations and unaffected by maternal treatment.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There was no evidence that maternal treatment with Sodium Xylene Sulphonate at doses up to and including 1000 mg/kg/day had any adverse effect on litter data, as assessed by the mean numbers of implantations, resorptions, live young and pre- and post-implantation losses, at any of the doses investigated. Sex ratio, as assessed by the percentage of males per litter, was in line with expectations and unaffected by maternal treatment.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
There was no evidence that maternal treatment with Sodium Xylene Sulphonate at doses up to and including 1000 mg/kg/day had any adverse effect on litter data, as assessed by the mean numbers of implantations, resorptions, live young and pre- and post-implantation losses, at any of the doses investigated. Sex ratio, as assessed by the percentage of males per litter, was in line with expectations and unaffected by maternal treatment.
Early or late resorptions:
no effects observed
Description (incidence and severity):
There was no evidence that maternal treatment with Sodium Xylene Sulphonate at doses up to and including 1000 mg/kg/day had any adverse effect on litter data, as assessed by the mean numbers of implantations, resorptions, live young and pre- and post-implantation losses, at any of the doses investigated. Sex ratio, as assessed by the percentage of males per litter, was in line with expectations and unaffected by maternal treatment.
Dead fetuses:
no effects observed
Description (incidence and severity):
There was no evidence that maternal treatment with Sodium Xylene Sulphonate at doses up to and including 1000 mg/kg/day had any adverse effect on litter data, as assessed by the mean numbers of implantations, resorptions, live young and pre- and post-implantation losses, at any of the doses investigated. Sex ratio, as assessed by the percentage of males per litter, was in line with expectations and unaffected by maternal treatment.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
There was no evidence that maternal treatment with Sodium Xylene Sulphonate at doses up to and including 1000 mg/kg/day had any adverse effect on litter data, as assessed by the mean numbers of implantations, resorptions, live young and pre- and post-implantation losses, at any of the doses investigated. Sex ratio, as assessed by the percentage of males per litter, was in line with expectations and unaffected by maternal treatment.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): There was no evidence that maternal treatment with Sodium Xylene Sulphonate at doses up to and including 1000 mg/kg/day had any adverse effect on litter data, as assessed by the mean numbers of implantations, resorptions, live young and pre- and post-implantation losses, at any of the doses investigated. Sex ratio, as assessed by the percentage of males per litter, was in line with expectations and unaffected by maternal treatment.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
There was no evidence that maternal treatment with Sodium Xylene Sulphonate at doses up to and including 1000 mg/kg/day had any adverse effect on litter data, as assessed by the mean numbers of implantations, resorptions, live young and pre- and post-implantation losses, at any of the doses investigated. Sex ratio, as assessed by the percentage of males per litter, was in line with expectations and unaffected by maternal treatment.
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
food efficiency
gross pathology
maternal abnormalities
number of abortions
pre and post implantation loss
total litter losses by resorption
effects on pregnancy duration
early or late resorptions
dead fetuses
changes in pregnancy duration
changes in number of pregnant
necropsy findings
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
There was no effect of maternal treatment on mean placental, litter or fetal weights at any dose level investigated.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): There was no effect of maternal treatment on mean placental, litter or fetal weights at any dose level investigated.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratio, as assessed by the percentage of males per litter, was in line with expectations and unaffected by maternal treatment.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There was no effect of maternal treatment on mean placental, litter or fetal weights at any dose level investigated.
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
The incidence of major and minor fetal abnormalities and skeletal variants showed no relationship to maternal treatment with Sodium Xylene Sulphonate.
Skeletal malformations:
no effects observed
Description (incidence and severity):
The incidence of major and minor fetal abnormalities and skeletal variants showed no relationship to maternal treatment with Sodium Xylene Sulphonate.
Visceral malformations:
no effects observed
Description (incidence and severity):
The incidence of major and minor fetal abnormalities and skeletal variants showed no relationship to maternal treatment with Sodium Xylene Sulphonate.
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Based on the results obtained in this study of embryo-fetal development, it was concluded that the dose level of 1000 mg/kg/day represented the No Observed Adverse Effect Level (NOAEL) for maternal toxicity and for embryo-fetal survival, growth and development.
Executive summary:

Based on the results obtained in this study of embryo-fetal development, it was concluded that the dose level of 1000 mg/kg/day represented the No Observed Adverse Effect Level (NOAEL) for maternal toxicity and for embryo-fetal survival, growth and development.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 7-24, 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Not a guideline study per se. GLP compliance. Full documentation
Justification for type of information:
Please see Category Approach
Qualifier:
no guideline followed
Principles of method if other than guideline:
Females were mated with males of the same strain and source. A block design was used to assign 30 mated females to controls and each of three dosing levels. Doses were selected based on a range finding study where the highest dose was 3000 mg/kg/day and no maternal or developmental toxicity was observed. The test material was prepared weekly. Analysis of dosing preparations stored for 10 days at room temperature verified the stability of the dosing preparation for at least a week. Dosing was done by intragastric intubation through needles at a volume of 10 ml/kg. Dosing was done on gestation days 6 through 15. A vehicle control was included in the study design. The concentration of the dosing preparation was confirmed analytically. 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 caesarean section. The uterus and ovaries 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. 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. Treatment and control groups were subjected to appropriate statistical comparison.
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
other: Charles River Crl:CD VAF/Plus
Details on test animals 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 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 71-71 degrees F- Humidity (%): 48-59%- Air changes (per hr): controlled- Photoperiod (hrs dark / hrs light): 12/12IN-LIFE DATES: From: February 7 To: February 24
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 temperatureVEHICLE- 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
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
Details on maternal toxic effects:
Maternal toxic effects:no effectsDetails 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.
Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: other:
Key result
Dose descriptor:
NOAEL
Effect level:
> 936 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: other:
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effectsDetails on embryotoxic / teratogenic effects:No indications of developmental toxicity including teratogenesis. All indices were comaparable to the corresponding controls.
Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
not specified
Developmental effects observed:
not specified
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.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
936 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available developmental study was fully documented and conducted in accordance with GLP. A study in a second species (New Zealand white rabbit) confirms this result with a NOEL of 1000 mg/kg bw/day
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

On the basis of the available toxicity data there is no justification to classify for reproductive or developmental toxicity.