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Toxicological information

Toxicity to reproduction

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
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%)],

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
SPF Crl:CD
Sex:
male/female

Administration / exposure

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.
Doses / concentrationsopen allclose all
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.

Examinations

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 (%)

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

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 / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Effect levels (P0)

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

Results: P1 (second parental generation)

General toxicity (P1)

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 / performance (P1)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
not examined

Results: F1 generation

General toxicity (F1)

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

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified

Results: F2 generation

General toxicity (F2)

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

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Applicant's summary and conclusion

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.