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Key value for chemical safety assessment

Effects on fertility

Additional information
Short description of key information:
Since there is no study on the effects of fertility of SDIBP, a read-across from the members of hydrotopes studies was considered. There is no fertility study in hydrotopes; however, the 90-day oral rat study and the 2-year chronic dermal rat study with sodium xylene sulphonate (CAS No. 1300-72-7) included examination of sex organs of both sexes. No treatment related effects on reproductive organs were reported at doses roughly equivalent to those in the developmental toxicity study for a closely related substance.

Effects on developmental toxicity

Description of key information
Since there is no study on the developmental toxicity of SDIBP, a read-across from a hydrotope study was considered. A single developmental toxicity study is reported for calcium xylene sulphonate (CAS No. 28088-63-3) which is closely related to the other compounds in the hydrotropes category. The 1994 developmental study did not follow a specific guideline but was fully documented and conducted in accordance with GLP requirements.  No adverse effects were reported. The NOAEL for both maternal and fetal toxicity was the highest dose tested 3000 mg/kg bw /day, which is equivalent to 936 mg active ingredient/kg bw/day. The conclusion of the study was no indications of developmental toxicity including teratogenesis.  
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
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
Reference:
Composition 0
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 m?/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 cesarean section. 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. 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
Test material information:
Composition 1
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 days


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


IN-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 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 / Concentrations:
150, 1500 and 3000 mg/kg/day
Basis:
analytical conc.
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 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
Basis for effect level:
other: other:
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.
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 which is equivalent to 936 mg active ingredient/kg bw/day.
Executive summary:

In the developmental toxicity study, thirty (30) female rats received 0, 150, 1500 or 3000 mg test substance per kilogram body weight 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 fetuses and resorptions. Fetuses 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/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 significant increase in food consumption for the 3000 mg/kg/day dose during gestation interval (day) 12-16 but this was considered normal biological variation and not a direct effect of the test 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.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
936 mg/kg bw/day
Additional information

Since there is no study on the developmental toxicity of SDIBP, a read-across from a hydrotope study was considered. In accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5., the member of hydrotropes, i.e. calcium xylene sulphonate (CAS No. 28088 -63 -3) to the SDIBP (CAS No. 28348 -54 -1) were assessed. In the developmental toxicity study, thirty (30) female rats received 0, 150, 1500 or 3000 mg test substance per kilogram body weight per day by oral gavage on days 6 to 15 of gestation (Ruetgers-Nease, 1994). 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 fetuses and resorptions. Fetuses 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/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 significant increase in food consumption for the 3000 mg/kg/day dose during gestation interval (day) 12-16 but this was considered normal biological variation and not a direct effect of the test 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.

Category Justification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances.

Applying the category approach read-across concept to SDIBP, data will be used from a representative member of the hydrotropes category to avoid unnecessary (animal) testing. The endpoints for which the read-across approach to SDIBP is applied, are: toxicokinetics, short-term toxicity to fish, toxicity to microorganism, acute toxicity (inhalation and dermal), skin irritation/corrosivity, skin sensitisation, genetic toxicity (in vitro, in vivo), repeated-dose toxicity (oral and dermal), screening for carcinogenicity, and screening for reproductive / developmental toxicity.

Hazard assessment related key information for SDIBP:

SDIPB and the hydrotrope members exhibit similar levels of low toxicity. Acute toxicity values are above the classification limits, they are not sensitizing and show no genotoxic effects. Both exhibit neglible irritation to the skin, but are moderately irritating to the eyes (Cat 2B). Together with the chemical structure similarity and their similar chemical properties, it is deemed correct to fill the existing data gaps on mammalian toxicity of SDIPB with the data of the hydrotrope category.

Justification for classification or non-classification

No classification for reproductive toxicity is needed according to the general classification and labeling requirements for dangerous substances and preparations (Directive 67-548-EEC) or the classification, labeling and packaging (CLP) regulation (EC) No 1272/2008.