Reaction mass of 4-hydroxybenzene-1,3-disulphonic acid and 4-hydroxybenzenesulphonic acid and sulphuric acid and water

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Data waiving:

other justification

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available (further information necessary)

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No fertility studies are reported for the aromatic sulphonic acids. These substances are very corrosive as was demonstrated in skin and eye irritation studies, in the acute oral studies, and in the single repeated dose oral study. For animal welfare, long-term exposures to corrosive substances are not recommended. There are however studies for the chemically related hydrotrope substances that looked at reproductive organs and development of offspring. Hydrotropes are the salt form of the sulphonic acids and therefore are used as read-across for this endpoint. The 90-day oral rat and oral mouse studies and the 2-year chronic dermal rat and mouse studies with the closely related compound sodium xylene sulfonate (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. The 1994 study with calcium xylene sulphonate (CAS No. 28088-63-3) 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 foetal toxicity was the highest dose tested - 3000 mg/kg bw /day which is equivalent to 936 mg active ingredient per kilogram body weight per day. The conclusion of the study was no indications of developmental toxicity including teratogenesis.

Short description of key information:
No effect

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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

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. QA statement)

Limit test:

no

Species:

rat

Strain:

other: Charles River Crl:CD VAF/Plus

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


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.

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

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

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 comaparable to the corresponding controls. The NOAEL based on active ingredient of the test substance is 936 mg/kg bw/day.

Justification for classification or non-classification

No classification as a repeated dose toxin is indicated 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.