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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16 July 2012 to 27 September 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to an internationally recognized protocol and all relevant GLP requirements were fulfilled.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
The study integrity was not adversely affected by the deviations.
Qualifier:
equivalent or similar to
Guideline:
other: US EPA OPPTS 870.3650, July 2000
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
other: white powder
Details on test material:
- Name of test material (as cited in study report): 5-(Sodiosulfo)isophthalic Acid
- Physical state: white powder
- Analytical purity: 99.4%
- Lot/batch No.: 6F21174000
- Expiration date of the lot/batch: 2 December 2013
- Stability under test conditions: stable
- Storage condition of test material: at room temperature in the dark
- Other: hygroscopic, store in a well-sealed container

Test animals

Species:
rat
Strain:
other: CrI:WI(Han) (outbred, SPF-Quality)
Sex:
male/female
Details on test animals and environmental conditions:
Refer to Section 7.5.1

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Refer to Section 7.5.1
Details on mating procedure:
Females were caged together with males on a one-to-one-basis in Macrolon plastic cages (MIII type, height 18 cm).

Post-mating Males were housed in their home cage (Macrolon plastic cages, MIV type, height 18 cm) with a maximum of 5 animals/cage. Females were individually housed in Macrolon plastic cages (MIII type, height 18 cm).

Following a minimum of 14 days of exposure for the males and females, one female was cohabitated with one male of the same treatment group, avoiding sibling mating. Detection of mating was confirmed by evidence of sperm in the vaginal lavage or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 post-coitum. Once mating occurred, the males and females were separated. A maximum of 14 days was allowed for mating, after which females who had not shown evidence of mating were separated from their males. Detection of mating was not confirmed for animal nos. 43 (Group 1), 58 (Group 2) and 62 (Group 3) which did deliver live offspring. The mating date of these animals were estimated at 21 days prior to the actual delivery dates. These days were designated Day 0 post-coitum.

The females were allowed to litter normally. Day 1 of lactation was defined as the day when a litter was found completed (i.e. membranes and placentas cleaned up, nest build up and/or feeding of pups started). Females that were littering were left undisturbed.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Refer to Section 7.5.1
Duration of treatment / exposure:
After acclimatization, four groups of ten male and ten female Wistar Han rats were exposed by oral gavage to the test substance at 0, 100, 300 and 1000 mg/kg/day. Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were exposed for 43 - 53 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation.
Frequency of treatment:
Refer to Section 7.5.1
Details on study schedule:
Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy. Females were exposed for 43-53 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation (up to the day prior to scheduled necropsy). Female nos. 41, 43 (Group 1), 62 , 70 (Group 3) and 77 (group 4) were not dosed during littering.

Doses / concentrations
Remarks:
Doses / Concentrations:
0 (vehicle only), 100, 300 and 1000 mg/kg/d
Basis:
nominal in water
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
PREPARATION OF DOSING SOLUTIONS:

Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. No adjustment was made for specific gravity/density of the test substance, vehicle, and/or formulation. No correction was made for the purity/composition of the test substance.

Doses were administered by plastic feeding tube.

Dose volume: 5 mL/kg
Positive control:
None

Examinations

Parental animals: Observations and examinations:
Male number paired with, mating date, confirmation of pregnancy, and delivery day were recorded. Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of pregnant females was examined to detect signs of abortion or premature birth. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined.
Oestrous cyclicity (parental animals):
Not determined
Sperm parameters (parental animals):
Parameters examined in selected 5 male parental animals:

testis weight, epididymis weight, prostate weight (after at least 24 h fixation), and weight of seminal vesicles including the coagulating glands

Refer to Section 7.5.1 for all histopathological analyses conducted in this study.
Litter observations:
Each litter was examined for the following if practicle and possible:

Mortality / Viability
The numbers of live and dead pups on Day 1 of lactation and daily thereafter were determined. If possible, defects or cause of death were evaluated.

Clinical signs

At least once daily, detailed clinical observations were made for all animals.

Body weights
Live pups were weighed on Days 1 and 4 of lactation.

Sex
Sex was determined for all pups on Days 1 and 4 of lactation.
Postmortem examinations (parental animals):
Refer to Section 7.5.1 of this IUCLID file
Postmortem examinations (offspring):
Necropsy

Pups surviving to planned termination were killed by decapitation on Days 5-7 of lactation. All pups were sexed and descriptions of all external abnormalities were recorded. The stomach was examined for the presence of milk. If possible, defects or cause of death were evaluated.
Statistics:
Refer to Section 7.5.1 of this IUCLID file
Reproductive indices:
Mating index (%): No. females mated / No. females paired x 100
Fertility index (%): No. pregnant females / No. of females placed x 100
Conception index (%): No. pregnant females / No. females mated x 100
Gestation index (%): No. females bearing live pups / No. pregnant females x 100
Duration ofgestation: No. days between confirmation of mating and the beginning of parturition.
Offspring viability indices:
Percentage live males at first litter check.
Percentage live females at first litter check.
Percentage of postnatal loss.
Viability index (%): No. live pups before necropsy / No. of pups born alive x 100

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
Refer to Section 7.5.1 of this IUCLID file
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Refer to Section 7.5.1 of this IUCLID file
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Refer to Section 7.5.1 of this IUCLID file
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Refer to Section 7.5.1 of this IUCLID file
Other effects:
not examined

Reproductive function / performance (P0)

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

Details on results (P0)

Refer to Section 7.5.1 of this IUCLID file for a more complete description of results.

Reproductive results:

No reproduction toxicity was observed up to the highest dose level tested (1000 mg/kg). No treatment-related toxicologically relevant changes were noted in any of the reproductive parameters investigated in this study (i.e. mating, fertility and conception indices, precoital time, and numbers of corpora lutea and implantation sites).

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on a lack of significant reproductive effects measured in the study.

Results: F1 generation

General toxicity (F1)

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:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

At 1000 mg/kg, sex ratio of the pups indicated more female than male pups (62% female pups compared to 47% of the control group); this was statistically significantly different from controls.

No treatment-related changes were noted in any of the remaining developmental parameters investigated in this study (i.e. gestation index and duration, parturition, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight and macroscopy).

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Reproduction data summary

   Control  100 mg/kg  300 mg/kg  1000 mg/kg
 Females paired  10  10  10  10
 Females mated  10  9  10  9
 Females non-mated  0  1  0  1
 Pregnant females  9  9  10  9
 Non-pregnant females  1  0  0  0
 Females with living pups on Day 1  9  9  10  9
 Mating index (%)  100.0  90.0  100.0  90.0
 Fertility index (%)  90.0  90.0   100.0  90.0
 Conception index (%)  90.0  100.0   100.0  100.0
Gestation index (%)   100.0  100.0   100.0  100.0

Applicant's summary and conclusion

Conclusions:
No significant reproductive toxicity was noted up to a dose of 1000 mg/kg/d. The NOAEL for reproductive toxicity is 1000 mg/kg.
Executive summary:

No reproduction toxicity was observed up to the highest dose level tested (1000 mg/kg). No treatment-related toxicologically relevant changes were noted in any of the reproductive parameters investigated in this study (i.e. mating, fertility and conception indices, precoital time, and numbers of corpora lutea and implantation sites).