Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study. According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
MPI Research 54943 North Main Street Mattawan, Ml 49071-9399 U.S.A.
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): C.I. Fluorescent Brightener 220
- Physical state: pale yellow powder
- Analytical purity: no data
- Lot/batch No.: DSR97 10004.006
- Expiration: October 2, 1999
- Storage conditions: room temperature; protected from light; dessicant added to storage container on July 30, 1999

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan
- Age at study initiation: 8 weeks
- Weight at study initiation: 170 to 223 g
- Fasting period before study: none
- Housing: individually in suspended, stainless steel, wire-mesh cages
- Diet: certified Rodent Chow #5002, PMI Feeds, Inc., St. Louis, Missouri; ad libitum
- Water: tap water; ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 22.2°C
- Humidity (%): 48 - 71
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
The test article was added to the vehicle to achieve the required concentrations, and mixed using a magnetic stir bar. The prepared test article solutions were transferred to amber glass containers by syringe and stored under refrigerated conditions.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test article was characterized using a combination of HPLC and 1H and 13C NMR
Details on mating procedure:
- Impregnation procedure: Females were time mated upon delivery, and the day on which evidence of copulation was observed was designated gestational day 0
- Proof of pregnancy: no data
Duration of treatment / exposure:
gestational day 6 to 19
Frequency of treatment:
once daily
Duration of test:
day 6 of gestation until day 20 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 400 and 1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
30 females/group
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice per day during the study period

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily from gestational day 6 - 20

BODY WEIGHT: Yes
- Time schedule for examinations: body weights recorded on gestational days 0, 6, 9, 12, 15, 18, and 20. Body weight change was recorded for gestational days 0 to 6, 6 - 9, 9 - 12, 12 - 15, 15 - 18, 18 - 20, 6 - 20, and 0 - 20.

FOOD CONSUMPTION: Yes
- Food consumption reported as g food consumed/animal/day for gestational days 0 - 6, 6 - 9, 9 - 12, 12 - 15, 15 - 18, 18 - 20, 6 - 20, and 0 - 20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus, any other organ showing gross lesions
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Position of cervix, gross examination of placentae, location of viable and non-viable fetuses, and location of early and late resorptions
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: No
Statistics:
Differences between groups were assessed using Levene’s test, Dunnett’s test, Welch’s test with a Bonferroni correction, Fischer’s exact test with a Bonferroni correction, Chi-square test, Kruskal-Wallis test, Mann-Whitney U-test, and Pearson Chi-square test.
Historical control data:
yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: not of biological relevance or treatment-related

Details on maternal toxic effects:
Discoloured faeces was observed in 77 and 100% of the animals in the 400 and 1000 mg/kg groups, respectively. This finding was considered to be of no toxicological importance.
One dam in the 1000 mg/kg group had a liver adhesion and a nodule on the right kidney, and 1 dam in the 100 mg/kg group had granular material on the surface of the right kidney. These findings were considered to be spontaneous and not treatment-related.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: not of biological relevance or treatment-related

Details on embryotoxic / teratogenic effects:
One fetus in the 1000 mg/kg group had omphalocele, and another fetus in the 1000 mg/kg group (from a different litter) had an absent tail and anal atresia. These findings were considered to be spontaneous and not treatment-related.
Vertebral malformation was observed in 7.1% of fetuses in the 1000 mg/kg group, compared to 0% in the control group. Slight increases in the incidence of rudimentary ribs and misaligned sternebra were noted in the 100 and 1000 mg/kg groups compared to the control. The incidence of misaligned sternebra and vertebral malformations were within historical control ranges, and were therefore not considered biologically relevant or treatment-related. Although the incidence of rudimentary ribs was slightly above the historical control range, a dose-related pattern was not observed, and there was no significant difference in incidence compared to the control group. Thus, the incidence of rudimentary ribs was not considered to be biologically relevant or treatment-related.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
As no adverse maternal or fetal effects were observed following the administration of 100, 400, or 1000 mg/kg/day to rats between gestational days 6 and 19, the results of this study indicate that test substance is not teratogenic to rats.