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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see RAC/35/2015/09
Justification for type of information:
Study identified as most relevant study and representative for Cr(VI) compounds in RAC/35/2015/09

Data source

Reference
Reference Type:
publication
Title:
Teratogenicity of hexavalent chromium in rats and the beneficial role of ginseng
Author:
Elsaieed, EM; Nada, SA.
Year:
2002
Bibliographic source:
Bull Environ Contam Toxicol 68(3):361-368

Materials and methods

Principles of method if other than guideline:
Effects of gestational exposure to Cr(VI) were investigated in Wistar rats (Elsaieed and Nada, 2002). Groups of 10 pregnant rats (mean initial body weight of 170 g) were administered drinking water containing 0 or 50 mg Cr(VI)/L as potassium dichromate on days 6 to 15 of gestation. During the exposure period, dams were evaluated for clinical signs of toxicity, body weights, and food and drinking water consumption. One day before delivery, rats were sacrificed and the following were evaluated: numbers of corpora lutea, pre- and post- implantation losses, resorptions, and live and dead fetuses; fetal weight; and visceral and skeletal anomalies.

GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Potassium dichromate.

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: drinking water
Duration of treatment / exposure:
days 6 to 15 of gestation
Frequency of treatment:
contineous
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/L drinking water
Remarks:
Cr(VI) (as potassium dichromate)
Dose / conc.:
50 mg/L drinking water
Remarks:
Cr(VI) (as potassium dichromate), corresponding to about 7.9 mg Cr(VI)/kg bw/d
No. of animals per sex per dose:
10 pregnant rats/dose

Examinations

Maternal examinations:
clinical signs of toxicity, body weights, and food and drinking water consumption
Ovaries and uterine content:
numbers of corpora lutea, pre- and post- implantation losses, resorptions
Fetal examinations:
live and dead fetuses; fetal weight; and visceral and skeletal anomalies.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Gestational weight gain was significantly (40%) less in treated dams, compared with controls (p < 0.05).
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
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:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
significant (p < 0.05) increases in post- implantation loss/litter (1.5 vs. 0)
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
significant (p < 0.05) increases in resorptions/litter (1.2 vs. 0),
Early or late resorptions:
not specified
Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
significant (p < 0.05) increases in dead foetuses/litter (1.2 vs. 0)
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified

Effect levels (maternal animals)

Dose descriptor:
LOAEL
Effect level:
7.9 mg/kg bw/day
Based on:
other: Cr(VI)
Basis for effect level:
body weight and weight gain
pre and post implantation loss
total litter losses by resorption
dead fetuses

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
decrease in foetal weight (33% decrease)
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): decrease in foetal weight (33% decrease)
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
decrease in live foetuses/litter (1.5 vs. 6.8 in control)
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
not specified
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
increased litters with skeletal anomalies (incomplete skull ossification: 1.0/litter)
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
increased litters with visceral anomalies(renal pelvis dilation: 2.1/litter)
Other effects:
not specified

Effect levels (fetuses)

Dose descriptor:
LOAEL
Effect level:
7.9 mg/kg bw/day
Based on:
other: Cr(VI)
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
skeletal malformations
visceral malformations

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
7.9 other: mg Cr(VI)/mg bw/day
Treatment related:
yes
Relation to maternal toxicity:
not specified
Dose response relationship:
yes
Relevant for humans:
yes

Applicant's summary and conclusion

Conclusions:
In this study, treatment of rats with Cr(VI) resulted in significant (p < 0.05) increases in post- implantation loss/litter (1.5 vs. 0), resorptions/litter (1.2 vs. 0), and dead foetuses/litter (1.2 vs. 0) and decreases in live foetuses/litter (1.5 vs. 6.8 in control) and foetal weight (33% decrease). In the exposed group, increased litters with foetal anomalies were observed including visceral (renal pelvis dilation: 2.1/litter) and skeletal (incomplete skull ossification: 1.0/litter) changes; no control foetuses showed these changes.
Executive summary:

In this study, treatment of rats with Cr(VI) resulted in significant (p< 0.05) increases in post- implantation loss/litter (1.5 vs. 0), resorptions/litter (1.2 vs. 0), and dead foetuses/litter (1.2 vs. 0) and decreases in live foetuses/litter (1.5 vs. 6.8 in control) and foetal weight (33% decrease). In the exposed group, increased litters with foetal anomalies were observed including visceral (renal pelvis dilation: 2.1/litter) and skeletal (incomplete skull ossification: 1.0/litter) changes; no control foetuses showed these changes.

The results of this study showed that exposure of pregnant Wistar rats to drinking water containing 50 mg Cr(VI)/L as potassium dichromate (approximately 7.9 mg Cr(VI)/kg bw/d) on days 6–15 of gestation produced adverse effects on reproductive outcome and foetal development. Thus a LOAEL of 7.9 mg Cr(VI)/kg bw/d was identified from this study.