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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Already evaluated by the Competent Authorities for Biocides and Existing Substance Regulations.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Principles of method if other than guideline:
No guideline followed; Pilot study to provide preliminary information on the potential maternal and developmental toxicity of copper hydroxide.

GLP compliance:
yes
Remarks:
Self-certified laboratory
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test material: Copper hydroxide
Lot/Batch number: 021121/1
Purity: 61.14 % copper
Description: Free flowing blue product, needles.
Stability: No evidence of instability was observed.

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Source: Covance, Denver, Pennsylvania, USA.
Sex: Female (pregnant)
Age at study initiation: 5 to 6.5 months old.
Weight at study initiation: 2885 to 4330 g (day of gestation).

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5 % aqueous methylcellulose
Details on exposure:
Concentration in vehicle: 0, 7.5, 15, 30 mg/mL.
Total volume applied: 1 mL/kg bw.
Details on mating procedure:
Mating period: Not stated in the report.
Duration of treatment / exposure:
Duration of exposure: Day 7 to 28 of gestation.
No. of animals per sex per dose:
Number of animals per group: 5 females (control group); 8 females (7.5 and 30 mg/kg bw); 9 females (15 mg/kg bw).
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
Body weight: Yes (daily)
Food consumption: Yes (daily)
Clinical signs: Yes (daily)
Gross pathology and histopathology: Yes, gross external and visceral examination was performed for all animals.
Postexposure period: Animals were sacrificed on day 29 of gestation.
Ovaries and uterine content:
Examination of uterine content: gravid uterine weight, number of corpora lutea, number of implantations.
Fetal examinations:
General: Number of live and dead foetuses, number of resorptions foetal weight, sex ratio, external alterations.
Skelet: No
Soft tissue: No

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Low incidences of diarrhoea were observed at all dose levels and were considered to be treatment-related. Treatment-related mortality was observed at a dose of 30 mg Cu/kg bw/day. One rabbit was sacrificed in extremis on day 9 of gestation and another rabbit was found dead on day 26 of gestation. Gross necropsy revealed stomach haemorrhages or a small liver that was moderately autolysed. Histopathology of selected tissues of the rabbit sacrificed non-scheduled indicated that the cause of death was related to a haemolytic event that resulted in haemoglobin nephropathy and probably renal failure.

Clearly compound-related reductions of maternal body weight, weight change and food consumption were observed at 15 and 30 mg Cu/kg bw/day. Generally these findings occurred during the first week of dosing and animals recovered thereafter. No treatment-related effects on maternal body weight or food consumption were observed at 7.5 mg Cu/kg bw/day.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
7.5 mg/kg bw/day
Based on:
element
Basis for effect level:
other: Maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
There was evidence of compound-related developmental toxicity at 30 mg Cu/kg bw/day. Mean foetal weights were reduced by 12 % relative to the control group. Foetal resorptions appeared slightly increased at this level and 4 foetuses (2 each from 2 litters) were observed with omphalocele (protrusion of intestines at the umbilicus). No evidence of developmental toxicity was observed at the other dose levels. One foetus of the 7.5 mg Cu/kg bw/day group had anasarca, domed head and a short tail. This finding was considered to be incidental since only one foetus showed these changes and no dose-response was observed. All other reproductive outcome and foetal data were comparable to the control group for all dose levels tested.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day
Based on:
element
Basis for effect level:
other: Developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Refer to Executive summary.
Executive summary:

Materials and Methods

Pregnant rabbits received 0, 7.5, 15 or 30 mg Cu/kg bw/day as copper hydroxide by gavage during day 7 to 28 of gestation. The animals were sacrificed on day 29 of gestation and the uterine contents were examined and described. The study was designed as a pilot study to assess the potential maternal and developmental toxicity of copper hydroxide.

Results and Discussion

Under the conditions of this study, no treatment-related maternal toxicity was observed at 7.5 mg Cu/kg bw/day and no treatment-related developmental toxicity occurred at 7.5 and 15 mg Cu/kg bw/day. Observed effects at the 30 mg/kg/day dose level included maternal mortality, and gastric ulcer, haemolytic anaemia and renal damage upon necropsy. Reduced mean foetal weights, slightly increased resorptions and increased malformations were observed at this dose level. In addition, reductions of maternal food consumption and body weights were noted at 15 and 30 mg Cu/kg bw/day.