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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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
other: summary of toxicity studies
Title:
Unnamed
Year:
2007
Report Date:
2007
Reference Type:
publication
Title:
Unnamed
Year:
2007
Report Date:
2007
Reference Type:
secondary source
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD 422
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Analytical verification of doses or concentrations:
not specified
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 12, 60, 300 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes


FOOD CONSUMPTION AND COMPOUND INTAKE : Yes

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice: no; animals were allowed to litter
- Organs examined: cf. section 7.5.1
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes; all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: at 60 and 300 mg/kg bw/day

Details on maternal toxic effects:
4 of 12 animals dead or moribund. Fatty changes in liver (4/8) and kidneys (2/8). Thymus atrophy (3/12)

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
12 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Nidation significantly reduced at 60 and at 300 mg/kg bw/day, i.e. implanation index and number of pups both low.
No external chaberrations noted at any dose

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
12 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
12 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
At 60 mg/kg/day significantly reduced number of implantations in the presence of moderatematernal toxicity
Executive summary:

3, ,5 ,5 -trimethylhexan-1-ol was tested in a combined repeated toxicity/reproduction toxicity screening test according to OECD TG 422 under GLP conditions in rats at 0, 12, 60, and 300 mg/kg bw/day (gavage). The repeated dose NOAEL was12 mg/kg bw/day in male and female parental animals (findings of this study are summarized in Chapter 7.5.1).

As to developmental toxicity, the following deviations from normal were seen: The number of implantations was significantly decreased at 60 and 300 mg/kg bw; therefore, the implantation index was significantly reduced (p<0.05) at these dose levels. Maternal toxicity was also seen at 60 and 300 mg/kg bw (moderat eat 60 mg/Kg bw/day, 33% mortality at the high dose; cf. summary of the same study in section 7.5.1). Thus, compared to controls, low values for the number of nidations, nidation index, number of births and the number of live births were seen at 60 mg/kg bw/day and in the 300 mg/kg/day group; a level of significance up to p<0.01 was gained for some of the parameters. Male and female pup weight at birth was slightly reduced at 60 mg/kg bw/day, and statistically significantly reduced at 300 mg/kg bw/day (p<0.5 (males), p<0.01 (females)). Male and female body weights increased and were comparable with that of the controls on day 4 past parturition. The viability index, i.e. survival of pups from birth until day 4 after birth, was significantly reduced in the group at 300 mg/kg bw/day (p<0.01). The authors related this to maternal toxicity during fetal development and during lactation. No external aberrations were confirmed in any of the cases in necropsies of deaths and newborn pups sacrificed on day 4 of nursing. The NOAEL value was 12 mg/kg bw/day for maternal, fetal and embryo toxicity, and 300 mg(kg bw/day for teratogenicity (screen level examinations) in this study. Overall, toxicity to reproduction was seen at maternal toxic dose levels. (Yoshimura, 1997).

The study is considered to be suitable for assessment. It should, however, be noted that compared to the more specific guideline studies for this endpoint (e.g. OECD 414) the list of parameters to be examined is reduced. Further, the animal number is relatively low in screening studies and the statistical power is therefore reduced compared to an endpoint-specific OECD guideline study. The reduced implantation index seen at the 60 mg/kg dose level may therefore have failed to gain a level of statistical significance, making it difficult to assign correctly NOAEL-values.