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Diss Factsheets

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:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
yes

Test material

Constituent 1
impurity 1
Test material form:
solid
Remarks:
soft waxy solid or gel
Details on test material:
Melting point of 82 deg C; also reported as 75-77 deg C. Crystallizes from alcohol (ethanol). UV absorption maximum at 295 nm. Additional impurity reports: polyvinyl stearate, up to 2.0% (CASRN not reported, but may be 9003-95-6).
Specific details on test material used for the study:
The test substance in the study was one of two formulations (off white solid) in which 12-HSA comprised 7%. Data supplied to the U.S. CIR from two chemical suppliers stated that the purity of 12-HSA is typically 84.0-84.9%, with impurities of stearic acid (8.3-9.5%), palmitic acid (0.9-1.0%), triglyceride (castor oil, 5.0%) and polyvinyl stearate of < 1.0-2%.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
Animals: mated Charles River Crl:CD VAF/Plus female rats, 12.5 weeks of age, weight 211 to 289 g.

Administration / exposure

Route of administration:
dermal
Details on exposure:
The test substance was applied (with gloved finger) to dorsal skin (clipped free of hair) of each animal, on gestation days 6-15, once daily, and left on for 6 hours each day. The test sites were covered (but not occluded) to prevent ingestion during the study. The control article (described as a clear liquid; no details on its composition were provided) was similarly applied to an additional group rats of the same strain.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
received pre-mated
Duration of treatment / exposure:
Days 6-15
Frequency of treatment:
once daily, 6 hours per day
Duration of test:
20 days of gestation
Doses / concentrations
Dose / conc.:
7 other: %
Remarks:
in formulation
No. of animals per sex per dose:
30 per formulation in 2 formulation groups
Control animals:
yes

Examinations

Maternal examinations:
clinical signs, condition of skin (especially of exposed area), body weight, gross pathology, reproductive parameters (number of implantations, post-implantation loss, number of corpora lutea, number of resorptions)
Fetal examinations:
fetal sex ratio, fetal body weight, uterine weight, number of viable fetuses, number of malformations (skeletal and soft tissue), fetal variations.
Statistics:
yes, significance level p < 0.05.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Both experimental groups displayed increases in the severity of erythema and desquamation at the application sites, compared to controls. Desquamation was observed in 20 of 30 control rats, along with very slight erythema (1 control animal had weel-defined erythema).
Mortality:
no mortality observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
There were no significant differences between experimental and control groups in clinical or necropsy observations. There were no differences between experimental and controls groups in reproductive parameters. In both experimental and control groups, the dermal erythema and desquamation at the application site increased through the 5th and 6th days, then diminished. There was no edema noted in any group. In the control group, 10 rats had very slight erythema and one had well-defined erythema; 20 of 30 had desquamation. In one experimental group, 10 rats had very slight erythema, 10 rats had well defined erytherma, and one rat had moderate to severe erythema; desquamation occurred in 26 rats. In the other experimental group, 16 rats had very slight erythema, 6 had well-defined erythema, and 3 had moderate to severe erythema. Desquamation in this group occurred in 28 of 30 animals.
Details on maternal toxic effects:
There were no significant differences between experimental and control groups with respect to implantations, postimplantation losses, corpora lutea, fetal sex ratio, mean fetal body weight or uterine weight. The incidence of postimplantation losses/resorptions was 14 of 325 viabile fetuses in the first experimental group and 20 of 316 viable fetuses in the second experimental group.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
> 7 other: % in formulation
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Key result
Abnormalities:
effects observed, treatment-related

Results (fetuses)

Details on embryotoxic / teratogenic effects:
There were no test article-related or statistically significant differences between experimental and control groups. The total number of litters with any malformation was comparable between experimental and control groups. In the first experimental group, the incidence of malformations was 2 of 325 viable fetuses, and in the second group, was 1 of 316 viable fetuses. Fetal variations occurred in 88 of 325 viable fetuses, in Group 1, and in 80 of 316 viable fetuses in Group 2. There were no increases in fetal malformations or variations in the experimental versus control groups.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 7 other: %
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
A dermal reproductive toxicity/teratology study (OECD 414) in rats was undertaken on two formulations which included 12-hydroxystearic acid at 7.0%.applied for 6 hours per day, non-occlusive, during organogenesis (days 6-15). There were no increases in deaths, clinical signs, gross pathology or female reproductive parameters, compared to controls. There were no increases in fetal death, malformations or variations over control values. There were increases in erythema but not edema of the skin in experimental groups compared with controls. The dermal NOAEL for systemic maternal toxicity and fetal effects is > 7.0%.