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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: 90-day oral gavage sub-chronic study
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
6 January 2006 to 18 September 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to generally valid and/or internationally accepted testing guidelines.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents) (Adopted 21 September 1998)
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Dimyrcetol
- Physical state: clear, colorless liquid
- Analytical purity: 99% (Certificate of Purity)
- Impurities: None identified
- Purity test date: 15 December 2005
- Lot/batch No.: SM/4103311 and SM/5073201
- Expiration date of the lot/batch: December 2006
- Stability under test conditions: Solutions in corn oil determined to be stable for at least 14 days
- Storage condition of test material: room temperature in the dark until 6 January 2006, thereafter approximately 4 deg C in the dark
- Other: The integrity of the supplied data relating to the identity, purity and stability of the test material was the responsibility of the Sponsor.

Statement from the Test Article Supplier (International Flavors and Fragrances, Lot SM 410331)
Dimyrcetol is a fragrance ingredient manufactured by IFF. It is not a single component but a mixture of two chemical entities, 2,6-dimethyl-7-octen-2-ol formate and 2,6-dimethyl-7-octen-2-ol. The percentage of each component from the certificate of analysis dated December 15, 2005, is 54.8% and 44.2%, respectively. These two components derive from the chemistry used to manufacture dimyrcetol. It is an equilibrium mixture of tertiary formate and tertiary alcohol.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Refer to study summary in Section 7.5.1 of this file.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Refer to study summary in Section 7.5.1 of this file.
Details on mating procedure:
Not applicable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Refer to study summary in Section 7.5.1 of this file.
Duration of treatment / exposure:
Ninety consecutive days
Frequency of treatment:
once daily
Details on study schedule:
Refer to study summary in Section 7.5.1 of this file.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 500 and 1000 mg/kg bwt/day
Basis:
other: nominal in corn oil
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Refer to study summary in Section 7.5.1.

Examinations

Parental animals: Observations and examinations:
Refer to study summary in Section 7.5.1.
Oestrous cyclicity (parental animals):
Estrous cycles were analyzed during the study. During weeks 6 and 7 and weeks 12 and 13, vaginal smears were taken daily and a sample placed on a glass slide. The smears were allowed to dry and then stained using a diluted giemsa stain. The slides were examined microscopically and the stage of estrous was recorded.
Sperm parameters (parental animals):
Semen Assessment
At necropsy, the following evaluations were performed on all males:
i) The left testes and epididymis were removed, dissected from connective tissue and weighed separately.
ii) For the testis, the tunica albuginea was removed and the testicular tissue stored frozen at aprox. -20 deg C. At an appropriate later date the tissue were thawed, re-weighed and homogenized in a suitable saline/detergent mixture. Samples of the homogenate were stained with a DNA-specific fluorescent stain and a sub-sample was analyzed for numbers of homogenization-resistant spermatids.
iii) For the epididymis, the distal region was incised and a sample of the luminal fluid collected and transferred to a buffered solution for analysis of sperm motility and sperm morphology. A minimum of 200 individual sperm were assessed using an automated semen analyzer, to determine the number of motile, progressively motile and non-motile sperm. The characteristics of motile sperm were also identified using a computer assisted sperm analyzer.
iv) A sample of semen was preserved in formalin and then stained with eosin. A sub-sample was placed on a glass slide with a coverslip and morphometric analysis of sample semen performed manually.
v) The cauda epididymis was separated from the body of the epididymis, and then weighed. The cauda epididymis was then frozen at approx. -20 deg C. At an appropriate later date the tissue was thawed, reweighed and homogenized in an appropriate saline/detergent mixture. Samples of the homogenate were stained with eosin and a subsample was analyzed for homogenization resistant spermatids.
vi) For both ii) and iv) above, samples from control and high dose groups were evaluated only as no significant effects were seen.
Litter observations:
Not applicable
Postmortem examinations (parental animals):
Not applicable
Postmortem examinations (offspring):
Not applicable
Statistics:
Refer to study summary in Section 7.5.1.
Reproductive indices:
Not applicable
Offspring viability indices:
Not applicable

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Refer to study summary in Section 7.5.1.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Refer to study summary in Section 7.5.1.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Refer to study summary in Section 7.5.1.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Refer to study summary in Section 7.5.1.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Refer to study summary in Section 7.5.1.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
effects observed, treatment-related

Details on results (P0)

ESTRUS CYCLE ASSESSMENTS
There were no treatment-related effects on female estrous cycles or on the type or proportion of females with anomalous estrous cycles.

GROSS AND HISTOPATHOLOGICAL ANALYSIS OF REPRODUCTIVE ORGANS
There were no gross or histopathological changes noted in reproductive organs of dosed animals.

SPERM ANALYSIS
According to the authors of this study, there were no treatment-related effects on the concentration, motility or morphology of samples of epididymal sperm. However, homogenization resistant spermatid counts in the testes of the high dose males were statistically significantly reduced versus the control (p < 0.01). A statistically significant increase in sperm counts in the cauda epididymis was recorded (p < 0.01).
In the testes:
- control counts (millions/g), 174 +/- 15.0; at 1000 mg/kg bwt/d, 136 +/- 22.5
In the cauda epididymis:
- control counts, 188.2 +/- 107.0; at 1000 mg/kg bwt/d, 372 +/- 82.6

It is stated that the statistically significantly reduced epididymal spermatid counts in males was considered of no toxicological significance due to the absence of any histopathological correlates. (see Overall Remarks in this endpoint record)

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion