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Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

There is no substance specific data available for Isoeicosane. However, an OECD 443 test is proposed for a structural analogue, isohexadecane. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

 

This endpoint will be updated subsequent to ECHA's approval of the testing proposal and availability of data upon completion of the study. Additionally, an OECD Guideline 422 screening reproductive/developmental toxicity study (oral route) in rodents is planned with isoeicosane (EC# 297-627-7).

Effects on developmental toxicity

Description of key information

There is no data available for isoeicosane. However, data is available for structural analogue Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, <2% aromatics. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

In a key guideline pre-natal developmental toxicity study (ExxonMobil, 1996), the test material (Hydrocarbons C16-C20 n-alkanes, isoalkanes, cyclics, <2% aromatics) was administered by oral gavage to three groups of Crl:CDBR female rats at doses of 400, 800, and 1000 mg/Kg/day. A fourth group (Group 1) served as a control and received the carrier (corn oil) only. Mated females were dosed once daily from Gestation Day (GD) 6 through GD 15. Dosing volumes were 5 mL/Kg for all groups and based on the animals' most recent body weights.

 

There was no evidence of overt systemic maternal toxicity at any dose level tested. overt signs of maternal toxicity were not apparent at any dose tested, as indicated by the absence of adverse clinical or post-mortem findings or effects on body weight, food consumption, and/or uterine implantation data.

 

Similarly, there were no treatment-related adverse effects on fetal development or growth observed at any dose level tested. There was a statistically significant increase in the incidence of rudimentary ribs in the low dose (400 mg/Kg/day) group, but not at the higher doses, compared with controls, which resulted in an increased incidence of total fetuses with skeletal variations in the 400 mg/Kg/day group. However, all these incidences were within the historical control range of this laboratory. Therefore, this common finding in fetal rats was not considered biologically important.

 

Accordingly, the maternal and developmental NOAELs (No Observable Adverse Effect Level) were established at 1000 mg/Kg/day under the conditions of this study.

Additionally, OECD Guideline 414 rodent and non-rodent species tests are proposed for a structural analogue, isohexadecane. This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the studies.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 29, 1995 to June 29, 1995.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Some deviations such as the treatment period (from GD6 to GD15 instead of GD5 to GD15 mentioned in OECD guideline 414).
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
females were dosed from Gestation Day (GD) 6 instead of GD 5; Administration volume 5 mL/kg (instead of 4mL/kg max).
Principles of method if other than guideline:
Guideline study
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston Facility, New York.
- Age at study initiation: females were approximately 10 weeks at GD 0
- Weight at study initiation: 216 to 295 g at GD 0
- Housing: Single housed during the study period, except during mating
- Diet: Certified Rodent Diet (5002 meal), ad libitum
- Water: ad libitum (Elizabethtown Water company)
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24.4°C
- Humidity (%): 40 - 70%
- Air changes (per hr): Not mentioned
- Photoperiod: 12 hrs dark / 12 hrs light


IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): OCT1295B
- Supplier: Best Foods, CPC International
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
At analytical chemistry analysis, excellent uniformity was observed. The percent relative standard deviation (%RSD) ranged from 1.43% to 2.97%. Stability data indicated that the test material was stable in corn oil at ambient temperature for at least 13 days. Concentration verification analysis indicated that the solution in corn oil was within 12% of the nominal concentrations for Week 1 and Week 3.
Details on mating procedure:

- M/F ratio per cage: 1:1 (male:female) ratio
- Length of cohabitation: one night
- Proof of pregnancy: Mating was confirmed by observation of a copulatory plug (vaginal) and/or by the presence of sperm in a vaginal rinse. The day on which mating was confirmed was the female's Day 0 of gestation (GD 0).
Duration of treatment / exposure:
from Gestation Day (GD) 6 through GD 15
Frequency of treatment:
Once daily
Duration of test:
Inlife test period: May 29, 1995 to June 29 1995.
Remarks:
Doses / Concentrations:
0, 400, 800 and 1000 mg/kg/day
Basis:
other: ingested doses
No. of animals per sex per dose:
25 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were selected based on a rangefinding study with Exxsol D130. Results of this study indicated no overt or consistent signs of toxicity at 1000 mg/kg (the limit dose for developmental studies) (OECD, 1981).
- Rationale for animal assignment (if not random): sequential Physical Identification Number
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily during the treatment period, otherwise at least once daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior the selection and daily during gestation

BODY WEIGHT: Yes
- Time schedule for examinations: on GD 0, 6, 9, 12, 15, 18, and 21

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: All females assigned to groups were examined by gross necropsies.

OTHER:
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- 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: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: [half per litter ]
Statistics:
Statistical treatment of the results was conducted where appropriate. Statistical evaluation of equality of means was done by an appropriate one way analysis of variance and a test for ordered response in the dose groups. First, Bartlett's Test was performed to determine if the dose groups had equal variance . If the variances were equal, the testing was done using parametric methods (ANOVA + Dunnett's), otherwise nonparametric techniques were used (Kruskl-Wallis + Dunn's Summed Rank Test).
Fetal malformation and variation incidence data were analyzed for statistical significance as follows: First, a standard chi-square analysis was performed to determine if the proportions of incidences differ between the groups tested. Next, each treatment group was compared to the control group using a 2 x 2 Fisher Exact Test.
Indices:
Maternal data:
Percentage of pre-implantation loss
Percentage of post-implantation loss
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No maternal toxic effects.
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
There were statistically significant differences in individual skeletal variations, but were limited to an increase in the incidence of rudimentary lumbar ribs in the 400 mg/kg dose group (14.2%) compared with controls (4.2%) on a per fetus basis. This increased incidence was within the historical control range of this laboratory (3.7-28.8), greater than that observed at higher doses, and thus, not considered biologically important.
The statistically significant increases in the total fetuses with skeletal variations in the 400 mg/kg dose groups were directly driven by the increased incidence of rib variations and thus, were similarly considered as biologically unimportant (within HC range).
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Developmental Toxicity
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

No remarks

Conclusions:
In conclusion, overt signs of maternal toxicity were not apparent at any dose tested, as indicated by the absence of adverse clinical or postmortem findings or effects on body weight, food consumption, and/or uterine implantation data. Similarly, there were no treatment-related adverse effects on fetal development or growth observed at any dose level tested. Accordingly, the maternal and developmental NOAELs (No Observable Adverse Effect Level) were established at 1000 mg/kg (the limit dose) under the conditions of this study.
Executive summary:

The test material was administered by oral gavage to three groups of Crl:CDBR female rats at doses of 400, 800, and 1000 mg/kg/day. A fourth group (Group 1) served as a control and received the carrier (corn oil) only. Mated females were dosed once daily from Gestation Day (GD) 6 through GD 15. Dosing volumes were 5 mL/kg for all groups and based on the animals' most recent body weights.

There was no evidence of overt systemic maternal toxicity at any dose level tested. overt signs of maternal toxicity were not apparent at any dose tested, as indicated by the absence of adverse clinical or postmortem findings or effects on body weight, food consumption, and/or uterine implantation data.

Similarly, there were no treatment-related adverse effects on fetal development or growth observed at any dose level tested. There was a statistically significant increase in the incidence of rudimentary ribs in the low dose (400 mg/kg/day) group, but not at the higher doses, compared with controls, which resulted in an increased incidence of total fetuses with skeletal variations in the 400 mg/kg/day group. However, all these incidences were within the historical control range of this laboratory. Therefore, this common finding in fetal rats was not considered biologically important.

Accordingly, the maternal and developmental NOAELs (No Observable Adverse Effect Level) were established at 1000 mg/kg/day under the conditions of this study.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Only available study.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on available read across data from structural analogues, isoeicosane does not warrant classification as a reproductive or developmental toxicant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

However, an OECD 422 test will be conducted on isoeicosane (EC# 297-627-7) and the endpoint will be updated upon completion of the study. Additional tests (OECD 443 and OECD 414 (rodent and 2nd species)) are proposed with a structural analogue isohexadecane and will be conducted subsequent to ECHA's approval of the same. This endpoint will be updated upon completion of the above studies subject to ECHA's approval.

Additional information