Decan-4-olide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

ECHA (ECHA-09-FS-05-EN, 15/09/2009) considers registration dossier for substance ≥ 10 t/y as technically complete even if it does not contain the results of a screening study for reproductive/developmental toxicity since the dossier contains the results of a pre-natal developmental toxicity study (see § 7.8.2).

Moreover the 28-day repeated dose toxicity study conducted on the supporting read-across substance, γ-Caprolactone, does not indicate adverse effects on reproductive organs (testes and ovaries) or tissues (Annex IX, Section 8.7.3).

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information as a whole meets the tonnage driven data requirement of REACH. Moreover, reliability and consistency are observed across the different studies.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

ECHA (ECHA-09-FS-05-EN, 15/09/2009) considers registration dossier for substance ≥ 10 t/y as technically complete even if it does not contain the results of a screening study for reproductive/developmental toxicity since the dossier contains the results of a pre-natal developmental toxicity study (see § 7.8.2).

Moreover the 28-day repeated dose toxicity study conducted on the supporting read-across substance, γ-Caprolactone, does not indicate adverse effects on reproductive organs (testes and ovaries) or tissues (Annex IX, Section 8.7.3).

Short description of key information:
No reproduction toxicity study is required based on the absence of effects up to the highest dose (1000 mg/kg bw/day) in a pre-natal developmental toxicity study and a 28-day repeated dose toxicity study, both conducted on the read-across substance, ɣ-Caprolactone.
γ-Caprolactone, as a linear saturated 4-hydroxycarboxylic acid derived-lactones, is considered adequate for read-across purpose (see §"Toxicokinetics").

Justification for selection of Effect on fertility via oral route:
The 28-day repeated dose toxicity study conducted on the supporting read-across substance, γ-Caprolactone, does not indicate adverse effects on reproductive organs (testes and ovaries) or tissues (Annex IX, Section 8.7.3).
γ-Caprolactone, as a linear saturated 4-hydroxycarboxylic acid derived-lactones, is considered adequate for read-across purpose (see §"Toxicokinetics").

Effects on developmental toxicity

Description of key information

In an OECD 414 study conducted on the read-across substance, ɣ-Caprolactone, the No Observed Adverse Effect Level (NOAEL) for developmental toxicity was 1000 mg /kg bw/d (K, rel. 2). 

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

From March 26, 2002 to June 14, 2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: OECD 414 guideline study in compliance with GLP. γ-Caprolactone, as a linear saturated 4-hydroxycarboxylic acid derived-lactones, is considered adequate for read-across purpose (see §"Toxicokinetics").

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD®(SD)IGS BR

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Caroline
- Age at study initiation: approximately 12 weeks old whenn paired fro breeding
- Weight at study initiation: 237 to 239 g on Day 0 of gestation
- Housing: upon arrival and until paring, individually housed in clean, wire-mesh cages suspended above cage-board. The rats were paired for mating in the home cage of the males. Following positive identification of mating, the femles were returned to an individual suspended wire-mesh cage, nesting material was not required as the females were euthanized prior to the data of expected parturition.
- Diet (e.g. ad libitum): ad libitum, PMI Nutrition International, Inc. Certified Rodent LabDiet® 5002 (analysis certified)
- Water (e.g. ad libitum): ad libitum, reverse-osmosis-treated (on-site) municipal water (analysis certified)
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.7 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): approximately 10 fresh air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: March 26, 2002 To: May 3, 2002

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

deioniszed

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The 1000 mg/kg bw/d test article formulation was a weight/volume (test article/vehicle) mixture. For this group, the appropriate amount of the test article was weighted into a tared weighting vessel. Approximately 60 % of the vehicle was added to a calibrated storage container, and a deep vortex was created with a magnetic stir bar. The test article was slowly transferred quantitatively into the rapidly stirring vehicle and stirred until dissolved (approximately one minute). The remaining amount of vehicle was added to bring the volume to the calibration mark. The formulation was stirred until uniform and throughout use, using a magnetic stirrer. The mixture was used as a stock formulation to prepare the 100 and 300mg/kg bw/d group dosing formulations. For these groups, the appropriate amount of the stock formulation was added to achieve the total volume for each group. The dosing formulations were stored refrigerated, protected from light. The test article formulations were prepared approximately weekly (as single formulations for each dose level), then separated into aliquots for daily dispensation. All test article formulations were stirred continuously throughout the preparation, sampling and dose administration procedures.

VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity, re-suspension homogeneity and stability of the test formulations at a similar range of concentrations as used in this study were established in a companion study (Repeated dose toxicity: oral, 28d, Kirkpatrick).
Prior to the initiation of dose administration (April 2, 2002), samples (10 mL each) for homogeneity determination were collected from the top, middle and bottom strata of the all dosing formulations, including the control group. In addition, duplicate samples (10 mL each) for stability determinations were collected from the top and bottom strata of these same dosing suspensions; one set was stored refrigerated for 10 days and one set was stored at room temperature for 10 days. Both sets were protected from light. Samples (10 mL each) for concentration analysis were collected from the first, second and third weekly preparations from each dosing formulation (including the control group.
All analyses were conducted by the Analytical Chemistry Department, WIL Research Laboratories, Inc. The test article formulations were found to be homogenous (the RSD for the overall mean concentration was ≤ 10 % at a concentration that is within the acceptable limits), contain the amount of test article specified in the protocol (analyzed concentrations were within ± 10 % of the target dose concentrations) and stable for at least 10 days when stored refrigerated or at room temperature (the mean concentrations were no less that 90 % of the time zero concentrations).

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Length of cohabitation: no data
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

From GD6 through GD19

Frequency of treatment:

Once daily

Duration of test:

14 days

Remarks:

Doses / Concentrations:
100, 300 and 1000 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

25 animals/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: selected based on the results of previous studies and were provided by the sponsor after consultation with the study director.
- Rationale for animal assignment (if not random):
- Other:

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily from day 0 through 20 of gestation. Animals were also observed for signs of toxicity approximately one hour following dose administration.

BODY WEIGHT: Yes
- Time schedule for examinations: on gestation days 0 and 6-20 (daily)
Group mean body weights were calculated for each of these days. Mean body weight changes were calculated for each corresponding interval and also for gestation days 6-9, 9-12, 12-20, 6-20 and 0-20.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Individual food consumption was recorded on gestation day 0 and 6-20 (daily). Food intake was reported as g/animal/day and g/kg/day for the corresponding bpdy weigh change intervals . On the occasions when food intake could not be measured for one of the days in a given interval (due to a weighting error, food spillage, obvious erroneous value, etc.), values were calculated using the appropriate number of days for that interval.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No, not a drinking water study

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: gross observations of organs, maternal tissues were preserved

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
- Visceral examination: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
- Soft tissue examinations (head): Yes: half per litter

Statistics:

All statistical tests were performed using appropriate computing devices or programs. Analyses were conducted using two-tailed tests (except as noted otherwise) for a minimum significance levels of 5 %, comparing each test article-treated group to the control group by sex. Each mean was presented with the standard deviation (S.D.) and the number of animals (N) used to calculate the mean. Due to the different rounding conventions inherent in the types of software used, the means and standard deviations on the summary and individual tables may differ by ± 1 in the last significant figure.
Mean maternal body weights (absolute and net), body weight changes (absolute and net) and food consumption, gravid uterine weights, number of corpora lutea, implantations sites and viable fetuses, and fetal body weights (separately by sex and combined) were subjected to a parametric one-way analysis of variance (ANOVA) to determine intergroup differences. If the ANOVA revealed statistical significant (p < 0.05) intergroup variance, Dunnett’s test was used to compare the test article-treated groups to the control group. Mean litter proportions (percent per litter) of prenatal data (viable and nonviable fetuses, early and late resorptions, total resorptions, pre- and postimplantation loss, and fetal sex distribution) were subjected to the Kruskall-Wallis nonparametric ANOVA test to determine intergroup differences. If the ANOVA revealed statistically significant (p < 0.05) intergroup variance, the Mann-Whitney U-test was used to compare the test article-related groups to the control group. Mean litter proportions (percent per litter) or total fetal malformations and developmental variations (external, visceral, skeletal and combined) and of each particular external, visceral and skeletal malformation or variation were analyzed by the Kruskall-Wallis nonparametric ANOVA test followed by the Mann-Whitney U-test (if appropriate) as described above.

Indices:

- Postimplantation loss/litter= (No. dead fetuses, resorptions (Early/Late)/Group) / No. Gravid Females/Group.
- Summation per group (%) = Sum of postimplantation loss/litter (%) / No. litters/group.
- Postimplantation loss/litter (%) = (No. dead fetuses, resorptions (Early/Late)/litter) / No. implantation sites/litter * 100
- Viable fetuses affected/litter (%) = (No. viable fetused affected/litter) / No. viable fetuses/litter * 100

Historical control data:

WIL Developmental historical control data [Crl:CD(SD)IGS BR Rats] is incuded in Appendix D of the study report. External, visceral and skeletal malformations and visceral and skeletal deviations were reported for 27 studies (635 fetuses)

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
MATERNAL CLINICAL OBSERVATIONS AND SURVIVAL
All animals survived to the scheduled necropsy. No test article-related findings were observed. Clinical findings, including hair loss or various body surfaces, yellow staining on the ventral abdomen and/or red material around the mouth or nose, were present prior to the initiation of dose administration, occurred infrequently, were noted similarly in the control group and/or did not occur in a dose-related manner.

MATERNAL BODY WEIGHTS AND GRAVID UTERINE WEIGHTS
No test article-related effects on mean body weights, body weight gains, net body weight gains or gravid uterine weights were observed.

MATERNAL FOOD CONSUMPTION
Food consumption, evaluated as g/animal/day and g/kg/day, was unaffected by test article administration. The only statistically significant (p < 0.05 or p < 0.01) differences from the control group were slight decreases in the 300 mg/kg bw/day group (g/kg/day only) during gestation days 17-19. The g/animal/day value in the 1000 mg/kg bw/day group was similar to that in the control group; therefore, the transient reduction in food consumed relative to body weight was not considered to be adverse. A reduction in the g/animal/day value similar to that observed in the 300 mg/kg /day group during gestation days 17-18 was not observed in the 1000 mg/kg bw/day group. Therefore, this transient decrease was not attributed to the test article.

MATERNAL NECROPSY DATA
There were no test article-related internal findings at the scheduled necropsy on GD20. One female in the 100 mg/kg bw/day group had cyst in the renal cortex and medulla (bilateral) and a rough surface of the liver. Another female in this same group had calculi in the urinary bladder, distended ureters and dilated renal pelves. In the 1000 mg/kg bw/day group, one female had dark red areas in the lungs. No other internal findings were observed.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: statistically significant reduced mean fetal body weight

Details on embryotoxic / teratogenic effects:
GD20 LAPAROHYSTERECTOMY DATA
Mean fetal body weights (male, female and combined) in the 1000 mg/kg bw/day group (3.5, 3.3 and 3.4 g, respectively) were reduced (statistically significant at p <0.05 or p < 0.01) compared to the control group value (3.7, 3.5 and 3.6 g, respectively). The values in the 1000 mg/kg bw/day group were equal to the minimum values in the WIL historical control data. The reduction in mean fetal body weight was attributed to the test article. Other intrauterine parameters, including mean viable litter size, fetal sex ratios and mean litter proportions of pre- and postimplantation loss, in this group were unaffected by test article administration.
Intrauterine growth and survival in the 100 and 300 mg/kg bw/day groups were unaffected by test article administration. The mean numbers of corpora lutea and implantation sites were similar in all groups.

FETAL MORPHOLOGICAL DATA
The number of fetuses (litters) available for morphological evaluation were 364(24), 376(24), 365(23) and 393(25) in the control, 100, 300 and 1000 mg/kg bw/day groups, respectively. Malformations (visceral and skeletal) were observed in 3(3) fetuses (litters) in the 300 mg/kg bw/day group and not treatment relationship as described below.

EXTERNAL MALFORMATIONS AND VARIATIONS
One fetus in the 300 mg/kg bw/day group had a meningocele (a portion of the meninges protruded through an opening of the cranium). No other external malformations were observed.
No external developmental variations were observed.

VISCERAL MALFORMATIONS AND VARIATIONS
One fetus in the 300 mg/kg bw/day group had a malpositioned descending aorta (the aorta coursed laterally to the left adrenal gland, between the adrenal and the left kidney, and resumed the normal position prior to the branching of the iliac artery). No other soft tissue malformations were observed.
Soft tissue developmental variations in the test article-treated groups included distended ureters, major blood vessel variations (the right carotid and right subclavian arteries arose independently from the aortic arch with no brachiocephalic trunk or a retroesophageal right subclavian artery, which joined the aortic arch adjacent to the right carotid artery, with no brachiocephalic trunk), an accessory spleen and a small spleen. These findings were observed in single fetuses or did not occur in a dose-related manner. No relationship to treatment was evident.

SKELETAL MALFORMATIONS AND VARIATIONS
One fetus in the 300 mg/kg bw/day group had a vertebral centra anormality (the right half of lumbar centrum no. 2 was absent, and the right half of lumbar centrum no. 1 was malpositioned). No other skeletal malformations were observed.
Skeletal developmental variations occurred in all dose groups, including the control group, and consisted primarily of unossified sternebra(e) nos. 5 and/or 6, 14th rudimentary ribs, 7th cervical ribs, cervical centrum no. 1 ossified and unossified hyoid. A statistically significant (p < 0.05) increase in the mean litter proportion (% per litter) of 7th cervical ribs was observed in the 100 mg/kg bw/day group compared to the control group value. Similar increases were not observed in the 300 and 1000 mg/kg bw/day groups; therefore this increase was not attributed to test article. Other skeletal variants observed on the test article-treated groups occurred infrequently, were within the range of the WIL historical control data or did not occur in a dose-related manner. No relationship to treatment was evident.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

fetal/pup body weight changes

Abnormalities:

not specified

Developmental effects observed:

not specified

none

Conclusions:

Under the test conditions, the NOAEL for maternal toxicity was 1000 mg /kg bw/d. Due to slightly reduced foetal mean body weight in the high dose group compared to control, the NOAEL for developmental toxicity was 1000 mg/kg bw/day.

Executive summary:

In a developmental toxicity study conducted according to the OECD guideline No. 414 and in compliance with GLP, γ-Caprolactone diluted in deionized water was administered to 25 females Crl:CD®(SD)IGS BR rats/dose by gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day from days 6 through 19 of gestation (dose volume = 10 mL/kg bw).

 

All animals were observed twice daily for appearance and behavior. Clinical observations, bodyweight and food consumption were recorded at appropriate intervals. On gestation day 20, a laparohysterectomy was performed on each female. The uteri and ovaries were examined, and the number of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighted, sexed and examined for external, visceral and skeletal malformations and developmental variation.

 

All animals survived to the scheduled necropsy on GD20. There were no test article-related maternal clinical observations or effects on mean body weights, body weight gains, net body weights, net body weight gains, gravid uterine weights or food consumption at any dose level. There were no test article-related internal findings at the scheduled necropsy. The mean fetal sex ratio and mean numbers and/or litter proportions of viable fetuses and pre- and postimplantation losses in the 1000 mg/kg bw/day group were not affected by test article administration. Intrauterine growth and survival were unaffected in the 100 and 300 mg/kg bw/day groups. No test article-related fetal malformations or developmental variations were noted at any dose level in this study.

Test article-related effects noted in the 1000 mg/kg bw/day group consisted of statistically significant reduced mean fetal body weight (5.6 % lower than the control group value for combined fetal weight). This slight decrease was not considered of toxicological concern. No other indicators of developmental toxicity were noted.

Based on the results of this study, the dose level of 1000 mg/kg bw/day was considered to be the NOAEL for maternal toxicity and the dose level of 1000 mg/kg bw/day was considered to the NOAEL for developmental toxicity.

Under the test conditions, γ-Caprolactone is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and the Directive 67/548/EEC.

This study is acceptable and satisfies the requirement for developmental toxicity endpoint.

γ-Caprolactone, as a linear saturated 4-hydroxycarboxylic acid derived-lactones, is considered adequate for read-across purpose (see §"Toxicokinetics").

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:

The available information as a whole meets the tonnage driven data requirement of REACH. Moreover, reliability and consistency are observed across the different studies.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No developmental toxicity study was located on γ-Decalactone while a reliable study is available on γ-Caprolactone, aliphatic γ-lactone considered adequate for read-across purpose(see § "Toxicokinetics").

Hence, in a developmental toxicity study conducted according to the OECD guideline No. 414 and in compliance with GLP, γ-Caprolactone diluted in deionized water was administered to 25 females Crl:CD®(SD)IGS BR rats/dose by gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day from days 6 through 19 of gestation.

 

All animals survived to the scheduled necropsy on GD20. There were no test article-related maternal clinical observations or effects on mean body weights, body weight gains, net body weights, net body weight gains, gravid uterine weights or food consumption at any dose level. There were no test article-related internal findings at the scheduled necropsy. The mean fetal sex ratio and mean numbers and/or litter proportions of viable fetuses and pre- and postimplantation losses in the 1000 mg/kg bw/day group were not affected by test article administration. Intrauterine growth and survival were unaffected in the 100 and 300 mg/kg bw/day groups. No test article-related fetal malformations or developmental variations were noted at any dose level in this study.

Test article-related effects noted in the 1000 mg/kg bw/day group consisted of statistically significant reduced mean fetal body weight (5.6 % lower than the control group value for combined fetal weight). This slight decrease was not considered of toxicological concern. No other indicators of developmental toxicity were noted. No other indicators of developmental toxicity were noted.

Based on the results of this study, the dose level of 1000 mg/kg bw/day was considered to be the NOAEL for both maternal toxicity and developmental toxicity.

Justification for selection of Effect on developmental toxicity: via oral route:
Key study conducted on the read-across aliphatic lactone, ɣ-Caprolactone (OECD 414, K, rel. 2).

Justification for classification or non-classification

Harmonized classification:

ɣ-Decalactone has no harmonized classification according to the Regulation (EC) No 1272/2008 including ATP2.

Self-classification:

Based on the available data, no additional classification is proposed according to the Regulation (EC) No. 1272/2008 and of the Directive 67/548/EEC.