Octanoic acid, mixed tetraesters with 2-ethylhexanoic acid, heptanoic acid and pentaerythritol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

RA study

Justification for type of information:

Refer to the section 13 of IUCLID dataset for details on the read across justification. The combined repeat dose-reproductive developmental screening toxicity study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CHARLES RIVER LABORATORIES JAPAN, INC. Atsugi breeding center
- Age at study initiation: (P) 10 wks- Weight at study initiation: (P) Males: 330.8-420.4 g; Females: 207.2-245.0 g
- Housing: 2 animals per cage at mating
- Diet: ad libitum
- Water: ad libitum- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0-25.0
- Humidity (%): 40.0-75.0
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hrs. dark/12 hrs light

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on mating procedure:

- M/F ratio per cage: 1/1- Length of cohabitation: up to 2 weeks- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as Day 0 of pregnancy

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration of test substance was analyzed by GC method (mean content 107-110%)

Duration of treatment / exposure:

42 days for males and 42-54 days for females

Frequency of treatment:

Once daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

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

No. of animals per sex per dose:

12 animals (5 animals for satelite groups)

Control animals:

yes, concurrent vehicle

Positive control:

Not applicable

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily during breeding period and recovery period, twice daily during dosing

DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: once a week

BODY WEIGHT: Yes
- Time schedule for examinations: for males weekly and at necropsy, for females weekly during dosing and on Days 0, 7, 14 and 20 of gestation and on Days 0 and 4 of lactation and at necropsy

Oestrous cyclicity (parental animals):

Mean time of estrous cycle and incidence of animals with estrous cycle other than a 4 day cycle per dose was determined beginning at the start of dosing until confirmation of mating.

Sperm parameters (parental animals):

Not applicable

Litter observations:

Number of (live) pups and sex ratio on Days 0 and 4.

Postmortem examinations (parental animals):

SACRIFICE- Male animals: Animals were sacrificed 43 days after satrting dosing or 16 days after starting recovery period. - Maternal animals: Animals were sacrificed 15 days after starting lactation. Animals that did not deliver were saclificed 26 days after pregnancy. For satelite group, sacrifice was done 15 days after starting recovery period.

Postmortem examinations (offspring):

Not applicable

Statistics:

Fisher’s exact test (significance level: 5%) was performed on the function test results, on the incidence of animals showing changes in estrous cycle, on the copulation rate, on the impregnation rate and on the incidence of morphological abnormalities in the offspring.Among the histopathological findings in the test substance treatment groups, the graded data was tested for significance in relation to the control group using Mann-Whitney U-testing (significance level: 5%), while the total values for positive grades were tested for significance with the control group using Fisher’s exact one-sided testing (significance level: 5%).For the other data, the values obtained for each individual or the mean values for each litter were used as single samples, and these samples were compared with the values within the satellite group or within the other groups. Where two groups were used in the analysis, F-testing was performed first, followed by Student t-testing if no significant differences were observed. If a significant difference was observed in the F-testing, Aspin-Welch testing was performed. When three or more groups were used in the analysis, the Bartlett method was used first in order to test for uniformity of variance in each group (significance level: 5%).If the variance was uniform, one-way analysis of variance (significance level: 5%) was performed. If a significant difference was observed between groups, the Dunnett method was used to perform a multiple comparison (significance level: 5%). On the other hand, if the variance in any of the groups was 0 and if the variance was not uniform, Kruskal-Wallis rank testing (significance level: 5%) was performed. If a significant difference was observed between groups, the Dunnett testing method was used to perform a multiple comparison (significance level: 5%).

Reproductive indices:

Copulation index, Fertility index, Gestation index, Imlantation index, Delivery index.

Offspring viability indices:

Birth index, Live birth index, Viability index.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

Estrous cycle: no treatment related effect on incidence and length of estrous cycle

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

Reproductive performance: No significant differences were observed between the control group and any of the treatment groups in impregnation rate, number of days to copulation or number of estrous during this period. No significant differences were observed for corpus luteum count, implantation count or implantation rate between control and treated groups.

Systemic toxicity details for parental animals are described at 7.5.1 Repeated dose toxicity: oral section.

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: There were no effects related to test substance treatment.

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

No effect on birth index, live birth index, viability index or sex ratio was observed. Morphological observations on Day 0 of lactation showed a kinked tail in one pup at 1000 mg/kg bw/d. As no tail abnormalities were observed in any of the other animals, this was considered to be a spontaneous malformation. At necropsy no tail abnormalities were found (not clear if pup with kinked tail had died or not).

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: There were no effects related to test substance treatment.

Key result

Reproductive effects observed:

no

Conclusions:

Under the study conditions, the NOAEL for fertility and fetal toxicity of the substance in rats was determined to be greater than 1000 mg/kg bw/day.

Executive summary:

A study was conducted to determine the repeated dose toxicity of the read-across substance CAS 7299 -99 -2 in rats according to OECD Guideline 422, in compliance with GLP. A combined repeated dose-reproductive developmental screening study was conducted in rats in which the test substance was administered to groups of 12 animals per sex through oral gavage at dose levels of 100, 300 and 1000 mg/kg bw/day for 42 days (males) or 42 -54 days (for females). Males and females were co-habited in 1:1 ratio in the cages during the dosing period for a period of 2 weeks till there is proof of pregnancy. Mortality, clinical signs, food consumption and body weight measurements were performed on a regular basis during the dosing period. After the scheduled necropsy of the pregnant females, reproductive and fetal developmental parameters were examined. Apart from few non-treatment related effects, no adverse effects were observed in any of the treated groups. Under the study conditions, the NOAEL for fertility and fetal toxicity of the substance in rats was determined to be greater than 1000 mg/kg bw/day (MHLW, 2005).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Toxicity to reproduction: other studies

Additional information

A study was conducted to determine the repeated dose toxicity of the read-across substance CAS 7299 -99 -2 in rats according to OECD Guideline 422, in compliance with GLP. A combined repeated dose-reproductive developmental screening study was conducted in rats in which the test substance was administered to groups of 12 animals per sex through oral gavage at dose levels of 100, 300 and 1000 mg/kg bw/day for 42 days (males) or 42 -54 days (for females). Males and females were co-habited in 1:1 ratio in the cages during the dosing period for a period of 2 weeks till there is proof of pregnancy.Mortality, clinical signs, food consumption and body weight measurements were performed on a regular basis during the dosing period. After the scheduled necropsy of the pregnant females, reproductive and fetal developmental parameters were examined. Apart from few non-treatment related effects, no adverse effects were observed in any of the treated groups. Under the study conditions, the NOAEL for fertility and fetal toxicity of the substance in rats was determined to be greater than 1000 mg/kg bw/day (MHLW, 2005).

Justification for classification or non-classification

Based on the combined repeat dose-reproductive-developmental screening toxicity study with the read-across substance CAS 7299 -99 -2, no classification is warranted according to EU CLP (EC 1272/2008) criteria.