Pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

No analysis of dose levels. No individual data. Compared to OECD 414, the following parameters were not examined: gravid uterus weight, number of corpora lutea, foetal sex., only gestation days 6 to 15

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1975

Report date:

1975

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

Doses administered from day 6 of pregnancy instead of day 5 post mating to day 15 instead of until birth. Uteri were not weighted and corpora lutea not counted. The sex of the fetuses was not determined.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate)

EC Number:

229-722-6

EC Name:

Pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate)

Cas Number:

6683-19-8

Molecular formula:

C73H108O12

IUPAC Name:

3-{[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoyl]oxy}-2,2-bis({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoyl]oxy}methyl)propyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoate

Details on test material:

- Substance type: Organic
- Physical state: Solid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Closed SPF breeding colony
- Weight at study initiation: females: 240 g
- Housing: Throughout the experiment the successfully mated females were kept in groups of 5 in Macrolon cages
- Diet (e.g. ad libitum): Standard diet Nafag No.890
- Water (e.g. ad libitum): Ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 0.5
- Humidity (%): 56 ± 5
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Substance in 2 % CMC (acqueous solution)

VEHICLE
- Justification for use and choice of vehicle (if other than water): Substance insoluble in water
- Amount of vehicle (if gavage): 1 mL/100 g bw

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/3
- Length of cohabitation: Overnight
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

10 days, from day 6 to 15 of gestation

Frequency of treatment:

Daily

Duration of test:

21 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

150 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

500 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day

No. of animals per sex per dose:

25 dams for the test substance and 30 dams for the control

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: During the period of treatment daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: During the period of treatment daily

BODY WEIGHT: Yes
- Time schedule for examinations: During the period of treatment daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: dam's organs, especially ovaries and uterus (mucosa and contents, including amniotic fluid and placentae)

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- 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: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

At the 150 and 500 mg/kg dose level the feed consumption was increased when compared with controls. The mean body-weight gain, however, appeared to be comparable in all groups.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

At the 150 and 500 mg/kg dose level the feed consumption was increased when compared with controls. The mean body-weight gain, however, appeared to be comparable in all groups.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Maternal developmental toxicity

Description (incidence and severity):

The rates of implantation and embryolethality (resorptions) as well as the average weights of the foetuses were comparable for all groups.

Effect levels (maternal animals)

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: no adverse effects reported

Results (fetuses)

External malformations:

no effects observed

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Skeletal assessment revealed a decrease in the numbers of not yet ossified phalangeal nuclei of the hind-limb and calcanei in the 150 mg/kg and 500 mg/kg dose group, No further clear-cut deviations from the control group were found.

Visceral malformations:

no effects observed

Effect levels (fetuses)

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: no adverse effects reported

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1. Skeletal assessment (figures in brackets refer to %)

Dose group (mg/kg/day)	No. of skeletons examined	Phalangeal nuclei^a		Calcaneus^a	Sternebrae^d	Vertebrae^e
		Fore-limb^b	Hind-limb^c
150	193	2 (1.0)	17 (8.8)	9 (4.7)	49 (25.4)	1 (0.5)
500	177	2 (1.1)	31 (17.5)	20 (11.3)	41 (23.2)	0
1000	157	5 (3.2)	45 (28.7)	45 (28.7)	44 (28.0)	0
CMC control	205	6 (2.9)	61 (29.6)	43 (20.9)	63 (30.6)	1 (0.5)
99 % Confidence limits		0.69	21.95	14.48	23.46	0.00
of the CMC control		-7.57	-38.99	-29.84	40.81	-3.66

a) Ossification still absent. b) Proximal phalanges. c) Proximal phalanges. d) Particularly ossification centers of the 5th sternebra still incompletely ossified (bipartite). e) Centres of some thoracic vertebrae still dumbbell-shaped. f) Centres displaced and irregularly ossified. g) Centres of some thoracic vertebrae bipartite.

Applicant's summary and conclusion

Conclusions:

Embryonic development was not adversely affected by the treatment. No teratogenic effects were noted.