2,2,6,6-tetramethylpiperidin-4-ol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline compliant

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1998

Reference 2

Reference Type:

secondary source

Title:

SIDS DOSSIER: 2,2,6,6-Tetramethylpiperidin-4-ol, CAS-No: 2403-88-5

Author:

OECD SIDS

Year:

2002

Bibliographic source:

OECD SIDS

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Remarks:

Biosafety Research Center, Food, Drugs and Pesticides (An-Pyo Center), Japan

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2,6,6-tetramethylpiperidin-4-ol

EC Number:

219-291-2

EC Name:

2,2,6,6-tetramethylpiperidin-4-ol

Cas Number:

2403-88-5

Molecular formula:

C9H19NO

IUPAC Name:

2,2,6,6-tetramethylpiperidin-4-ol

Details on test material:

- Name of test material (as cited in study report): 2,2,6,6-Tetramethylpiperidin-4-ol

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 10 weeks old for female and male animals
- Weight at study initiation: 359 - 400g for males; 227 - 282g for females

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: at the most 3 days, until proof of pregnancy
- Proof of pregnancy: vaginal plug / sperm in vaginal smear

Duration of treatment / exposure:

Male: for 48 days from 2 weeks prior to mating
Female: for 41-52 days from 2 weeks prior to mating to day 3 postpartum throughout mating and pregnancy

Frequency of treatment:

once daily

Duration of test:

Male: for 49 days
Female: for 42-53 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 60, 200, 600 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day

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

BODY WEIGHT: Yes
- Time schedule for examinations: for males: once a week, the first and the last day of the administration, the sacrificed day; for pregnant females: on day 0, 14 and 20 of gestation, on day 0 and 4 of lactation

FOOD CONSUMPTION: Yes
- Time schedule: once a week, on the same day when body wt. determined

CAGE SIDE OBSERVATIONS: Yes / No / No data
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes / No / No data
- Time schedule for examinations:

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on lactation day 4
- Organs examined: all organs which might be expected to have histopathological changes at the higher dose

OTHER:

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: Yes: all per litter (macroscopic examination)
- Head examinations: Yes: all per litter (macroscopic examination)

Statistics:

Dunnett's or Scheffe's test for continuous data and Chi square test for quantal data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Body weight gain was decreased at more than 200 mg/kg/day. In clinical signs, blepharoptosis and mydriasis were observed in all groups, and their changes were dose-related. In 60 mg/kg/day group, the incidence for mydriasis was low and was observed concurrently with blepharoptosis at a slight degree and only sporadically. Mortality occurred in one female at 60 mg/kg/day, and one female at 600 mg/kg/day. At 600 mg/kg/day, the discontinued rats revealed reddish spots in digestive tracts, abnormal foci with gastric ulcer and the vacuolar degeneration in renal tubular epithelium. On the basis of clinical signs, a NOAEL of less than 60 mg/kg/day was set under the conditions of the study.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

< 60 mg/kg bw/day (nominal)

Basis for effect level:

clinical signs

Maternal abnormalities

Abnormalities:

not specified

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: pups of the 600mg/kg group showed lower body weight on day 4 of lactation

Details on embryotoxic / teratogenic effects:
With regard to the effects on neonates, viability on day 4 of lactation was decreased in the 600 mg/kg group, and male and female pups of the 600 mg/kg group showed lower body weights on day 4 of lactation. There are no significant differences in the delivery index and live birth index. Also, no exteral and visceral abnormalities related to the test substance were detected in any of the offspring.

Effect levels (fetuses)

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Litter results of rats treated orally with 2,2,6,6 -Tetramethylpiperidin-4 -ol:

Dose level (mg/kg/day)	0	60	200	600
No. of pups born	16.3±2.0	15.3±3.3	15.4±1.5	15.7±2.7
Delivery index (%)	92.9±7.0	90.3±16.2	85.2±6.9	92.1±6.0
No. of pups alive on day 0 of lactation
Total	16.3±2.0	15.2±3.3	15.3±1.4	15.7±2.7
Male	8.2±2.2	7.7±2.3	7.9±1.8	7.0±3.0
Female	8.2±1.5	7.5±2.6	7.4±2.2	8.7±2.3
Live birth index (%)	100±0.0	99.5±1.8	99.5±1.7	100±0.0
Sex ratio (Male/Female)	1.05±0.37	1.15±0.46	1.22±0.60	0.90±0.57
No. of pups alive on day 4 of lactation
Total
Male	7.8±2.0	7.5±2.2	6.5±2.7	4.3±2.9
Female	7.4±1.1	6.5±2.5	6.3±2.5	6.4±3.7
Viability index (%)
Total	96.1±7.5	96.8±5.4	82.7±28.4	67.2±39.2
Male	91.9±9.9	86.2±10.4	85.8±20.3	70.7±35.0
No. Of total dead pups born (mean±S.D.)	0.0±0.0	0.1±0.3	0.1±0.3	0.0±0.0
Stillbirth	0.0±0.0	0.0±0.0	0.0±0.0	0.0±0.0
cannibalism	0.0±0.0	0.1±0.3	0.1±0.3	0.0±0.0

Delivery index (%) = (No. of pups born/No. of implantation sites) x 100

Live birth index (%) = (No. of live pups on day 0/No. of pups born) x 100

Viability index (%) = (No. of live pups on day 4/No. of live pups on day 0) x 100

Sex ratio = Total No. of male pups/ Total No. of female pups

Values are expressed as Mean±S.D. except sex ratio