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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1998
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:
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

Reference
Name:
Unnamed
Type:
Constituent
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)
Sex:
male/female
Details on test animals 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
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: at most 3 days, until proof of pregnancy
- Proof of pregnancy: vaginal plug or sperm in vaginal smear
Analytical verification of doses or concentrations:
yes
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
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 60, 200, 600
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and 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

Oestrous cyclicity (parental animals):
estrus cycle assessed during study
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.

OTHER: General appearance once a day
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after 49 days
- Maternal animals: All surviving animals after the last litter of each generation was weaned


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.


HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weights (brain, thymid gland, liver, kidney, spleen, adrenal, thymus and for males, testes and epididymis. Dead animals in 60 and 600 mg/kg group, and the parent from which all pups died in 600 mg/kg group : brain, spinal cord, pituitary gland, eyeball, harderian gland, salivary gland, tongue, thyroid gland (including parathyroid gland), thymus, heart, trachea, bronchus, esophagus, lung, liver, kidney, adrenal, spleen, stomach, duodenum, small intestine, large intestine, pancreas, urinary bladder, sternum, bone marrow, sciatic nerve, lymph node, testes, epididymis, prostate, seminal vesicle, ovary, uterus, vagina, mammary gland, skin. All pregnant males and females in 60 and 200 mg/kg group: kidney and any organs which might be expected to have histopathological changes at the higher doses.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at #4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination) as follows: Full macroscopic examination on all of pups


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

Statistics:
Dunnett's or Scheffe's test for continuous data and Chi square test for quantal data
Reproductive indices:
copulation index (No. of pairs with successful copulation/No. of pairs mated x 100), fertility index (No. of pregnant animals/No. of pairs with successful copulation x 100), implantation index (No. of implantation sites/No. of corpora lutea x 100), gestation index (No. of females wilth live pups/No. of living pregnant females x 100), delivery index (No. of pups born/No. of implantation sites x 100)
Offspring viability indices:
live birth index (No. of live pups on day 0/No. ofpups born x 100), viability index (No. of live pups on day 4/No. of live pups on day 0 x 100)

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
Deaths caused by the test substance were observed one female (on day 16) of the 60 mg/kg group, and three males (on day 6 - 9) and one female (on day 3) of the 600 mg/kg group.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
Low body weight gain during the premating period in females at 200 mg/kg was observed (Dunnets test p < 0.05).
Food/water consumption: For males, a tendency for increase in food consumption during administration period was observed at 600 mg/kg, and statistical significant difference from controls was noticed on day 8 to 48 of the administration. For females, statistical significant difference from controls was observed during premating period (on day 8- 15) and gestation period (on day 7 - 14), respectively.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS):
Estrous cycle examination: continuous diestrus was observed in three females of the 600 mg/kg group and the mean estrous cycle of this group showed extension compared with the control group (p < 0.05).

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
No statistical significant difference from controls.

GROSS PATHOLOGY (PARENTAL ANIMALS): No statistically significant effects were observed in all groups.

Effect levels (P0)

open allclose all
Dose descriptor:
NOEL
Effect level:
> 600 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: no effects at the highest dose (600mg/kg)
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: other: estrus cycle increased significantly in the 600mg/kg group

Results: F1 generation

Details on results (F1)

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 (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
200 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: pups of the 600mg/kg group showed lower body weight on day 4 of lactation

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

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

Dose level (mg/kg/day) 0 60 200 600
No. of pairs mated 12 11 12 10
No. of pairs mated with successful copulation 12 11 12 10
Copulation index (%) 100 100 100 90.9
No. of pregnant females 12 11 12 10
Fertility index (%) 100 100 100 100
Pairing days until copulation (mean ± S.D.) 2.9±1.1 2.3±0.9 2.4±0.7 3.1±0.8
No. of corpora lutea (mean ± S.D.) 18.8±1.5 20.6±2.9 19.6±2.5 18.6±1.7
No. of implantation sites (mean ± S.D.) 17.6±1.6 17.2±3.3 18.2±1.9 17.0±2.3
Implantation index (%, Mean ± S.D.) 93.4±5.4 83.5±14.3 93.2±7.5 91.3±8.0
No. of pregnant females with parturition (mean ± S.D.) 12 11 12 10
Gestation length (days, mean ± S.D.) 22.7±0.5 22.3±0.5 22.6±0.5 22.4±0.5
Gestation index (%) 100 100 100 100
Estrus cycle (days, mean ± S.D.) 4.1±0.3 4.1±0.3 4.3±0.5 4.5±0.4?

Copulation index (%) = (No. of pairs with successful copulation / No. of pairs mated) x 100

Fertility index (%) = (No. of pregnant females / No. of pairs with successful copulation) x 100

Gestation index (%) = (No. of females with live pups / No. ofpregnant females) x 100

Significant difference from control group

? = P<0.05

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

Applicant's summary and conclusion

Conclusions:
On the basis of these findings, NOEL of 2,2,6,6-Tetramethyl-4-hydroxypiperidine for reproductive toxicity to parental rats were considered to be more than 600 mg/kg/day for males, and 200 mg/kg/day for females. Moreover, NOEL of the test substance to F1 offspring was established to be 200 mg/kg/day.