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REACH

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

EC number: 219-291-2 | CAS number: 2403-88-5

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

oral: NOEL < 60 mg/kg/day (GLP-OECD Guideline study, MHW, 1998)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:: short-term repeated dose toxicity: oral
Remarks:: combined repeated dose and reproduction / developmental screening
Type of information:: experimental study
Adequacy of study:: key study
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: other: Guideline study (OECD)
Qualifier:: according to guideline
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
Species:: rat
Strain:: Crj: CD(SD)
Sex:: male/female
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
Route of administration:: oral: gavage
Vehicle:: water
Analytical verification of doses or concentrations:: not specified
Duration of treatment / exposure:: Males: for 48 days (from 2 weeks prior to mating)
Females: for 41 - 52 days (from 14 days before mating to day 3 of lactation)
Frequency of treatment:: once daily
Remarks:: Doses / Concentrations:
0, 60, 200, 600 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:: 12
Control animals:: yes, concurrent vehicle
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day

DETAILED CLINICAL OBSERVATIONS: Yes (see table)

BODY WEIGHT: Yes (see table)
- Time schedule for examinations: On the first day, the last day of the administration, the day of sacrifice and once a week during the administration period. For pregnant females: on the day 0, 14, and 20 of gestation and on day 0 and 4 of lactation.

FOOD CONSUMPTION: was determined on the same dy when body weight was determined for 24 hours.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at time of necropsy
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: only males

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at time of necropsy
- Animals fasted: No data
- How many animals: only males

URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
Sacrifice and pathology:: GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:: Dunnett's or Scheffe's test for continuous data and Chi square test for quantal data
Dose descriptor:: NOAEL
Effect level:: < 60 mg/kg bw/day (nominal)
Sex:: male/female
Basis for effect level:: other: clinical signs: 8/12 of the male and in all female rats blepharoptosis was found
Critical effects observed:: not specified
Conclusions:: Body weight gain was decreased at more than 200 mg/kg/day in both sexes. In clinical signs, blepharoptosis and mydriasis were observed in all groups of both sexes, 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 in three males 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 mortality as well as clinical signs, a NOAEL of less than 60 mg/kg/day was set under the conditions of the study.

Endpoint conclusion

Endpoint conclusion:: adverse effect observed
Dose descriptor:: NOAEL
Study duration:: subchronic
Species:: rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Species:: rat

Additional information

There is only one report of a repeated oral toxicity study using rats. In an oral (via gavage) rat study according to the OECD combined repeated dose and reproductive/development toxicity screening test [OECD TG 422], organ weight and histopathological changes were observed (MHW, Japan, 1998). This MHW study was identified as the key study because it was well conducted and used a current protocol. Details of the study are as follows. The study was conducted at doses of 0, 60, 200, and 600 mg/kg/day. In males of the 600 mg/kg group, 1 and 2 rats died after 6 and 9 days, respectively. One female of the 60 mg/kg as well as one female of the 600 mg/kg group died after 16 and 3 days, respectively. In male rats and female rats (during the gestation period) at 200 mg/kg a tendency for low body weight gain during the administration period was observed and a statistically significant difference from controls was noticed. In both sexes at 600 mg/kg, a remarkable body weight decrease was observed. Blepharoptosis and mydriasis were observed in all dose groups of both sexes in a dose-related manner. 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. There were no evidence of alterations in haematology and biochemistry. Relative adrenal weights in the 600 mg/kg group of both sexes were increased, and relative liver weights in the 600 mg/kg group of females were increased. Only animals that died prematurely revealed histopathological findings. They consisted of reddish spots in the digestive tracts, abnormal foci with gastric ulcer and vacuolar degeneration in the renal tubular epithelium. On the basis of mortality as well as clinical signs, a NOAEL of less than 60 mg/kg/day was set under the conditions of the study.

Conclusion: On the basis of mortaliy and clinical signs observed also at the low-dose, a NOAEL of less than 60 mg/kg/day was set under the conditions of the study.

Justification for classification or non-classification

There is currently no need for classification based upon repeated oral exposure to 2,2,6,6 -tetramethylpiperidin-4 -ol, since none of the observed effects would lead to a hazard relevant for classification.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Dose level (mg/kg)	0	60	200	600
No. of animals	12	12	12	12 (N)
Days of experiment
1	385±12	385±11	385±11	385±12 (12)
8	403±17	399±23	395±13	368±41 (11)
15	422±21	419±23	409±20	402±21 (9)*
22	445±20	436±28	428±19	416±17 (9)**
29	473±20	463±29	448±19*	441±20 (9)**
36	493±21	484±32	463±23*	455±22 (9)**
43	503±18	494±29	474±24*	465±24 (9)**
49	482±19	475±32	450±26**	438±19 (9)**
Gain 1 - 43	118±14	109±22	89±20**	81±19 (9)**

Dose level (mg/kg)	0	60	200	600
Before mating period
No. of animals	12	12	12	12 (N)
Days of before mating
1	251±14	252±13	253±15	252±14 (12)
8	259±16	257±13	253±18	255±12 (11)
15	268±14	266±13	261±19	270±17 (11)
Gain 1- 15	17±8	14±9	8±8	17±14 (11)*

Dose level (mg/kg)	0	60	200	600
Gestation period
No. of animals	12	11	12	10
Day of gestation
0	281±15	276±22	274±18	280±19
7	310±16	310±18	301±22	301±22
14	350±17	349±15	339±23	336±19
21	458±20	457±22	432±30*	418±27**
Gain 0-21	176±12	181±11	158±18**	138±15**

Dose level (mg/kg)	0	60	200	600
Lactation period
No. of animals	12	11	12	10 (N)
Days of lactation
0	315±21	323±27	293±32	288±25
4	332±23	327±21	308±26	312±26 (9)
Gain 0-4	18±24	4±21	15±24	20±24 (9)

Dose level (mg/kg)		0	60	200	600
Before mating period
No. of animals		12	12	12	11
Days of before mating	1-8	21±1	22±1	21±2	21±1
	8-10	21±2	23±1	24±2	27±2**
Cumulative consumption	1-15	305±21	310±19	314±24	341±25**
Gestation period
No of dams		12	11	12	10
Day of gestation	0-7	27±2	28±1	28±2	29±4
	7-14	28±2	31±1	31±3	31±3*
	14-24	29±39	31±2	29±2	29±4
Cumulative consumption	0-21	539±12	626±23	614±41	627±57
Lactation period
No of dams		12	11	12	9
Day of lactation	0-4	35±10	32±8	33±8	35±10

Dose level (mg/kg)		0	60	200	600
No of animals		12	12 (N)	12	12 (N)
Days of experiment	1-8	28±2	29±4	28±2	24±7
	8-15	30±2	31±2	31±2	35±3 (9)**
	22-29	31±2	31±2 (11)	31±2	34±3 (9)**
	29-36	32±2	32±3	32±2	35±2 (9)**
	36-43	30±2	31±2	31±2	34±2 (9)**
	43-48	30±2	31±2	30±3	34±3 (9)**
Cumulative consumption	1-15	410±28	416±36	413±30	428±36 (9)
	22-48	798±38	810±56 (11)	811±49	889±51 (9)**

	Dose level (mg/kg)	Days experiment
mydriasis		1-7	8-14	15-21	22-28	29-35	36-42	43-49	Total
	0	0/12	0/12	0/12	0/12	0/12	0/12	0/12	0/12
	60	0/12	1/12	0/12	0/12	0/12	1/12	0/12	1/12
	200	4/12	4/12	0/12	0/12	0/12	8/12	2/12	9/12
	600	12/12	11/11	7/9	9/9	9/9	9/9	8/9	12/12

blepharoptosis	0	0/12	0/12	0/12	0/12	0/12	0/12	0/12	0/12
	60	3/12	2/12	1/12	1/12	0/12	6/12	0/12	8/12
	200	12/12	12/12	12/12	12/12	12/12	12/12	12/12	12/12
	600	12/12	10/11	9/9	9/9	9/9	9/9	9/9	12/12

dead	0	0	0	0	0	0	0	0	0
	60	0	0	0	0	0	0	0	0
	200	0	0	0	0	0	0	0	0
	600	1	2	0	0	0	0	0	3

	Dose level (mg/kg)	Days experiment
mydriasis		1-7	8-14	15-21	22-28	29-35	36-42	43-49	Total
	0	0/12	0/12	0/12	0/0	0/0	0/0	0/0	0
	60	0/12	1/12	0/12	0/0	0/0	0/0	0/0	1
	200	3/12	1/12	0/12	0/0	0/0	0/0	0/0	4
	600	12/12	11/11	10/11	2/1	1/1	1/1	1/1	12

blepharoptosis	0	0/12	0/12	0/12	0/0	0/0	0/0	0/0	0
	60	11/12	12/12	8/12	0/0	0/0	0/0	0/0	12
	200	12/12	12/12	12/12	0/0	0/0	0/0	0/0	12
	600	12/12	11/11	11/11	2/1	1/1	1/1	1/1	12

dead	0	0	0	0	0	0	0	0	0
	60	0	0	1	0	0	0	0	1
	200	0	0	0	0	0	0	0	0
	600	1	0	0	0	0	0	0	1

	male			female
Dose level (mg/kg/day)	0	200	600	0	200	600
Absolute weight
Liver (g, mean ± SD)	13.56±0.08	12.94±1.92	11.76±1.09**	14.45±1.82	14.56±1.07	15.43±2.43
Adrenals (mg, mean ± SD)	66±2	67±12	71±8	80±10	862±8	87±10
Relative weight
Liver (mg, mean ± SD)	2.815±0.086	2.867±0.315	2.682±0.206	4.341±0.396	4.741±0.270	4.927±0.535**
Adrenal (mg, mean ± SD)	13.688±1.934	14.865±2.922	16.250±1.836*	24.142±2.978	26.647±2.910	27.825±2.976**