Registration Dossier

Administrative data

Description of key information

Acute toxicity after single oral application was tested in male and female rats, which received doses up to 1590 mg/kg bw. The observed mortality was as follows: 
1000 mg/kg bw: no male and 3 females died
1260 mg/kg bw: 3 males and 1 female died
1590 mg/kg bw: 4 males and 4 females died
Abnormal clinical signs in the treated animals appeared 1 hour after administration of the test item. Lethargy, prostratio, subdued behaviour and tremors were observed until 4 hours after treatment. The necropsy did not reveal any effect. The LD50 value for acute oral toxicity was calculated to be 1253 mg/kg bw. Based on the result of this study N,N’-Bis(2,2,6,6-tetramethyl-4-piperidinyl)isophthalamide has to be labelled as harmful (H 302) according to regulatory requirements.
N,N’-Bis(2,2,6,6-tetramethyl-4-piperidinyl)isophthalamide was tested for its dermal toxicity properties. Single dermal application of the test item to rats at a dose of 2000 mg/kg body weight was associated with no mortality and neither signs of toxicity nor signs of irritation. The dermal LD50 was determined to be > 2000 mg / kg body weight.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline conform GLP study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Rat Ico : OFA.SD. (IOPS Caw)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IFFA-CREDO, L'Arbresle Cedex - France
- Age at study initiation: 5 to 7 weeks
- Weight at study initiation: 130-220 g (males), 120-190 g (females)
- Fasting period before study: overnight (15-20 h before dosing)
- Housing: in groups of up to 5 of the same sex and dose group in polycarbonate cages type FI for preliminary study and type MI for the main study
- Diet (e.g. ad libitum):pelleted complete diet (Diet reference A04 C10, Usine d#Alimentation Rationelle, Villemoisson, Epinay, France), ad libitum
- Water (e.g. ad libitum): softened and filtered drinking water, ad libitum
- Acclimation period: 5 days minimum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air changes (per hr): 8
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
other: 1 % aqueous dispersion of carboxymethylcellulose
Details on oral exposure:
VEHICLE
- Concentration in vehicle:
2.5%, 5.0% and 10% (w/v) - preliminary study; 5.00%, 6.30% and 7.95% (w/v) - main study
- Amount of vehicle (if gavage): 20 mL/kg
- Lot/batch no. (if required): house preparations 22. Aug 1995 and 12. Sept. 1995



Doses:
- Preliminary study:
500, 1000 and 2000 mg/kg bw
- Main study:
0, 1000, 1260 and 1590 mg/kg bw
No. of animals per sex per dose:
- Preliminary study:
2
- Main study:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration:
14 days
- Frequency of observations and weighing:
Examinations for mortality and abnormal clinical signs were performed 15 min after intubation, then 1, 2 and 4 hours, and then daily for the 14 day study period. All the animals were weighed on the day before treatment, immediately before administration of the test item, on days 8 and 15, as well as at time of death from day 2 onwards
- Necropsy of survivors performed:
yes
Statistics:
LD50 calculation:
- Bliss' method
- Litchfield & Wilcoxon' s method
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 253 mg/kg bw
95% CL:
1 054 - 1 490
Mortality:
Main study:
Male: 1000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 1260 mg/kg bw; Number of animals: 5; Number of deaths: 3
Male: 1590 mg/kg bw; Number of animals: 5; Number of deaths: 4
Female: 1000 mg/kg bw; Number of animals: 5; Number of deaths: 3
Female: 1260 mg/kg bw; Number of animals: 5; Number of deaths: 1
Female: 1590 mg/kg bw; Number of animals: 5; Number of deaths: 4
Clinical signs:
- Mortality
Mortality occurred from 1 hour to 4 hours after treatment in all groups.

- Clinical signs
Abnormal clinical signs in the treated animals appeared 1 hour after administration of the test item. Lethargy, prostratio, subdued behaviour and tremors were observed until 4 hours after treatment.


- Necropsy:
There were no macroscopic findings that could bee associated with treatment in animals which died during the observation period or killed at the end of the study.
Body weight:
- Body weights
The body weight changes in group 2 males (1000 mg/kg bw) and group 3 females (1260 mg/kg bw) were similar to those of the controls throughout the observation period. The mortality rate noted in group 2 females, group 3 males and both sexes of group 4 (1590 mg/k g bw) did not allow analysis of their body weight gain.
Gross pathology:
- Necropsy:
There were no macroscopic findings that could bee associated with treatment in animals which died during the observation period or killed at the end of the study.
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
From the results obtained under the experimental conditions of this OECD 401 study the LD50 was derived at 1253 mg/kg bw.
Executive summary:

The test item was tested for its acute oral toxicity potential. 5male and 5 female rats were treated with doses of 0, 1000, 1260 or 1590 mg/kg bw and observed for 14 days.

The median lethal dose of test item (LD50) was 1253 mg per kg body weight. Based on the result of this study the test substance has to be labelled as harmful (H 302) according to regulatory requirements.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 253 mg/kg bw
Quality of whole database:
reliable without restrictions

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline conform GLP study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Rat Ico : OFA.SD. (IOPS Caw.)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IFFA-CREDO (L'Arbresle Cedex, France)
- Age at study initiation: 7 - 9 weeks
- Weight at study initiation: 200 - 300 g
- Fasting period before study: no
- Housing: individually in polycarbonate cages type FI
- Diet (e.g. ad libitum): pelleted complete diet (Diet reference A04 C10, Usine d'Alimentation Rationelle, Epinay s/Orge, France), ad libitum
- Water (e.g. ad libitum): softened and filtered mains drinking water, ad libitum
- Acclimation period: 5 days minimum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air changes (per hr): 8
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
- Preparation of the animals:
The day before the acclimatisation of the test article, the back and the flanks of each animal were carefully clipped, to expose an area of skin which was not less than 10'% of the total body surface area. At the time of aplication, only those animals showing perfectly healthy skin and with no sign of macroscopic irritation, were kept for the test.

- Method of administration:
The powder was prepared as a paste, moistened with water for injection. The test item was held in contact with the skin by a semi-occlusive bandage. This bandage covered fully the treated area, in order to prevent ingestion of the test item. At the end of the 24 hour period, the binders were removed and the skin wiped clean of residual test article using water.
Duration of exposure:
24 h
Doses:
Preliminary study:
1000 or 2000 mg/kg bw
Main study:
2000 mg/kg bw
No. of animals per sex per dose:
Preliminary study:
2
Main study:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration:
14 days
- Frequency of observations and weighing:
Examinations for mortality and abnormal clinical signs were performed 15 min after application, then at 1, 2 and 4 hours and then daily for the 14 day study period. All animals were weighed immediately before application of the test item (day 1), on days 8 and 15, as well as at time of death from day 2 onwards.
- Necropsy of survivors performed:
yes
- Other examinations performed:
cutaneous examinations were performed from day 2 to 15.
Statistics:
- Body weight: analysis of variance and Student's t test
- Mortality: calculated as percentage to determine the innocuity or degree of toxicity
- LD50: expressed in mg/kg bw with a 95% confidence limit interval evaluated according to Bliss and Litchfield & Wilcoxon's methods
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
Main study
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 1
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
- Mortality:
One male was found dead on day 2

-Clinical signs:
There were no abnormal clinical signs in any of the treated animals during the observation
Body weight:
Body weight changes in the treated animals were not influenced by treatment.
Gross pathology:
There were no macrosocpic findings that could be associated with the treatment.
Other findings:
The local tolerance of the test item was good: no cutaneous lesions (erythema or oedema) was noted to the application site of the test item during the observation period.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
From the results obtained under the conditions of this OECD 402 dermal toxcity study the LD50 greater than 2000 mg/kg bw.
Executive summary:

Under the conditions of the present study, single dermal application of the test item to rats at a dose of 2000 mg/kg body weight was associated with no mortality and neither signs of toxicity nor signs of irritation. The dermal LD50 was determined to be > 2000 mg / kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
reliable without restrictions

Additional information

Based on the results of the oral and dermal toxicity studies the LD50(oral) value for acute oral toxicity was considered to be 1253 mg/kg bw and the LD50(dermal) was found to be greater than 2000 mg/kg bw.
In accordance with REACH “Column 2” in Annex VIII there is sufficient weight of evidence from several independent sources of information leading to the conclusion that N,N’-Bis(2,2,6,6-tetramethyl-4-piperidinyl)isophthalamide does not exert systemic toxic effects after acute inhalation exposure and thus does not have to be classified, because
- N,N’-Bis(2,2,6,6-tetramethyl-4-piperidinyl)isophthalamide does not have to be classified as skin irritating,
- exposure via inhalation to workers and consumers can be excluded, since the substance is handled as granules, with no inhalable particles occurring and
-occupational health surveillance did not report any reverse effect.
Therefore, it is concluded that testing of acute inhalation toxicity of N,N’-Bis(2,2,6,6-tetramethyl-4-piperidinyl)isophthalamide is not scientifically necessary.


Justification for selection of acute toxicity – oral endpoint
Guideline conform GLP study

Justification for selection of acute toxicity – inhalation endpoint
n.a.

Justification for selection of acute toxicity – dermal endpoint
Guideline conform GLP study

Justification for classification or non-classification

Due to the findings described in the acute oral and dermal toxicity studies (LD50(oral) in rats: 1253 mg/kg bw; LD50(dermal) in rats: > 2000 mg/kg bw) N,N’-Bis(2,2,6,6-tetramethyl-4-piperidinyl)isophthalamide has to be classified as harmful if swallowed (H 302). Based on the substance's physico-chemical and non-irritant properties, as well as the exclusion of exposure no higher systemic exposure via inhalation is expected to occur than that tested in the course of the oral and dermal toxicity studies.