p-phenylene diisocyanate

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11 Jun 2018 to 09 Jul 2018.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

OECD Guideline 402. Acute Dermal Toxicity, 2017.

Deviations:

yes

Remarks:

See "Any other information" for details

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

p-phenylene diisocyanate

EC Number:

203-207-6

EC Name:

p-phenylene diisocyanate

Cas Number:

104-49-4

Molecular formula:

C8H4N2O2

IUPAC Name:

1,4-diisocyanatobenzene

Test material form:

solid: flakes

Details on test material:

Identification: Paraphenylene diisocyanate (PPDI)
Appearance: White Chips
Batch: 20171126004
CAS number: 104-49-4
Test item storage: At room temperature
Stable under storage conditions until: 25 November 2018 (expiry date)

Additional information
Test Facility test item number: 209403/A
Purity/Composition correction factor: No correction factor required
Test item handling: No specific handling conditions required
Molecular structure:
Molecular formula: C8H4N2O2
Molecular weight: 160.0
Irritant or corrosive: Yes
Volatile: Not indicated
Solubility in water: Not available
Stability in water: Not stable

Specific details on test material used for the study:

No further details specified in the study report.

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Species: Rat
Strain: Crl: WI(Han)
Condition: Outbred, SPF-Quality
Source: Charles River Deutschland, Sulzfeld, Germany
Number of Animals: 3 females (nulliparous and non-pregnant).
Age at the Initiation of Dosing: Young adult animals (approximately 11 weeks old) were selected.
Weight at the Initiation of Dosing: 183 to 194 g.

Justification for Test System and Number of Animals
The Wistar Han rat was chosen as the animal model for this study as recognized by international guidelines as a recommended test system. The test method and number of animals were based on the test guidelines.
The study plan was reviewed and agreed by the Animal Welfare Body of Charles River Laboratories Den Bosch B.V. within the framework of Appendix 1 of project license AVD2360020172866 approved by the Central Authority for Scientific Procedures on Animals (CCD) as required by the Dutch Act on Animal Experimentation (December 2014).

Animal Identification
At study assignment, each animal was identified using a tail mark with indelible ink.

Environmental Acclimation
The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.

Selection, Assignment, Replacement, and Disposition of Animals
Animals were assigned to the study at the discretion of the coordinating biotechnician according to body weights, with all animals within ± 20% of the sex mean. Animals in poor health or at extremes of body weight range were not assigned to the study.
Before the initiation of dosing, a health inspection was performed and any assigned animal considered unsuitable for use in the study were replaced by alternate animals obtained from the same shipment and maintained under the same environmental conditions.
The disposition of all animals was documented in the study records.

Husbandry
Housing
On arrival, animals were group housed (up to 5 animals of the same sex together) in polycarbonate cages (Makrolon MIV type; height 18 cm.) and following assignment to the study, animals were individually housed in polycarbonate cages (Makrolon MIII type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles.
The room in which the animals were kept was documented in the study records.
Animals were separated during designated procedures/activities. Each cage was clearly labeled.

Environmental Conditions
Target temperatures of 18 to 24°C with a relative target humidity of 40 to 70% were maintained. The actual daily mean temperature during the study period was 21 to 22°C with an actual daily mean relative humidity of 32 to 70%. A 12-hour light/12-hour dark cycle was maintained. Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.

Food
Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures.
The feed was analyzed by the supplier for nutritional components and environmental contaminants. Results of the analysis were provided by the supplier and are on file at the Test Facility.
It is considered that there were no known contaminants in the feed that would interfere with the objectives of the study.

Water
Municipal tap-water was freely available to each animal via water bottles.
Periodic analysis of the water was performed, and results of these analyses are on file at the Test Facility.
It is considered that there were no known contaminants in the water that would interfere with the objectives of the study.

Animal Enrichment
For psychological/environmental enrichment, animals were provided with paper (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom), except when interrupted by study procedures/activities.

Veterinary Care
Veterinary care was available throughout the course of the study; however, no examinations or treatments were required.

Administration / exposure

Type of coverage:

occlusive

Vehicle:

peanut oil

Details on dermal exposure:

A single dose of test item was administered to the appropriate animals by dermal application on Day 1. One day before dosing, an area of approximately 5x7 cm on the back of the animals was clipped. The test item was applied in an area of approximately 10% of the total body surface, i.e. approximately 18 cm² for females. The test item was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D), successively covered with Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only. The application period was 24 hours, after which the dressing was removed and the skin cleaned of residual test item using water.
The dose volume for each animal was based on the body weight measurement prior to dosing.
A dose volume of 10 mL/kg body weight will be used for each dose.
The dosing formulations were stirred continuously during dose administration.

Duration of exposure:

24 hours

Doses:

Single dose 2000 mg/kg

No. of animals per sex per dose:

Rnage finding study: 1 animal
Main study: 2 animals

Control animals:

not required

Details on study design:

In-life Procedures, Observations, and Measurements
Mortality/Moribundity Checks
Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings.

Clinical Observations
Postdose Observations
Postdose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter. The observation period was 14 days.
All the animals were examined for reaction to dosing. The onset, intensity and duration of these signs was recorded (if appropriate), particular attention being paid to the animals during and for the first hour after dosing.

Body Weights
Animals were weighed individually on Day 1 (predose), 8 and 15.

Irritation
The skin reactions were assessed approximately 24, 48 and 72 hours after the removal of the dressing and test item. Adjacent areas of untreated skin of each animal served as controls.

Terminal Procedures
All animals were sacrificed by oxygen/carbon dioxide procedure at the end of the observation period. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities were recorded.

Statistics:

All results presented in the tables of the report are calculated using values as per the raw data rounding procedure and may not be exactly reproduced from the individual data presented.
The dermal LD50 value of the test item was ranked within the following ranges: 0-50, 50-200, 200-1000 or 1000-2000 mg/kg b.w. or as exceeding 2000 mg/kg b.w.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture, shallow respiration, piloerection and/or chromodacryorrhoea of the snout were noted for the animals between Days 1 and 4.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Other findings:

Irritation
Very slight to well-defined erythema, fissures, scales, scabs and white discoloration were noted for the treated skin area of the animals between Days 2 and 15.

Any other information on results incl. tables

MORTALITY DATA

TEST DAY	1	1	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15
HOURS AFTER TREATMENT	0	2	4
FEMALES 2000 MG/KG FEMALES 2000 MG/KG	- -	- -	- -	- -	- -	- -	- -	- -	- -	- -	- -	- -	- -	- -	- -	- -	- -

 

CLINICAL SIGNS

TEST DAY		1	1	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15
HOURS AFTER TREATMENT	MAX GRADE	0	2	4
FEMALES 2000 MG/KG
ANIMAL 1 Skin / fur            General erythema (Treated skin)            Fissures (Treated skin)            Scales (Treated skin) Secretion / excretion            Chromodacryorrhoea (Snout)	(4) (3) (3)   (3)	- - -   -	- - -   1	- - -   -	- - -   -	1 - 1   -	1 - 1   -	1 1 1   -	1 1 1   -	1 1 1   -	1 - 2   -	1 - 1   -	1 - 1   -	1 - 1   -	1 - 1   -	. . .   .	. . .   .	- - 1   -
FEMALES 2000 MG/KG
ANIMAL 2 Posture            Hunched posture Breathing            Shallow respiration Skin / fur            General erythema (Treated skin)            Piloerection            Scales (Treated skin)            Scabs (Treated skin) Various            White (Treated skin)	(1)   (3)   (4) (1) (3) (3)   (1)	-   -   - - - -   -	-   -   - - - -   -	-   -   - - - -   -	1   1   2 1 1 -   1	1   -   2 - 1 -   1	1   -   2 - 1 -   1	-   -   2 - 1 -   1	-   -   2 - 1 -   1	-   -   1 - 1 1   -	-   -   1 - 1 1   -	-   -   1 - 1 1   -	-   -   - - - 1   -	-   -   - - - 1   -	-   -   - - - -   -	-   -   - - - -   -	-   -   - - - -   -	-   -   - - - -   -
ANIMAL 3 Posture            Hunched posture Breathing            Shallow respiration Skin / fur            General erythema (Treated skin)            Piloerection            Scales (Treated skin) Secretion / excretion            Chromodacryorrhoea (Snout) Various            White (Treated skin)	(1)   (3)   (4) (1) (3)   (3)   (1)	-   -   - - -   1   -	-   -   - - -   1   -	-   -   - - -   1   -	1   1   2 1 -   -   1	-   -   1 - -   -   1	-   -   1 - 1   -   1	-   -   1 - 1   -   1	-   -   1 - 1   -   1	-   -   - - 1   -   -	-   -   - - 1   -   -	-   -   - - 1   -   -	-   -   - - 1   -   -	-   -   - - -   -   -	-   -   - - -   -   -	-   -   - - -   -   -	-   -   - - -   -   -	-   -   - - -   -   -

- = Sign not observed

. = No observation recorded

 

BODY WEIGHTS (GRAM)

SEX/DOSE LEVEL	ANIMAL	DAY 1	DAY 8	DAY 15
FEMALES 2000 MG/KG
	1   MEAN ST. DEV. N	194   194 --- 1	203   203 --- 1	212   212 --- 1
FEMALE 2000 MG/KG
	2 3   MEAN ST. DEV. N	183 188   186 4 2	199 195   197 3 2	210 207   209 2 2

 

MACROSCOPIC FINDINGS

ANIMAL	ORGAN	FINDING	DAY OF DEATH
FEMALES 2000 MG/KG
1		No findings noted	Scheduled necropsy Day 15 after treatment
FEMALES 2000 MG/KG
2 3		No findings noted No findings noted	Scheduled necropsy Day 15 after treatment Scheduled necropsy Day 15 after treatment

 

IRRITATION

SEX/DOSE LEVEL	ANIMAL	24 HOURS		48 HOURS		72 HOURS
		Erythema	Oedema	Erythema	Oedema	Erythema	Oedema
FEMALES 2000 MG/KG
	1	1	0	1	0	1	0
FEMALES 2000 MG/KG
	2 3	2 1	0 0	2 1	0 0	2 1	0 0

 

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 value of PPDI in Wistar rats was established to exceed 2000 mg/kg body weight.
Based on these results, PPDI does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Executive summary:

The objective of this study was to determine the potential toxicity of Paraphenylene diisocyanate (PPDI), when given by a single dermal dose.

The study was carried out based on the guidelines described in:

-OECD No. 402 (2017) "Acute Dermal Toxicity"

Initially, PPDI was administered to a single female Wistar rat by a single dermal application at 2000 mg/kg body weight for 24 hours in a range finder study. Based on the results, the main study was performed by dosing two females at 2000 mg/kg. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

 

RESULTS

No mortality occurred.

Very slight to well-defined erythema, fissures, scales, scabs and white discoloration were noted for the treated skin area of the animals between Days 2 and 15.

Hunched posture, shallow respiration, piloerection and/or chromodacryorrhoea of the snout were noted for the animals between Days 1 and 4.

The body weight gain shown by the surviving animals during the observation period was within the range expected for rats used in this type of study.

No abnormalities were found at macroscopic post mortem examination of the animals.

 

CONCLUSION

The dermal LD50 value of PPDI in Wistar rats was established to exceed 2000 mg/kg body weight.

Based on these results, PPDI does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).