Hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate

Endpoint summary

Description of key information

Oral (OECD 423), rat: LD50 cut-off 5000 mg/kg bw

Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw

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:

27 Jul - 18 Aug 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

adopted in 2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

adopted in 2008

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

adopted in 2002

GLP compliance:

yes (incl. QA statement)

Remarks:

Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Schwabach, Germany

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: WISTAR Crl: WI(Han)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 9 - 10 weeks
- Weight at study initiation: 173 - 180 g (step 1), 157 - 166 g (step 2)
- Fasting period before study: yes
- Housing: groups in IVC cages, type III H, polysulphone cages, Altromin saw fibre bedding
- Diet: Altromin 1324 maintenance diet for rats and mice, ad libitum
- Water: tap water, sulphur acidified to a pH value of approximately 2.8
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

other: polyethylene glycol 400

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.4 g/mL
- Amount of vehicle (if gavage): 5 mL/kg bw
- Justification for choice of vehicle: Several vehicles were evaluated and preparation and solubility tests were performed (corn oil, sterile water for injection, polyethylene glcol 400 (PEG 400) and 1% carboxymethylcellulose). Only the preparation with PEG 400 yielded a suspension which was considered to be applicable to animals.
- Lot/batch no.: S7106885 (Merck)

MAXIMUM DOSE VOLUME APPLIED: 5 mL/kg bw

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed several times oin the day of dosing and daily thereafter; individual body weights were examined on day 1 (prior to the administration) and on days 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, morbidity, mortality, body weight

Sex:

female

Dose descriptor:

LD50

Effect level:

5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured during the study period.

Clinical signs:

No clinical signs of toxicity were observed up to the end of the 14-day observation period.

Body weight:

Body weight gains were within the normal ranges in females during the whole study period.

Gross pathology:

Necropsy examination revealed no substance-related findings.

Interpretation of results:

other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008

Conclusions:

CLP: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

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:

19 Jul 03 Aug 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted in 1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

adopted in 2008

GLP compliance:

yes (incl. QA statement)

Remarks:

Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Schwabach, Germany

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: WISTAR Crl: WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 7 - 8 weeks (males), 8 - 9 weeks (females)
- Weight at study initiation: 220 - 255 g (males), 211 - 220 g (females)
- Fasting period before study: no
- Housing: individual in IVC cages, Type III H, polysulphone cages on Altromin saw fibre bedding
- Diet: Altromin 1324 maintenance diet for rats and mice, ad libitum
- Water: tap water, sulphur acidified to a pH value of 2.8, ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal area of the trunk
- % coverage: approximately 10%
- Type of wrap if used: The test material was held in contact with the skin with a gauze-dressing and non-irritating tape. An additional dressing was used for fixation in a suitable manner.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test material was removed with aqua ad iniectabilia.
- Time after start of exposure: 24 h

TEST MATERIAL
The test material was used as delivered.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw/day

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed several times on the day of dosing and once daily thereafter; individual body weights were examined on day 1 (prior to the application) and on days 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured during the study period.

Clinical signs:

No clinical signs of toxicity were observed up to the end of the 14-day observation period.

Body weight:

Body weight gains were within the normal ranges in females during the whole study period.

Gross pathology:

Necropsy examination revealed no substance-related findings. Small testes and epididymides was observed in 1/5 male. This was an incidental finding and not considered to be test substance-related.

Other findings:

Erythema grade 1 was observed in 4/5 female animals and desquamation was observed in 1/5 female animals on study day 2. All signs of irritation were were reversible within 3 study days.

Interpretation of results:

other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008

Conclusions:

CLP: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Reliable studies regarding acute oral and dermal toxicity are available for the test substance.

Oral:     

The acute oral toxicity of the test substance was assessed in a study performed according to OECD Guideline 423 and in compliance with GLP (Holalagoudar, 2016). Two groups of three female WISTAR Crl: WI(Han) rats were treated with the test material at a dose level of 2000 mg/kg bw. The test material was administered in a single application by gavage formulated in polyethylene glycol 400 at a concentration of 0.4 g/mL and a dose volume of 5 mL/kg bw. The animals were observed for 14 days and body weights were measured. All animals were subjected to a necropsy and a macroscopic examination. No mortality was observed and treatment with the test substance did not cause any clinical signs during the observation period. Body weight and body weight gain of treated animals showed no indication of a treatment-related effect. There was no evidence of macroscopic observations at a dose level of 2000 mg/kg bw. Thus, under the conditions of this study, the acute oral LD50 value of the test substance was found to be > 2000 mg/kg bw in female Crl: WI(Han) rats. According to OECD Guideline 423 a LD50 cut-off value of 5000 mg/kg bw/day is specified since no animal died.

Dermal:

The acute dermal toxicity of the test substance was assessed in a study performed according to OECD Guideline 402 and in compliance with GLP (Holalagoudar, 2016). Five male and five female WISTAR Crl: WI(Han) rats were treated with the test substance by a single semi-occlusive dermal application at 2000 mg/kg bw. The animals were observed for 14 days and body weights were measured. All animals were subjected to a necropsy and a macroscopic examination. No mortality occurred and no clinical signs were observed. Signs of slight local irritation (erythema grade 1 in 4/5 females and desquamation in 1/5 female) were reversible within 3 days. There were no treatment related effects on body weight or body weight gain. There was no evidence of any observations at a dose level of 2000 mg/kg bw at necropsy. Thus, under the conditions of this study, the acute dermal LD50 value of the test substance was found to be > 2000 mg/kg bw in male and female Crl: WI(Han) rats.

Justification for classification or non-classification

The available data on acute oral and dermal toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.