Registration Dossier

Administrative data

Description of key information

skin irritation (OECD 404): not classified at a concentration of 58%; inconclusive for anhydrous TMT
eye irritation (OECD 405): highly irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
occlusive application
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: males: 45 and 46 months; female: 46 months
- Weight at study initiation: males: 2.41 and 2.97 kg; female: 3.07 kg
- Housing: 1 animal/cage in stainless steel cages with grating floor
- Diet: approx. 120 g/animal/day, Standard diet, ssniff K-Z, complete diet for rabbits - breeding (ssniff Spezialdiäten GmbH, Soest, Germany)
- Water: tap water, ad libitum
- Acclimation period: 1 day

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.0-20.0
- Humidity (%): 48 - 92
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 11 Nov 1997 To: 02 Dec 1997
Type of coverage:
occlusive
Preparation of test site:
other: clipped
Vehicle:
water
Controls:
other: control site on the same animal
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 g

VEHICLE
- Amount(s) applied: 0.2 mL

Duration of treatment / exposure:
4 hours
Observation period:
Duration of the observation period: 3 or 14 days after application
Reading time points: 1, 24, 48, 72 hours after removal of the patches, thereafter once daily
Number of animals:
Total number of animals: 3
2 males and 1 female
Details on study design:
TEST SITE
- Area of exposure: 6.25 cm²
- Type of wrap if used: 1. cellulose fabric coated with natural rubber 2. synthetic film glue

REMOVAL OF TEST SUBSTANCE
- Washing: After the end of exposition time remaining test substance was gently washed off as far as possible
- Time after start of exposure: 4 hours


SCORING SYSTEM:
Draize Scoring Index

Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 hours
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 hours
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 9 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritant / corrosive response data:
One animal showed very slight erythema (grade 1) one hour after patch removal until day 1 and very slight edema (grade 1), which subsided within 24 hours.
In the second animal erythema was well defined or moderate to severe (grade 2-3) and was still present (grade 1) at the end of the 14-day observation period. In this animal also slight or moderate edema (grade 2-3) was noted until day 2 and thereafter the edema was very slight (grade 1) until day 8. In addition, in the same animal indentation up to 1 mm and brown discolouration of the application site were found until day 5 after removal of the patch. Eschar was formed from day 1 until day 5, started to peel off on day 6 and was no longer detected on day 11 of observation.
Neither erythema nor edema formation was noted in the third animal after patch removal and up to 3 days after application.
Other effects:
There were no systemic toxic effects after dermal application of the test substance.
Interpretation of results:
other: not classified for hydrated form TMT 55; inconclusive for anhydrous TMT
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
Under the conditions of this skin irritation study in the rabbit the test item TMT 55 was slightly irritating to the skin. However, the data is conclusive but not sufficient for classification of TMT 55. For anhydrous TMT, the available data on skin irritation/corrosion is inconlusive for classification.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
EEC Guideline 92/69/EEC
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Age at study initiation: 33 - 39 months
- Weight at study initiation: females 2.69 - 2.74 kg
- Housing: 1 animal/cage
- Diet: approx. 120 g/animal/day, Standard diet, ssniff K-Z, complete diet for rabbits - breeding (ssniff Spezialdiäten GmbH, Soest, Germany)
- Water: tap water, ad libitum
- Acclimation period: at least 1 day

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.0 - 19.5
- Humidity (%): 54 - 87
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From 02 June 1998 To 23 June 1998
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye of the same animal served as control
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 68.6 mg, 75.7 mg, 84.3 mg (representing a volume of ca. 0.1 mL)

Duration of treatment / exposure:
single application without washing
Observation period (in vivo):
6, 10 or 21 days after application
Reading time points: 1, 24, 48 and 72 hours after application, thereafter once daily
Number of animals or in vitro replicates:
3 females
Details on study design:
SCORING SYSTEM: Draize scoring system

Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility not applicable
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
2
Reversibility:
other: reversibility not applicable
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 5 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
1.67
Max. score:
3
Reversibility:
fully reversible within: 6 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 10 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 5 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
2.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
The cornea of one animal showed easily discernible translucent areas of opacity (grade 2) in more than three quarters of the cornea. Details of iris were slightly obscured. In a second rabbit only scattered diffuse opacity was recorded in more than three quarters of the cornea. The iris was clearly visible. The findings in these two animals were reversible within 7 days after instillation of the test item. The third rabbit did not show any corneal lesions.
Changes of the iris, namely moderate circumcorneal hyperemia (grade 1) were found in two animals between 1 and 4 days after treatment.
The conjunctiva reacted with reddening and swelling in all three rabbits. Diffuse crimson discolouration (grade 2) to beefy redness (grade 3) was present 1 hour after treatment. One animal recovered within 6 days, while slight redness (grade 1) remained in a second animal for the total observation period of 21 days and in a third animal for 9 days. Swelling also developed within 1 hour in all rabbits. In two animals grade 3 with eyes about half closed was the maximum severity. The finding disappeared within 7 days in one animal and was still present in a second animal after 21 days while a third animal showed only slight swelling (grade 1) until day 4 after treatment.
Additional lesions were slight to considerable discharge moistening lids and hairs around the eye, white mucous in the eye and light brown discolouration of the rim of the lower lid.
The irritation index derived in the original study report is 29, corresponding to moderately irritant in this test system. Although one animal had not recovered completely within the 21-day observation period, the findings clearly showed a tendency to recovery. In the other two animals all changes were reversible within 5 to 9 days of the observation period.
Other effects:
There were no systemic effects after conjunctival application of the test substance.
Interpretation of results:
Category 2A (irritating to eyes) based on GHS criteria
Remarks:
Migrated information: for hydrated form TMT 55
Conclusions:
Under the conditions of this eye irritation study in the rabbit the test item TMT 55 caused strong irritation to the eye.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin

Skin irritation by TMT 55 (analytical purity: 58%) was examined in a GLP study according to OECD Guideline 404 (97-0068-DGT). 0.5 g of the test substance moistened in 0.2 mL water was applied to the clipped skin of 3 White russian rabbits (2 males and 1 female) under occlusive conditions for 4 hours. The skin reaction was examined 1, 24, 48 and 72 h after removal of patches and once daily thereafter up to 14 days after application. A very slight erythema (grade 1) and edema (grade 1) was observed in one animal 1 h after patch removal. Reversibility occurred within 48 h for erythema and within 24 h for edema, respectively. Slight or moderate edema (grade 2 or 3) was noted in a second animal during the first 5 days and remained as very slight edema (grade 1) up to the end of the study. This animal also showed slight to moderate edema (grade 2 or 3) until day 2 and thereafter the edema was very slight (grade 1) until day 8. In addition, indentation up to 1 mm and brown discolouration of the application site were noted in the same animal until day 5 after patch removal as well as eschar from day 1 until day 11 of observation. The third animal did not show any skin reactions at all. The individual mean scores over 24, 48 and 72 h were 0.33, 2.67 and 0 for erythema and 0, 1.67 and 0 for edema, respectively. No systemic toxicological reactions were noted.

 

In an acute dermal toxicity study according to OECD guideline 402 TMT 55 in a concentration of 2000 mg/kg bw was applied under occlusive conditions for 24 hours to the clipped skin of 5 male and 5 female rats (93-0163-FGT). Skin reactions were observed and consisted of perceptible signs of irritation (slight erythema) to signs of strong irritation (severe erythema with slight edema) with irreversible skin damage (scaring). At the end of the 14-day observation period, scars were present at the application site for all females and one male rat.

In the pilot study of a sensitisation assay (GPMT) TMT 55 at concentrations up to 75% in water was applied topically for 24 h to guinea pig skin. The patches with the test concentrations were secured to each animal using an elastic wrap. No signs of irritation (erythema and/or edema) were evident 24 h after patch removal.

 

In conclusion, there was evident variability of responses among rabbits, rats and guinea pigs after application of TMT 55 to skin. The responses ranged from no reaction to irreversible skin damage among the animals.

Since, in the acute dermal toxicity study with rats the 24 h exposure duration and occlusive patch can be considered as very severe test conditions, the results of the in vivo skin irritation/corrosion study in rabbits were used as key information. The in vivo test in rabbits according to OECD Guideline 404 is the standard test for the hazard assessment and classification required under the REACH Annex VIII provisions (10 tons per year and more). Moreover, rabbit skin is more sensitive than rat skin and guinea pig skin. Thus, under the conditions of this skin irritation study in the rabbit, TMT 55 (analytical purity: 58%) does not meet the classification criteria for irritation/corrosion.

Skin irritation by TMT 15 was examined in two tests performed according or similar to OECD guideline 404. No irritant response or abnormal clinical signs were noted during a 72 h observation period in any of 3 Hra:(NZW) SPF rabbits after occlusive application of 0.5 mL of the test item for 4 h (93-0161-FGT). In the second study TMT 15 was applied under occlusive conditions in a single dose of 0.5 mL to the intact and abraded skin of 3 male Himalayan rabbits for 4 h (81-0017-DKT). In two animals erythema and edema reactions of grade 1 or 2 were noted at the intact sites starting at one hour after patch removal. Reversibility occurred within 7 days and 72 h for erythema and edema, respectively. The resulting mean scores for erythema and edema (intact sites) out of all 3 animals over 24, 48 and 72 h were 1 and 0.6, respectively. The abraded sites showed even moderate or severe edema and erythema in all three animals. However, the reactions on abraded sites were not taken into account for assessment.

In conclusion, under the conditions of this skin irritation studies in rabbits no or slightly irritating effects were determined for TMT 15.

 

Eye

Eye irritation by TMT 55 (analytical purity: 58%) was examined in a GLP study according to OECD guideline 405 (98-0039-DGT). A single dose of 75.7, 84.3 and 68.6 mg, representing a volume of 0.1 mL was instilled into the right eyes of three female White Russian rabbits. The untreated left eye of each animal served as control. The treated eyes were not rinsed. The resulting ocular reactions to the test item were evaluated until day 21 after treatment.

The cornea of one animal showed easily discernible translucent areas of opacity (grade 2) in more than three quarters of the cornea. Details of iris were slightly obscured. In a second rabbit only scattered diffuse opacity was recorded in more than three quarters of the cornea. The iris was clearly visible. The findings in these two animals were reversible within 7 days after instillation of the test item. The third rabbit did not show any corneal lesions. The mean scores over 24, 48 and 72 h for corneal changes for each of the three animals were 1.67, 1 and 0, respectively.

Changes of the iris, namely moderate circumcorneal hyperemia (grade 1) were found in two animals. These iris findings were present between day 1 and 4 after treatment.

At the conjunctivae level diffuse crimson and discolouration (grade 2) to beefy redness (grade 3) was noted 1 h after treatment.The conjunctival redness was totally reversible in two animals on day 6 and 10, respectively and remained on day 21 (last day of the test) in the third animal (slight redness, grade 1). The mean scores for conjunctival redness over 24, 48 and 72 h for each of the rabbits were 3, 1.67 and 3, respectively.

Swelling also developed within 1 h after treatment. As maximum severity swelling with lids about half closed (grade 3) were recorded within the first 72 h in two animals. In one animal slight swelling was still present after 21 days, whereas the chemosis findings had disappeared within 5 and 7 days in the other two animals, respectively.

Additional lesions were slight to considerable discharge moistening lids and hairs around the eye, white mucous in the eye and light brown discolouration of the rim of the lower lid.

In conclusion, TMT 55 (analytical purity: 58%) caused serious effects on the eye, however a clear tendency to recovery has been observed, and is therefore considered as highly irritant. This result is transferred to anhydrous TMT.


Justification for selection of skin irritation / corrosion endpoint:
The selected in vivo test in rabbits according to OECD Guideline 404 is the standard test for the hazard assessment and classification required under the REACH Annex VIII provisions (10 tons per year and more)

Justification for selection of eye irritation endpoint:
There is only one study available.

Effects on eye irritation: highly irritating

Justification for classification or non-classification

Skin

In 1 out of 3 animals the occlusive application of TMT 55 (analytical purity: 58%) for 4 hours resulted in slight to moderate edema and eryhema (grade 2 and 3) after patch removal (97-0068-DGT). This single animal showed a more distinct skin reaction than the remaining two animals. In the course of the study in the respective animal the grading for erythema and eschar declined from grade 3 to grade 1 and complete recovery from edema was observed on day 9. Thus, taking into account the complete recovery from edema and the clear tendency for recovery with regard to erythema and eschar, the more rigorous test conditions by using occlusive patche as well as the immoderate sensitivity in only one animal compared to remaining animals showing only very slight or even no skin effects, TMT at a concentrations of 58% does not meet the criteria for classification according to Regulation (EC) 1272/2008.

It is not possible to convert this non-classification to anhydrous TMT. Therefore, the available data on skin irritation/corrosion is insufficient for the classification or non-classification of anhydrous TMT.

 

Eye

Taking into account the severity of lesions but tendency to recovery observed in a study performed according to OECD Guideline 405, TMT 55 (analytical purity: 58%) is classified as "Eye Irritant 2 (H319)" according to the criteria of Directive 1272/2008/EC (CLP).

This classification can be transferred to anhydrous TMT. Therefore, anhydrous TMT is classified as "Eye Irritant 2 (H319)" according to the criteria of Directive 1272/2008/EC (CLP).