Registration Dossier

Administrative data

Description of key information

Skin:

Skin irritation, Rabbit, 4h, OECD 404: very slight to well defined erythema (1.66), absent to slight edema (0.78) (Cray Valley, MB Research Labs 1997, Kieffer L.A.)

Skin irritation, Rabbit, 4h, OECD 404: very slight or well-defined erythema (2.0), very slight or slight oedema (1.78) (Cray Valley, Huntingdon 1990. Ligget M.P.).

Skin irritation, Rabbit, 4h, OECD 404: very slight to well defined erythema (1.78) with or without very slight oedema (0.78) (Cytec, Huntingdon 1987, Liggette M. P.)

Eye:

Eye irritation, rabbit, FDA guideline: slight to defined cornea damage (opacity 1.33), slight iritis (0.67), moderate to severe conjunctivae lesions (2.5 redness; 2.0 chemosis), 7 day investigation, possible reversible (BASF, Central Institute for Nutrition 1978 a, Beek L. van)

Eye irritation, rabbit, FDA guideline: slight to defined cornea damage (opacity 1.33), slight iritis (1), moderate to severe conjunctivae lesions (2.5 redness; 3.0 chemosis), 7 day investigation, possible reversible (BASF, Central Institute for Nutrition 1978 b, Beek L. van)

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are valid in vivo studies data available to assess the irritation potential of trimethylolpropane triacrylate (TMPTA) to skin and eye.

Skin:

Company data:

A few detailed studies using long-term application (24h, CFR etc.) investigating the irritating effects to skin are available:

A skin irritation study with test material trimethylolpropane triacrylate (code no. 77/766) was performed to investigate the primary skin and eye irritating properties in experiments with albino rabbits (BASF 1978, Beek L. van). Therefore, six albino rabbits were treated with 0.5ml of the test substance for 24h to intact skin. Gradings were recorded 24h and 48h after end of treatment. Very slight or well-defined erythema and very slight oedema could be observed on intact skin. For the intact skin a mean erythema score of 1 (intact skin, 24h, 72h reading) and a mean edema score 0.33 (intact skin, 24h, 72h reading) could be calculated.

In another identical study another batch TMPTA (code no. 77/767) was tested for skin irritation (BASF 1978, Beek L. van b). Therefore, six albino rabbits were treated with 0.5ml of the test substance for 24h to intact skin. Gradings were recorded 24h and 48h after end of treatment. Very slight to moderate erythema, slight ischemia and slight incrustation, and very slight to slight edema could be observed (intact skin). For the intact skin a mean erythema score of 2.25 (intact skin, 24h, 72h reading) and a mean edema score 1.5 (intact skin, 24h, 72h reading) could be calculated.

A further study was conducted according to the protocol of Draize et al. (Cytec, Bio Test Laboratories 1977, Scibor G.). Therefore, 6albino rabbits were exposed for 24h (occlusive) to 0.5 ml test substance (two batches). Scored 2 - 3 erythema and edema were investigated after 24h whereas superficial and diffuse second degree chemical burn (that will not result in fibrosis) was observed by most of the animals at 72h reading (5/6 for batch No2 and 6/6 for batch No 6). No escharosis and/or necrosis were reported. For both batches, severely irritating effects were concluded.

Another study was conducted according to the specifications of the Federal Hazardous Substances Act (Cytec, Bionetics 1972, Hart E. R.). 0.5 mL undiluted TMPTA was applied to the intact and abraded skin of six rabbits via 24 h occlusive patch. The patches and the cover were left in place for 24 h. After 24 h, the patches and cover were removed, and skin reactions scored. Scoring was repeated 72 h after the initial application. Primary dermal irritation index was calculated to be 2.2 (out of 8). Only one score of 3 was recorded.

Another study assessed the skin irritation potential according to CFR guideline at the back of 6 New Zealand White Rabbits (Rahn, Huntingdon 1988, Liggett M. P.). After 24h application of 0.5ml test item grading were recorded after 24h and 72h. TMPTA is considered to be mildly irritating to rabbit skin. Very slight erythema was observed in all six animals at the 24h reading. At 72h reading well defined erythema with slight oedema had developed at two intact and three abraded sites. Very slight erythema with or without oedema persisted in the remaining four intact and three abraded sites. The primary Irritation Index was 2.0

 

OECD 404 conform studies:

In a study according to OECD 404 under GLP conditions investigating the irritant potential of TMPTA New Zealand White rabbits were dosed dermal to 0.5ml test substance (Cray Valley, MB Research Labs 1997, Kieffer L. A.). The test article was kept in contact with the skin for 4 hours at which time the wrappings were removed. Dermal reactions were scored at 1 hour after removal of wrappings. Reactions were scored again at 24, 48 and 72 hours and on day 7. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction at these time periods. Erythema scores ranged from very slight to well defined through 72 hours after patch removal, and from absent to very slight on day 7. Edema scores ranged from absent to slight through 48 hours after patch removal, and from absent to very slight through day 7. The modified Primary Irritation Index is 2.00

In another study according to OECD Guideline 404 six Rabbit were treated 4h with 0.5ml TMPTA according to guideline (Huntingdon 1990. Ligget M. P.). Very slight or well-defined erythema with very slight or slight oedema was present at all sites on Day 1 and persisted the following four days. Reactions had ameliorated slightly by Day 6 (very slight erythema with or without very slight or slight oedema) and had resolved by Days 9, 10 or 14. Desquamation of the stratum corneum, noted at all sites by Day 6, was still present on Day 14.

Another study was conducted to evaluate the skin irritation of TMPTA (Cytec, Huntingdon 1987, Ligget M. P. b). The study was performed according to the OECD guideline No 404 and EU method B.4. TMPTA (0.5 mL) was applied to the intact skin of 3 male New Zealand White rabbits via 4 h semi-occlusive patch. Examination of the treated skin was made on day 1 (i. e. approximately 30 min. after removal of the patches) and on days 2, 3 and 4. Additional observations were made on days 5 through 14. At the 24, 48 and 72 h intervals, scores ranged from very slight to well defined erythema with or without very slight oedema. Desquamation of the stratum corneum (one animal; day 9-11) and spots on the treatment site (one animal; day 5-7) were also observed. The mean irritation index for erythema and oedema were 1.8 and 0.9, respectively. The combined index was calculated to be 2.7. All the reactions were reversible within the 14-d observation period.

 

Assessment skin irritation:

All available information is taken into account to assess the irritating potential of TMPTA, but an increased dermal reaction can be expected if TMPTA is applied (maybe occlusive) for 24h. Therefore, these reactions were devaluated. Additional less reading was done in some 24h application studies or company data records and sometimes the study was terminated to early leading to a study worth little for classification.

In summary, company data and less documented studies were rated as less of reliability and 24h application studies were classified as less of relevance for classification. Taken together, very slight to slight skin irritation can be observed if TMPTA is applied for 4h. Reaction can be found to be reversible in most animals by day 14. If the contact is intensified (increased application time, occlusive application, and abraded skin) a moderate to severe skin reaction can be observed.

Due to its OECD guideline conformity the study (Cray Valley, MB Research Labs 1997, Kieffer L.A.) was assigned as key study (4h application). Nevertheless 1990 or Cytec 1987 are also adequate and used as supporting studies. Due to the latest result the study of 1997 is used. The result of all studies was in the same range and leads to the same GHS classification.

 

Key study assignment:

Due to its OECD guideline conformity the study (Cray Valley, MB Research Labs 1997, Kieffer L. A.) was assigned as key study. Nevertheless 1990 or Cytec 1987 are also adequate and can be used as key study. Due to the latest result the study of 1997 is used. The result of all studies was in the same range and leads to the same GHS classification.

Eye irritation:

Company data:

To determine the eye irritant potential of TMPTA 50µL of the test substance was applied to the eye of one rabbit (BASF 1974, Zeller H.). Gradings were recorded after 1h, 24h and 8 days. Slight to define redness, oedema, cornea opacity and iritis.

 

Guideline conform studies:

In another study the test material trimethylolpropane triacrylate (code no. 77/766) was examined for primary skin and eye irritating properties in experiments with albino rabbits (BASF, Central Institute for Nutrition 1978 a, Beek L. van). The eye irritation test was conducted according to general techniques as published by the FDA of the (Fed. Reg. 28 (119), 5582, 1963) and Draize and Kelley (Drug Gasmet. Industr. 71 (1952) 36). Two New Zealand White albino rabbits received 100 milligrams of the test substance. No washout followed the instillation and the eyes are examined at one hour, 24, 48, 72 hours and 7 days after instillation of the test material. Ocular reactions are judged using the scoring scale as published by Draize and Kelley (Drug. Cosmet. Industr. 71 (1952) 36). During the first day after instillation the eyes showed slight corneal damage, slight iritis and moderate to severe lesions of the conjunctivae. In the course of the seven-day observation period the degree and type of corneal damage remained unchanged or increased. The lesions of the iris and conjunctivae cleared up partly during the observation period. After seven days slight or moderate-severe corneal opacity, slight iritis and slight or moderate conjunctivitis was observed.

 

In another study the test material trimethylolpropane triacrylate (code no. 77/766) was examined for primary skin and eye irritating properties in experiments with albino rabbits (BASF, Central Institute for Nutrition 1978 a, Beek L. van). The eye irritation test was conducted according to general techniques as published by the FDA of the (Fed. Reg. 28 (119), 5582, 1963) and Draize and Kelley (Drug Gasmet. Industr. 71 (1952) 36). Two New Zealand White albino rabbits received 100 milligrams of the test substance. No washout followed the instillation and the eyes are examined at one hour, 24, 48, 72 hours and 7 days after instillation of the test material. Ocular reactions are judged using the scoring scale as published by Draize and Kelley (Drug. Cosmet. Industr. 71 (1952) 36). During the first day after instillation the eyes showed slight corneal damage, slight iritis and moderate to severe lesions of the conjunctivae. In the course of the seven-day observation period the degree and type of corneal damage remained unchanged or increased. The lesions of the iris and conjunctivae cleared up partly during the observation period. After seven days slight or moderate-severe corneal opacity, slight iritis and slight or moderate conjunctivitis was observed.

A second eye irritation study according to the general techniques as published by the FDA of the (Fed. Reg. 28 (119), 5582, 1963) and Draize and Kelley (Drug Gasmet. Industr. 71 (1952) 36) was conducted to assess the eye irritation potential of TMPTA (BASF, Central Institute for Nutrition 1978 b, Beek L. van). Therefore, two New Zealand White albino rabbits received 100 milligrams of the test substance. No washout followed the instillation and the eyes are examined at one hour, 24, 48, 72 hours and 7 days. Ocular reactions are judged using the scoring scale as published by Draize and Kelley (Drug. Gosmet. Industr. 71 (1952) 36)

During the first day after instillation the eyes showed slight corneal damage, slight iritis and moderate to severe lesions of the conjunctivae. In the course of the seven-day observation period the degree of corneal damage increased. After seven days, the following ocular lesions were observed: moderate or moderate-severe corneal opacity, slight iritis and moderate conjunctivitis.

Another study was conducted to evaluate the ocular toxicity of TMPTA in rabbits (Cytec, Litton Bionetics 1972 Hart E. R.). Therefore, 0.1 mL of the test material was instilled into the left eye of six New Zealand White rabbits; the right eye served as an untreated control. Observations were done at 1 h after the initial application, at 24, 48 and 72 h. Irritation was scored by Draize scoring system. Scores of 2 and 3 (maximum is 4) with respect to corneal opacity were recorded in five of the six animals at 24 h. All but one of these had regressed partially or completely by 72 h. Moderate to marked degrees of redness, chemosis and discharge were also recorded and followed a similar time course.

A Bovine Corneal Opacity and Permeability test (BCOP) was performed with TMPTA in 2018 according to OECD guideline 437 and GLP principles. TMPTA was applied undiluted. The mean in vitro irritancy score of the positive control (Ethanol) was 35, and the mean in vitro irritancy score of the negative control (physiological saline) was -0.3. TMPTA did not induce ocular irritation through both endpoints, resulting in a mean in vitro irritancy score of 0.9 after 10 minutes of treatment.

 

Assessment eye irritation:

All available information is taken into account to assess the irritating potential of TMPTA, but company data and less documented studies were rated as less of reliability. Due to leak of documentation the Cytec study has to be graded in reliability. Anyhow the most critical results are reported in the BASF studies. Taken together slight to define cornea damage, slight iritis and moderate to severe lesions of conjunctivae can be observed. Moderate to severe eye irritation can be concluded if instillation into eye. The observation of reversibility was stop latest on day 7 without completion of regeneration. Additional no washout after instillation was performed.

 

Key study assignment:

All available information is taken into account to assess the irritation potential of TMPTA. Both BASF are adequate documented and lead to the most critical result. Therefore, these were chosen as possible key studies. Because of the more critical effects of the second TMPTA batch this study (BASF, Central Institute for Nutrition 1978 b, L. van Beek) is used as key study. The BCOP guideline study conducted in 2018 is considered as supportive, but will not overrule the existing key studies.

 

Effects on skin irritation/corrosion: slightly irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Skin:

As according to GHS and DSD an application of 4h under GLP condition and OECD guideline is preferred. Only studies fulfilling these criteria were used for classification.

Clear skin irritating effects were observed in three skin irritation studies according to OECD guideline. The scores obtained from the study led to no classification according to GHS EC 1272/2008 as the mean value are below 2.3 for erythema/eschar or oedema in at least 2 of 3 animals and as the inflammation does not persist in 2 animals over a 14 day observation period. Nevertheless as there is an official classification (CLP annex) and therefore this classification was taken over. According to EU-criteria (67/548/EEC) the substance has to be classified as Xi R-38 based on the result of two studies. In these two studies 2 animals showed a mean value for erythema equal or above 2 which derives the classification irritant to skin.

Labelling:

GHS: Skin irritating (cat. 2)

DSD: Xi R-38

Eye:

Clear eye irritating effect were observed in an eye irritation study: The scores obtained in this study led to a classification as an irritating to eye (cat. 2) due to criteria of classification EC 1272/2008 and Xi R-36 according to EU-criteria (67/548/EEC)as there were two animals having an cornea damage above 1.

To fulfil all requirements of the legislations above a long term observation for 14 or 21 days is needed investigated the reversibility of the irritating effects. This investigation was not done within the old protocols but as the chemosis and redness decreases within 7 days after application reversibility can be assumed. Additional today it is also usual to performed a wash out of the substance. That was also not done in the old protocols. Therefore also an overestimation of the effect can be assumed.. Based on these assumptions a higher classification as the above made is not justified.

Labelling:

GHS: irritating to eye (cat. 2)

DSD: Xi R-36