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EC number: 212-449-1 | CAS number: 818-08-6
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Endpoint summary
Administrative data
Description of key information
Hong (2021): Guinea pig maximisation test with DBTO (OECD 406, GLP), Hartley guinea pigs, induction: 0.47 % intradermal and 100 % epicutanous, occlusive, challenge: 3.13 % in olive oil epicutanous, occlusive: negative
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 31 MAY 2021 - 16 FEB 2023
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Version / remarks:
- adopted 17 July 1992
- Deviations:
- no
- GLP compliance:
- yes
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- Although the murine Local Lymph Node Assay (LLNA) is currently the preferred assay for chemicals under EU REACH regulation, guinea pig assays are equally acceptable under other regulations.
The guinea pig has been found informative for predictive sensitisation tests and is used as animal model since several decades. - Species:
- guinea pig
- Strain:
- Hartley
- Remarks:
- ElmSam:HA, SPF
- Sex:
- male
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Samtako Inc., Republic of Korea
- Age at study initiation: 5 weeks
- Weight at study initiation: 297-365 g
- Housing: Polycarbonate cage, W260 × L420 × H180 (mm), one animal per cage, cages and feeders were replaced once weekly.
- Diet (e.g. ad libitum): Pellet feed for experimental animal (Purina experimental diet for guinea pig 38065, Lot No.: P210329WSH, P210529LCS, supplied by the Biopia lnc (LS-ro, Gunpo-si, Gyeonggi-do, Republic of Korea) was provided in feeders ad libitum.
- Water (e.g. ad libitum): Public tap water in Gyeonggi-do was filtered and irradiated by ultraviolet light and provided ad libitum.
- Acclimation period: All animals were quarantined for 5 days (day of animal arrival was considered day 1)
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18–22°C
- Humidity (%): 30–70%
- Air changes (per hr): 10–15 times/hr
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle (light on 7 AM to light off 7 PM) (light at 150–300 Lux) - Route:
- intradermal
- Vehicle:
- olive oil
- Concentration / amount:
- 1) water for injection-Freunds Complete Adjuvant (WFI-FCA) emulsion
2) 0.47% test substance
3) 0.47 % test substance-FCA emulsion
each injection 0.1 mL - Day(s)/duration:
- on day 0
- Adequacy of induction:
- highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
- Route:
- epicutaneous, occlusive
- Vehicle:
- other: moistened with 0.2 mL water
- Concentration / amount:
- 100 % / 0.2 g
- Day(s)/duration:
- on day 7 after first induction, dressing removed after 24 hours
- Adequacy of induction:
- highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
- No.:
- #1
- Route:
- epicutaneous, occlusive
- Vehicle:
- olive oil
- Concentration / amount:
- 3.13 % / 0.1 mL
- Day(s)/duration:
- on day 21, dressing was removed after 24 hours
- Adequacy of challenge:
- highest non-irritant concentration
- No. of animals per dose:
- 20 animals in the test group and 10 animals in the (negative) control group
- Details on study design:
- RANGE FINDING TESTS:
In the preliminary study, 4 male animals were examined in order to select appropriate concentrations for induction and challenge.
Intradermal: The shoulder region of two guinea pig was clipped (JC-4107, JOAS, Republic of Korea) and shaved (SR-292S, JOAS, Republic of Korea) free of hair. Six sites, three each on the left and right sides of the midline of the shaved shoulder region were selected. The left and right sides were injected intradermal with 0.1 mL of the test substance at dose levels of 15, 7.5, 3.75, 1.88, 0.94 and 0.47% 1-mL disposable syringes (26G needle).
Dermal: The left and right flanks of two guinea pig were clipped and closely shaved free of hair. Six areas, on left and right sides of the midline, were selected as application sites. 0.1 g of 100% test substance was applied on a 2×2 cm patch and the patches were placed on the application sites, moistened with 0.1mL of water for injection. 0.1 mL of each test substances was applied at concentrations of 50, 25, 12.5, 6.25 and 3.13% using 1-mL disposable syringes on a 2×2 cm patch and the patches were placed on the application sites. Animals were wrapped with at 7.5 cm adhesive tape (Silkytex, Alcare Co., Ltd., Japan) and the secured with surgical tape (Steri-Drape No. 1040, 3M Co., Ltd., Republic of Korea) for 24 hours occlusive dressing. The occlusive dressing was removed at 24 hours after application. The application sites were gently wiped off with absorbent cotton (DaeHan Medical Supply Co., Ltd., Republic of Korea) moistened with tepid water after patch removal.
The skin reactions were evaluated at 24 and 48 hours after injection and at 24 and 48 hours after patch removal according to the evaluation standard of skin reactions by Magnusson and Kligman.
As a result of the preliminary study, intense redness (score 3) with skin necrosis were observed in both animals at 15, 7.5, 3.75, 1.88 and 0.94% test substances at 24 and 48 hours after intradermal injection. Redness (score 3) was observed at 0.47% test substance.
At 24 and 48 hours after patch removal, redness (score 1) was observed in both animals at 100 and 6.25% test substance. Redness (score 2) was observed in both animals at 50, 25 and 12.5% test substances. The 3.13% test substances did not reveal any evidence of adverse skin reactions in both animals.
In accordance with the result of the preliminary study, the dose level for the first induction was the highest concentration of the test substance at which necrosis was not confirmed at the intradermal injection sites. Therefore, the dose level was selected at 0.47% test substance. Also, the dose level for the second induction will be the highest concentration of the test substance at which mild to moderate skin reactions are confirmed at the topical application sites. Therefore, the dose level was selected at 100% test substance. The challenge dose level will be selected at 3.13% test substance, the highest concentration at which skin reaction is not confirmed at the topical application sites.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: two inductions: intradermal and epicutaneous
- Exposure period: induction on day 0, epicutaneous induction on day 7, for 24 hours
- Test groups:
1) First induction
One day prior to the first induction, the shoulder region of guinea pigs was clipped and shaved free of hair. The first induction day (Day 0), the sensitization site of 2×4 cm area was selected on the left and right by midline. A volume of 0.1 mL of each dose (1-3 from head to tail, see scheme below) to each group with a total six sites, three on the left and right were injected using 1-mL disposable syringes (26G needle):
HEAD
1: WFI-FCA emulsion
2: test substance (0.47%)
3: test substance (0.47%)-FCA emulsion
TAIL
2) Second induction
On Day 6 after the first induction (Day 6), the induction sites were clipped with electric clippers and an electric shaver. On Day 7, an amount of 0.2 g of the 100% test substance and 0.2 mL of moisture water for injection on a 2×4 cm patch (TegadermTM+Pad, No. 3582, 3M Co., Ltd., U.S.A.) was applied to the shoulder region of induction sites of the test substance group.
Patches were wrapped with the expandable adhesive tape and the secured with surgical tape for 48 hours occlusive dressing. Wrappings and patches were removed at 48 hours after application. Then, the application site was wiped clean gently with absorbent cotton moistened with tepid water.
- Control group:
1) First induction
One day prior to the first induction, the shoulder region of guinea pigs was clipped and shaved free of hair. The first induction day (Day 0), the sensitization site of 2×4 cm area was selected on the left and right by midline. A volume of 0.1 mL of each dose (see scheme below) to each group with a total six sites, three on the left and right were injected using 1-mL disposable syringes (26G needle):
HEAD
1: WFI-FCA emulsion
2: olive oil
3: olive oil-FCA emulsion
TAIL
2) Second induction
On Day 6 after the first induction (Day 6), the induction sites were clipped with electric clippers and an electric shaver. On Day 7, a volume of 0.2 mL of olive oil was applied to the induction sites of the control groups.
Patches were wrapped with the expandable adhesive tape and the secured with surgical tape for 48 hours occlusive dressing. Wrappings and patches were removed at 48 hours after application. Then, the application site was wiped clean gently with absorbent cotton moistened with tepid water.
- Concentrations: 0.47 % was used for the first intradermal induction and 100 % was applied dermally for the second induction
B. CHALLENGE EXPOSURE
- No. of exposures: one challenge was performed
- Day(s) of challenge: on day 21 for 24 hours
- Exposure period:
- Test groups: On Day 13 after the second induction (Day 20), the left and right dorsal application sites were trimmed with electric clippers and electric shaver. On Day 21, the shaved areas (2×2 cm) were selected as challenge sites. A volume of 0.1 mL of 3.13% test substance was applied to the left challenge sites of the test substance and control groups. At the right challenge site, 0.1 mL of olive oil was applied. Patches were wrapped loosely with the expandable adhesive tape and then secured with surgical tape for 24 hours occlusive dressing. Wrappings and patches were removed at 24 hours after application. Then, the application sites were wiped clean with absorbent cotton moistened with tepid water.
- Control group: On Day 13 after the second induction (Day 20), the left and right dorsal application sites were trimmed with electric clippers and electric shaver. On Day 21, the shaved areas (2×2 cm) were selected as challenge sites. A volume of 0.1 mL of 3.13% test substance was applied to the left challenge sites of the test substance and control groups. At the right challenge site 0.1 mL of olive oil was applied. Patches were wrapped loosely with the expandable adhesive tape and the secured with surgical tape for 24 hours occlusive dressing. Wrappings and patches were removed at 24 hours after application. Then, the application sites were wiped clean with absorbent cotton moistened with tepid water.
- Evaluation (hr after challenge): Challenge sites were observed visually at 24 and 48 hours after challenge patch removal - Challenge controls:
- none
- Positive control substance(s):
- yes
- Positive control results:
- Recent reliability check was performed during the period from Apr 15, 2021 to May 21, 2021. The sensitisation rate after application of the positive control substance was 100%, classified as "V, Extreme", confirming the validity of this test system (results are included below)
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 3.13 % test substance
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Clinical observations:
- No abnormal signs were observed in any animal of each group. All animals of each group exhibited normal body weight gain.
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 3.13 % test substance
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Clinical observations:
- No abnormal signs were observed in any animal of each group. All animals of each group exhibited normal body weight gain.
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- 3.13 % test substance
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- No abnormal signs were observed in any animal of each group. All animals of each group exhibited normal body weight gain.
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- 3.13 % test substance
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- No abnormal signs were observed in any animal of each group. All animals of each group exhibited normal body weight gain.
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- 10 % hexylcinnamaldehyde
- No. with + reactions:
- 5
- Total no. in group:
- 5
- Remarks on result:
- positive indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- 10 % hexylcinnamaldehyde
- No. with + reactions:
- 5
- Total no. in group:
- 5
- Remarks on result:
- positive indication of skin sensitisation
- Interpretation of results:
- other: EU GHS criteria not met
- Conclusions:
- Based on the result of this study, the test substance, Dibutyltin oxide, did not induce skin sensitization under the conditions of this study.
- Executive summary:
This study was conducted in accordance with OECD Guideline 406 and under GLP compliance, to evaluate the skin sensitization potential of the test substance, Dibutyltin oxide, by Maximization test using male Hartley guinea pigs at the age of 5 weeks. Test groups consisted of two groups with a test substance group (20 animals) and control group (10 animals).
In the test substance group, 0.47% test substance was injected intradermally for the first induction. The second induction was conducted with 100% test substance occluded for 48 hours. The challenge was conducted with the 3.13% test substance and olive oil occluded for 24 hours. The skin reaction, such as erythema and swelling, was evaluated at 24 and 48 hours after removal of the challenge patch.
In the control group, the first and second inductions were done with olive oil and the challenges with 3.13% test substance and olive oil. The skin reaction, such as erythema and swelling, was evaluated at 24 and 48 hours after the removal of the challenge patch.
In the test substance and control group, no skin reactions such as erythema and swelling were observed in any animal in test substance and olive oil site at 24 and 48 hours after challenge patch removal.
During the observation period, no abnormal clinical signs or body weight gain was observed in any animal of each group.
Based on the result of this study, the test substance, Dibutyltin oxide, did not induce skin sensitization under the conditions of this study.
Reference
Evaluation of Skin Sensitization
a: test substance group
Group | Substance for challenge | Animal ID | Score of skin reaction | |
24 hours | 48 hours | |||
Test substance | Test substance | 1101 | 0 | 0 |
1102 | 0 | 0 | ||
1103 | 0 | 0 | ||
1104 | 0 | 0 | ||
1105 | 0 | 0 | ||
1106 | 0 | 0 | ||
1107 | 0 | 0 | ||
1108 | 0 | 0 | ||
1109 | 0 | 0 | ||
1110 | 0 | 0 | ||
1111 | 0 | 0 | ||
1112 | 0 | 0 | ||
1113 | 0 | 0 | ||
1114 | 0 | 0 | ||
1115 | 0 | 0 | ||
1116 | 0 | 0 | ||
1117 | 0 | 0 | ||
1118 | 0 | 0 | ||
1119 | 0 | 0 | ||
1120 | 0 | 0 | ||
Total score | 0 | 0 | ||
control | 1101 | 0 | 0 | |
1102 | 0 | 0 | ||
1103 | 0 | 0 | ||
1104 | 0 | 0 | ||
1105 | 0 | 0 | ||
1106 | 0 | 0 | ||
1107 | 0 | 0 | ||
1108 | 0 | 0 | ||
1109 | 0 | 0 | ||
1110 | 0 | 0 | ||
1111 | 0 | 0 | ||
1112 | 0 | 0 | ||
1113 | 0 | 0 | ||
1114 | 0 | 0 | ||
1115 | 0 | 0 | ||
1116 | 0 | 0 | ||
1117 | 0 | 0 | ||
1118 | 0 | 0 | ||
1119 | 0 | 0 | ||
1120 | 0 | 0 | ||
Total score | 0 | 0 |
b: control group
Group | Substance for challenge | Animal ID | Score of skin reaction | |
24 hours | 48 hours | |||
Control group | Test substance | 1201 | 0 | 0 |
1202 | 0 | 0 | ||
1203 | 0 | 0 | ||
1204 | 0 | 0 | ||
1205 | 0 | 0 | ||
1206 | 0 | 0 | ||
1207 | 0 | 0 | ||
1208 | 0 | 0 | ||
1209 | 0 | 0 | ||
1210 | 0 | 0 | ||
Total score | 0 | 0 | ||
control | 1201 | 0 | 0 | |
1202 | 0 | 0 | ||
1203 | 0 | 0 | ||
1204 | 0 | 0 | ||
1205 | 0 | 0 | ||
1206 | 0 | 0 | ||
1207 | 0 | 0 | ||
1208 | 0 | 0 | ||
1209 | 0 | 0 | ||
1210 | 0 | 0 | ||
Total score | 0 | 0 |
Reliability check data (Experimental period: Apr 15, 2021 to May 21, 2021)
Test group | Substance for induction | Substance for challenge (concentration) | Score of skin reactiona) | Number of animals | Number of animals with positive reactions | Sensitisation rate (%) | Classification of sensitisation grade | ||
1st (concentration) | 2nd (concentration) | 24 hoursb) | 48 hoursb) | ||||||
Positive substance | HCA (0.5 %) | HCA (50%) | HCA (10%) | 0 | 0 | 0 | 5/5 | 100 | V (Extreme) |
1 | 1 | 1 | |||||||
2 | 4 | 4 | |||||||
3 | 0 | 0 | |||||||
Mean score | 1.8 | 1.8 | |||||||
Olive oil | 0 | 5 | 5 | 0/5 | 0 | I (Negative) | |||
1 | 0 | 0 | |||||||
2 | 0 | 0 | |||||||
3 | 0 | 0 | |||||||
Mean score | 0 | 0 |
a): Magnusson & Kligman grading scale
b): Observation after patch removal for challenge
HCA: hexylcinnamaldehyde
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
- Additional information:
This study was conducted in accordance with OECD Guideline 406 and under GLP compliance, to evaluate the skin sensitization potential of the test substance, Dibutyltin oxide, by Maximization test using male Hartley guinea pigs at the age of 5 weeks. Test groups consisted of two groups with a test substance group (20 animals) and control group (10 animals).
In the test substance group, 0.47% test substance was injected intradermally for the first induction. The second induction was conducted with 100% test substance occluded for 48 hours. The challenge was conducted with the 3.13% test substance and olive oil occluded for 24 hours. The skin reaction, such as erythema and swelling, was evaluated at 24 and 48 hours after removal of the challenge patch.
In the control group, the first and second inductions were done with olive oil and the challenges with 3.13% test substance and olive oil. The skin reaction, such as erythema and swelling, was evaluated at 24 and 48 hours after the removal of the challenge patch.
In the test substance and control group, no skin reactions such as erythema and swelling were observed in any animal in test substance and olive oil site at 24 and 48 hours after challenge patch removal.
During the observation period, no abnormal clinical signs or body weight gain was observed in any animal of each group.
Based on the result of this study, the test substance, Dibutyltin oxide, did not induce skin sensitization under the conditions of this study.
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Based on the above mentioned study results, classification of the registered substance DBTO for skin sensitisation is not warranted according to Regulation (EC) No 1272/2008.
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