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Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Remarks:
Not sensitising - Migrated information - See Material and Method
Type of information:
experimental study
Adequacy of study:
key study
Study period:
3 December 1979 to 8 February 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No guideline is available for the conduct of sensitization testing in humans
Reason / purpose for cross-reference:
reference to same study
Qualifier:
no guideline available
Principles of method if other than guideline:
Shelanski HA and Shelanski MD (1953). A new technique of human patch tests. Proceedings of the Scientific Section of the Toilet Goods Association, No. 19, 46-49.
Substance applied to a patch of at least 6.5 square cm for 24 hr on 3 days/week for a total of 5 weeks, allowing the skin to recuperate for 24 hr between exposures. 2-3 weeks after the final induction treatment the test substance is reapplied for usually 48 hr. This method was reported to detect not only primary sensitizers and primary irritants but also cumulative irritants.
GLP compliance:
not specified
Type of study:
patch test
Justification for non-LLNA method:
The LLNA method was not available yet by the time the study was conducted
Species:
human
Sex:
male/female
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
No. of animals per dose:
200 human subjects completed the single dose study (out of 208 that started it)
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 15
- Exposure period: 24 hr
- Test groups: Two groups each receiving the same treatment
- Control group: no
- Site: no data
- Frequency of applications: three times weekly on alternate weekdays for 3 weeks, then a 2-week break (during Christmas period) followed by a further 2 weeks of thrice weekly application
- Concentrations: 0.2 ml of undiluted test substance

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 2 weeks after the last induction exposure
- Exposure period: 24 hr
- Test groups: Two groups each receiving the same treatment
- Control group: no
- Site: no data; new site to that used for induction
- Concentrations: 0.2 ml of undiluted test substance
- Evaluation (hr after challenge): 0, 24, 48 and 72 hr by testing laboratory, then self assessment for a further week.
Challenge controls:
no
Positive control substance(s):
no
Remarks:
not ethical
Reading:
1st reading
Hours after challenge:
0
Group:
negative control
Dose level:
0.2 ml of undiluted test substance
No. with + reactions:
0
Total no. in group:
0
Clinical observations:
no effects
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 0.0. Group: test group. Dose level: 0.2 ml of undiluted test substance. No with. + reactions: 0.0. Total no. in groups: 200.0. Clinical observations: no effects.
Reading:
1st reading
Hours after challenge:
0
Group:
test chemical
Dose level:
0.2 ml of undiluted test substance
No. with + reactions:
0
Total no. in group:
200
Clinical observations:
no effects
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 0.0. Group: test group. Dose level: 0.2 ml of undiluted test substance. No with. + reactions: 0.0. Total no. in groups: 200.0. Clinical observations: no effects.
Reading:
2nd reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.2 ml of undiluted test substance
No. with + reactions:
0
Total no. in group:
200
Clinical observations:
no effects
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0.2 ml of undiluted test substance. No with. + reactions: 0.0. Total no. in groups: 200.0. Clinical observations: no effects.
Reading:
other: 3rd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.2 ml of undiluted test substance
No. with + reactions:
0
Total no. in group:
200
Clinical observations:
no effects
Remarks on result:
other: Reading: other: 3rd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.2 ml of undiluted test substance. No with. + reactions: 0.0. Total no. in groups: 200.0. Clinical observations: no effects.
Reading:
other: 4th reading
Hours after challenge:
72
Group:
test chemical
Dose level:
0.2 ml of undiluted test substance
No. with + reactions:
0
Total no. in group:
200
Clinical observations:
no effects
Remarks on result:
other: Reading: other: 4th reading. . Hours after challenge: 72.0. Group: test group. Dose level: 0.2 ml of undiluted test substance. No with. + reactions: 0.0. Total no. in groups: 200.0. Clinical observations: no effects.
Reading:
1st reading
Hours after challenge:
0
Group:
positive control
Dose level:
0.2 ml of undiluted test substance
No. with + reactions:
0
Total no. in group:
0
Clinical observations:
no effects
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 0.0. Group: test group. Dose level: 0.2 ml of undiluted test substance. No with. + reactions: 0.0. Total no. in groups: 200.0. Clinical observations: no effects.
Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
Santicizer 160 (butyl benzyl phthalate) showed no sensitizing potential when applied to the skin of 200 human volunteers in a repeated-dose patch test.
Executive summary:

Santicizer 160 (butyl benzyl phthalate) was assessed for its skin sensitizing potential in humans using a repeated insult patch test method.


 


During the induction phase 200 healthy volunteers were exposed to 0.2 ml of the undiluted test substance applied to an occusive patch for 24 hours on fifteen separate occasions; after a 2 week period the same dose was applied as a challenge (24 -hour covered) to a new area of the skin. The skin was assessed for irritation after each induction exposure and for sensitization 0, 24, 48 and 72 hours after the challenge.


 


No evidence of sensitization (or irritation) was reported for any of the volunteers during the study.


 


Santicizer 160 (butyl benzyl phthalate) showed no skin sensitization (or irritation) potential in healthy human subjects in a repeated insult patch test.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Santicizer 160 (BBP) showed no skin sensitisation potential in a human repeated insult patch test. During the induction phase, 200 healthy volunteers were exposed to 0.2 ml of the undiluted test material applied to an occlusive patch for 24 hours on fifteen separate occasions; after a 2 -week period, the same dose was applied as a challenge (24 -hour covered contact) to a new area of the skin. The skin was assessed for irritation after each induction exposure and for sensitisation 0, 24, 48 and 72 hours after the challenge. No evidence of sensitisation was observed by the investigators or reported by any of the volunteers during the study (Shelanski, 1980).

In a reliable study, no skin sensitisation was seen in guinea pigs after intradermal induction and epicutaneous challenge with BBP.

Induction involved intradermal injection of BBP (1 mM) with Freunds Complete Adjuvant into the four footpads of each of 4 guinea pigs. Epicutaneous challenges were applied, 14 days later, to the shaved abdominal skin of each animal, with three concentrations of BBP (3.6, 36 and 360 mM) and of the vehicle (acetone/corn oil). The skin was washed after 18 hours and skin reactions were read 24 and 48 hours after the start of the challenge exposure. Approximately 5 weeks later, a rechallenge using the highest concentration was made and skin reactions read at 48 hours. Four guinea pigs were treated with a positive control substance, 2,4 -dinitrofluorobenzene, in the same way. BBP did not induce skin reactions at any of the challenge sites, whereas clear positive responses were seen in the positive control animals (Little, 1983a).

Two other reliable studies, both ear swelling tests involving epicutaneous administration of BBP to the skin of AKR and BALB/c mice and subsequent challenge application to the ears, showed no evidence of skin sensitisation (Little, 1983b,c).

Migrated from Short description of key information:

Benzyl butyl phthalate (BBP) has shown no evidence of skin sensitisation potential in a human repeated insult patch test or in laboratory animal studies (a guinea-pig footpad test and two mouse ear swelling tests). Although none of these are guideline studies, all appear to be reliable with restrictions (reliability code 2).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The potential for respiratory tract sensitisation by butyl benzyl phthalate (BBP) and certain other phthalate esters (DEHP, DINP and di-isohexyl phthalate) was investigated in B6C3F1 mice using an experimental procedure developed by Dearman et al., 1992 (J. Appl. Toxicol. 12(5), 317 -323). Repeated dermal applications of these four phthalates did not increase serum levels of IgE or of the interleukins IL-4 or IL-13, in contrast to the effects observed with the known respiratory sensitiser, trimellitic anhydride. Based on these results, it was concluded that these phthalates "have little, if any, potential to produce antibody-mediated respiratory allergy" (Butala et al., 2004).

A more recent study by Dearman et al. (2009) assessed the strength of immune responses induced in BALB/c mice immunised subcutaneously with the reference allergen ovalbumin, when they received a concurrent topical application of BBP. When the BBP was applied either near to or distant from the site of ovalbumin immunisation, it had no impact on anti-ovalbumin IgE antibody responses. However, when applied at the same site as the immunisation, the high dose of BBP (100 mg) did produce a modest increase in anti-ovalbumin IgG1 antibody production, in the absence of any effect on IgE antibody production. The investigators concluded that "the doses of phthalate [BBP] encountered in the home environment are unlikely to be a major factor contributing to the increased incidence of asthma and allergy in the developed world" (J. Appl. Toxicol. 2009, 29(2), 118 -125).

Migrated from Short description of key information:

Data on butyl benzyl phthalate and other phthalate esters do not indicate a potential for respiratory tract sensitisation (Butala et al., 2004; Dearman et al. 2009). In addition, as the high-molecular-weight phthalates have provided no indication of skin sensitisation, a respiratory sensitising effect is considered unlikely. The low  vapour pressures of these substances provide additional reassurance, as exposure by inhalation is likely to be minimal.

Justification for classification or non-classification

Based on the available data, BBP does not need to be classified as a sensitiser.