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Description of key information

Santicizer 160 (benzyl butyl phthalate) has shown no convincing evidence of skin or eye irritation in rabbit tests involving 24-hour application. Only transient effects were observed, not sufficient for classification as a skin or eye irritant. Although details of the two studies are only available in a brief summary report (hence they have been assigned reliability code 4), the data are considered adequate for assessment. A lack of skin irritation was also reported in a human repeat insult patch test and in two mouse ear swelling tests (reliability code 2), which were designed to evaluate skin sensitisation.

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
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 skin irritation 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. This method was reported to detect not only primary irritants but also cumulative irritants.
GLP compliance:
no
Species:
other: 200 human subjects completed the single dose study (out of 208 that started it)
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.2 ml
- Concentration (if solution): 100%; undiluted

VEHICLE
none
Duration of treatment / exposure:
Three times weekly for 24 hr each application on alternate weekdays for 3 weeks, then a 2-week break (during Christmas period) followed by a further 2 weeks of the same thrice-weekly applications.
Observation period:
Examined for signs of irritation on removal of each patch and 24 hr later.
Number of animals:
200 human subjects completed the single dose study (out of 208 that started it)
Details on study design:
TEST SITE
- Area of exposure: no data
- % coverage: no data
- Type of wrap if used: Parke-Davis Readi-Bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

SCORING SYSTEM: Reactions judged by the investigators to be due to the test substance and not, for example, to the adhesive dressing were scored as follows:
? - questionable change
1/2 - mild erythema covering less than half of the contact site
1 - erythema confined to the contact site which exceeds that of the untreated skin
2 - erythema confined to the contact site which definitely exceeds that of the untreated skin, with or without papules
3 - erythema, with some skin hardening, with or without papules
4 - erythema, skin hardening, with one or more complications, such as extension beyond the margins of the contact area, vesiculation or ulceration
Irritation parameter:
edema score
Remarks:
0
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: no effect
Remarks on result:
no indication of irritation
Remarks:
0 and 24 hr after patch removal, repeated on alternate weekdays for 5 weeks
Irritation parameter:
erythema score
Remarks:
0
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: no effect
Remarks on result:
no indication of irritation
Remarks:
0 and 24 hr after patch removal, repeated on alternate weekdays for 5 weeks
Irritant / corrosive response data:
No irritant or corrosive responses
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Santicizer 160 (butyl benzyl phthalate) showed no irritating 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 potential to cause skin irritation 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 occlusive patch for 24 hours on fifteen separate occasions. The skin was assessed for irritation after each induction exposure.

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

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

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Only brief summary data and results table available.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The undiluted test material was placed into the eye(s) of each of six rabbits, and subsequently removed after 24 hours. The eyes were assessed for signs of irritation over a period of a week.
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
no data
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml


Duration of treatment / exposure:
24 hours
Observation period (in vivo):
One week
Number of animals or in vitro replicates:
Six
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24 hours

SCORING SYSTEM: According to Federal Hazardous Substances Act (FHSA)
Irritation parameter:
cornea opacity score
Remarks:
1.43
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 1.43
Max. score:
110
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Affecting conjunctivae only, no effects on cornea or iris
Irritation parameter:
iris score
Remarks:
8
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 8
Max. score:
110
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Affecting conjunctivae only, no effects on cornea or iris
Irritation parameter:
conjunctivae score
Remarks:
4.3
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 4.3
Max. score:
110
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Affecting conjunctivae only, no effects on cornea or iris
Irritation parameter:
chemosis score
Remarks:
0
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
0
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Affecting conjunctivae only, no effects on cornea or iris
Irritant / corrosive response data:
Immediately after removal of the test material, discomfort was slight, and at 10 minutes copious discharge was noted. The discharge was still evident at 1 hour and, to a lesser extent, 24 hours post-exposure. Slight erythema was seen at 1 and 24 hours, but all signs of irritation had cleared by 48 hours post-exposure.
Other effects:
no data
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Slight eye irritation and copious discharge were seen shortly after undiluted Santicizer 160 was placed in the eyes of six rabbits for 24 hours, but this was fully reversible within 48 hours. Although few details are available for this study (reliability 4), the results are considered adequate for assessment.
Executive summary:

Undiluted Santicizer 160 (0.1 ml) was placed in the eyes of six New Zealand albino rabbits, and removed after 24 hours (presumably by rinsing). The treated eyes were assessed for signs of irritation during the 7-day observation period, and the data scored according to the method of FHSA.

 

Immediately after the 24-hour exposure period, slight discomfort was observed and after 10 minutes copious discharge was noted. At 1 hour after removal of the test material, copious discharge and slight erythema were reported, giving a mean irritation score of 8 out of a possible 110. At 24-hours post-exposure, slight erythema and slight to moderate discharge were reported (mean irritation score of 4.3/110). All effects were on the conjunctivae. Eyes appeared normal when examined 48, 72, 120 and 168 hours after removal of the test material, giving an overall irritation score of 1.43 (average of scores assessed at 24, 48 and 72 hours post exposure). The investigators classed the test material as slightly irritating to the eyes of rabbits, but noted that it would not be classed as an eye irritant under FHSA. Similarly under EU CLP regulations, this study would indicate that Santicizer 160 is not an eye irritant.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

When undiluted Santicizer 160 (0.5 ml) was applied to the intact and abraded skin of six New Zealand albino rabbits for 24 hours, erythema scores of 1 and 2 (by the method of FHSA) were seen in four and two animals respectively, 24 hours after exposure. At 48 hours, an erythema score of 1 was seen in three animals. No erythema was seen when assessed at 4, 72 or 168 hours after removal of the test material. An oedema score of 1 was seen in one animal at the 24 -hour observation point. The irritation scores were the same for intact and abraded sites. The investigators classed the test material as non-irritating when applied to the intact and abraded skin of rabbits (Birch, 1976c). Although details of this study are only available in a brief summary report (hence it has been assigned reliability code 4), the data are considered adequate for assessment.

When undiluted Santicizer 160 (0.1 ml) was placed in the eyes of six New Zealand albino rabbits, and removed after 24 hours (presumably by rinsing), slight discomfort was observed immediately after exposure. After 10 minutes, copious discharge was noted and after 1 hour, copious discharge and slight erythema were reported, giving a mean irritation score of 8 out of a possible 110 (by the method of FHSA). At 24 hours post-exposure, slight erythema and slight-to-moderate discharge were reported, with a mean irritation score of 4.3/110. All effects were on the conjunctivae. Eyes appeared normal when examined 48, 72, 120 and 168 hours after removal of the test material, giving an overall irritation score of 1.43 (average of scores assessed at 24, 48 and 72 hours post-exposure). The investigators classed the test material as slightly irritating to the eyes of rabbits, but noted that it would not be classed as an eye irritant under FHSA (Birch, 1976d). Again, details of this study are only available in a brief summary report (reliability code 4), but the data are considered adequate for assessment.

In two skin sensitisation studies in AKR and Balb/c mice using the mouse ear swelling test, the application of Santicizer 160 (30 µl at up to 110 mg/ml) to the ears during the induction and sensitisation phases was without effect on ear thickness, indicating that it was not irritating to mouse skin (Little, 1983b,c).

Santicizer 160 showed no skin irritation potential in humans when tested for skin sensitisation using a repeated insult patch test method. 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 and the skin was assessed for irritation after each induction exposure. No evidence of irritation (or sensitisation) was observed by the investigators or reported by any of the volunteers during the study (Shelanski, 1980).

No data are available on the potential of benzyl butyl phthalate to cause irritation of the respiratory tract.

Justification for classification or non-classification

The available studies on Santicizer 160 (benzyl butyl phthalate) are considered adequate for concluding that the compound does not need to be classified for skin or eye irritation, under the EU CLP regulations.