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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for data waiving:
other:
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1983

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
dermal absorption
Principles of method if other than guideline:
The percutaneous absorption of test material was investigated by the topical application of test material ointment in healthy and patient (receiving total parenteral nutrition) subjects followed by analysis of zinc content in serum.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Zinc oxide

Method

Type of population:
general
Subjects:
- Number of subjects exposed: Phase I: 6 in treatment group and 6 in control group; Phase II: 6 in treatment group
- Sex: Phase I: male; Phase II: male and female
- Age: Phase I: 21-24 yr; Phase II: 76, 18, 63, 68, 32 and 61 yr
- Known diseases: Phase II- Patient 1: chronic diverticulitis, patient 2: retroperitoneal tumour, patient 3: gastric carcinoma with metastasis to bone and liver, patient 4: oesophageal carcinoma, patient 5: crohn's disease, patient 6: recurrent duodenal ulcer
Ethical approval:
not specified
Route of exposure:
dermal
Reason of exposure:
intentional
Exposure assessment:
measured
Details on exposure:
Phase I: Treatment was done on two separate days, one wk apart. Commencing at 20:30 h the night before each of these two days, each subject fasted for 12 h, taking nothing by mouth except for tap water, ad libitum. No food or water was consumed during the study. In the morning of the first study day, the height and weight of each subject was measured from which body surface area was calculated. After the 12 h fast, baseline blood samples were drawn (10 mL of venous blood) followed by applications of the topical preparation. On the first day of the study, the preparation consisted of 100 g of 40 % test material in a white petrolatum base; in the cross-over, 60 g of 100 % white petrolatum base were employed. The ointment was applied to chest (the area defined superiorly by the clavicles and Inferiorly by the transverse plane intersecting the umbilicus), upper legs (anterolateral portion of both legs encompassing one-half the circumference of the legs from 3 in below the inguinal ligament to the superior edge of the patella), lower legs (the entire circumference of the lower leg from the inferior edge of the patella to the ankle). Following the application, blood samples (10 mL of venous blood) were drawn from each subject at 1 h intervals for a total of 3 h
Phase II: The systemic absorption from topical applications of 40 % test material ointment was investigated in hospitalized patients (excluding patients who had undergone surgery, other than the placement of a subclavian catheter within 7 d prior to the study) who had received TPN for a period of at least 3 d. 10-mL venous blood samples were drawn on 2 consecutive days. Following the second sample, and daily for the next 7 d (total of 8 d treatment), each patient received 15 g of 40 % test material ointment applied evenly to an area measuring 10x15 cm (outlined in pen on the medial aspect of either upper leg by use of a standard cardboard template). Ointment remaining from the previous day's application was removed with a dry cloth before applying the dose.The area was covered completely with one layer of plastic wrap (Saran Wrap, Dow Chemical, Toronto, Canada) and taped in place with waterproof tape to provide occlusion.
On Days 4, 6, and 8, just prior to the daily application of ointment, and on Day 10, at the same time each day, blood samples (10 mL venous blood) were drawn.
Examinations:
-Examination of Zinc content in serum
Medical treatment:
Patient 5 of phase II developed a rash with follicular pustules through out developed in the rectangular area that had received the test material ointment which was successfully treated by removal of the ointment and twice daily application of cool normal saline compresses for 2 d.

Results and discussion

Clinical signs:
No adverse effects
Results of examinations:
Phase I: Overall, there was a mean increase from 107.3±5.32 µg/dL to 116.1±5.02 µg/dL 1 h after application of 40 % test material ointment. This 8.8 µg/dL increase over baseline represents an 8.2 % rise in serum zinc. However, this increase is not statistically significant (p > 0.05). The mean baseline serum zinc level in control group was not significantly different from the baseline value determined in the treatment period (115.2±5.85 and 107.3±5.32 µg/dL, respectively). The greatest mean decrease in serum zinc level was noted after 1 h; the concentration fell from 115.2±5.85 to 103.5± 5.32 µg/dL. This decrease of 11.7 µg/dL over 1 h representing a 10.16 % decline in serum zinc was not statistically significant (0.5 > p > 0.05). For details see ‘Table 1A and 1B’ in the attached PDF.
Phase II: The mean baseline or pretreatment level of the 6 patients is 88.6±5.85, µg/dL which is significantly lower than the mean baseline level of the normal subjects (107.3±5.32) (p < 0.025). Three patients receiving total parenteral nutrition completed phase II of the protocol. Analysis of these patients' serum revealed that the zinc concentrations remained relatively constant over the l0 d study period. For details see ‘Table III’ in the attached PDF.
Effectivity of medical treatment:
The irritant dermatitis developed in patient 5 of phase II was successfully treated.
Outcome of incidence:
No data

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
A study was conducted to determine the percutaneous absorption topically applied 40% zinc oxide ointment in a series of healthy subjects (phase I) and in patients receiving total parenteral nutrition (phase II)

In phase I, six subjects completed a controlled, cross-over trial involving 3 hourly serum
sample determinations for zinc concentration following a massive application of 40 % test material ointment and plain petrolatum ointment. 1 hr after application of 40% zinc oxide ointment, there was a mean increase in serum zinc from 107.3±5.32 to 116.1±5.02 µg/dL, (p > 0.05). Three patients receiving total parenteral nutrition completed phase II of the protocol in which 40 % test material ointment was applied daily to a specified area of the thigh. Analysis of these patients serum revealed that the zinc concentrations remained relatively constant over the 10 d study period.

Topical applications of 40 % test material ointment do not result in significant absorption and hence there was no net increase in serum zinc concentration under the conditions of the test.
Executive summary:

A study was conducted to determine the percutaneous absorption topically applied 40% zinc oxide ointment in a series of healthy subjects (phase I) and in patients receiving total parenteral nutrition (phase II).

In phase I, six subjects completed a controlled, cross-over trial involving 3 hourly serum sample determinations for zinc concentration following a massive application of 40 % test material ointment and plain petrolatum ointment. 1 hr after application of 40% zinc oxide ointment, there was a mean increase in serum zinc from 107.3±5.32 to 116.1±5.02 µg/dL, (p> 0.05). Three patients receiving total parenteral nutrition completed phase II of the protocol in which 40 % test material ointment was applied daily to a specified area of the thigh. Analysis of these patients serum revealed that the zinc concentrations remained relatively constant over the 10 d study period.  

Topical applications of 40 % test material ointment do not result in significant absorption and hence there was no net increase in serum zinc concentration under the conditions of the test.