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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study report, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
other company data
Title:
Unnamed
Year:
1988
Report Date:
1988
Reference Type:
other company data
Title:
Unnamed
Year:
1989

Materials and methods

Principles of method if other than guideline:
Triethanolamine uniformly radiolabeled with 14C was administered to C3H/HeJ mice intravenously or dermally to study the skin penetration of the test substance in vitro.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): triethanolamine
- Analytical purity: 99.6 %
- Lot/batch No.: 7H-5317
- Radiochemical purity (if radiolabelling): 97-98 % (98.6 % by liquid chromatography reanalysis)
- Specific activity (if radiolabelling): 34.7 mCi/mmol
- Supplier: Amersham Cororation, Arlington Heights, IL, USA (labelled TEA)
- Supplier: Texaco Chemical Company, Austin, Texas, USA (unlabelled TEA)
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
mouse
Strain:
other: C3H/HeJ
Sex:
not specified
Details on test animals and environmental conditions:
- Source: Jackson Laboratories, Bar Harbor, ME
- Weight at study initiation: 20.4 to 38.3 g
- Fasting period before study: none
- Housing: glass Roth-style metabolism cages
- Individual metabolism cages: yes
- Diet: Purina® Certified Rodent chow #5002 ad libitum
- Water: tap water ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 40-60
- Air changes (per hr): ca. 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
occlusive
Vehicle:
other: acetone or water
Duration of exposure:
48 hours
Doses:
1000 or 2000 mg/kg bw
No. of animals per group:
1000 mg/kg bw: 9
2000 mg/kg bw (with acetone): 48
2000 mg/kg bw (with water): 21
Control animals:
no
Details on study design:
Dermal probe - 1000 mg/kg - mice. Nine male mice received a dermal dose of 14C-TEA in acetone vehicle targeted at 1000 mg/kg. The hair on the back of each mouse was clipped immediately prior to dosing and dose applied to an area of approximately 1 square centimeter in the interscapular area using a blunted microliter syringe. Following administration of the dose, the skin at the dose site was rubbed gently with the barrel of the dosing syringe needle. The dosing volume applied dermally was 96.3 ± 3.2 % (mean ± S.D.) of the target dosing volume of 0.05 ml. The average amount of radioactivity applied was 7.95 µCi/mouse. The speciflc activity of the dosing solution was 163.5 µCi/ml. Immediately following dosing the animals were returned to their cages. The animals designated for excreta collection and sacrifice at 24 hours post-dosing (final sacrifice) were placed in glass Roth cages. Prior to dosing the animals were acclimated to Roth cages for approximately 48 hours. Blood samples were collected from all animals via orbital Sinus puncture just prior to their sacrifice by cervical dislocation in groups of three at 6, 12 and 24 hours post-dosing. Urine and feces were collected at 6 hour intervals from the mice housed in Roth cages. Following the sacrifice of this group at 24 hours, the animals were
skinned, the liver and kidneys excised, and each Roth cage washed with a solution of acetone and water. Radioactivity in excreta, cage wash solution, livers, kidneys, skin and remaining carcass were determined as described below.

Dermal administration - 2000 mg/kg - mice. Forty-eight male mice (two groups of 24 as described below) were dosed dermally with a dose of 14C-TEA targeted at 2000 mg/kg (= ca. 40-60 µl of "neat" material). These mice were dosed to determine the blood concentration-time profile for radioactivity derived from 14C-TEA. In addition, the routes and rates of excretion, the distribution
of radioactivity to liver, kidney, skin, and the remaining carcass at peak blood concentrations and at 48 hours post-dosing were determined.
The first group of twenty-four mice were dosed dermally with no effort made to restrict access to the dosed site. The dosing volume applied dermally was 104.1 ± 5.2 % (mean ± S.D.) of the target dosing volume of 60 µl. The average amount of radioactivity applied was 1.86 µCi/mouse. The hair on the back of each mouse was clipped on the day prior to dosing, and dose applied to the
skin in an area af approximately 2 square centimeters using a blunted micoliter syringe.
The second group of twenty-four mice received the dose within a glass ring adhered to the back with cyanoacrylate and covered with nylon screen, as described above. The dosing volume applied dermally was 91.3 ± 7.5 % (mean ± S.D.) of the target dosing volume of 45 µl. The average amount of radioactivity applied was 2.76 µCi/mouse.

Immediately following dosing the animals from both groups scheduled for sacrifice at 48 hours post-dosing were placed in Roth cages for the separation of urine and feces. Urine and feces were collected at 6 and 12 hours postdosing (if available) and every 12 hours thereafter. Blood samples were collected from all animals via orbital Sinus puncture just prior to their sacrifice by cervical dislocation in groups of three at 0.083, 0.167, 0.5, 1, 2, 4, 6, 12, 24 and 48 hours post-dosing.

Following the sacrifice of the group killed at 48 hours, the skin from the dose site was excised, the remaining skin removed, the liver and kidneys excised, and each Roth cage was washed with a solution of acetone and water. The glass rings used to restrict access to the dosed site were removed from the skin and washed with water to recover any residual radioactivity on the rings. Radioactivity in excreta, cage wash solution, ring wash solution, liver, kidneys, skin and remaining carcass were determined as described below. The
concentration of radioactivity in the liver, kidney, skin from the dosed site, skin remote from the dosed site, and the remaining carcass was also determined for the animals sacrificed at 3 hours post-dosing which had access to the dosed site. Three hours post-dosing was the time where the blood concentTation of 14C-TEA derived radioactivity peaked.

Dermal probe - 2000 mg/kg - mice. Prior to the studies described above a dermal probe was carried out where six male mice were dosed dermally with a dose of 14C-TEA targeted at 2000 mg/kg (about 60 µl "neat" material). The purpose of probe was to examine if there were any demonstrable differences between results when access to the dermal dose site was restricted. The dosing
volume applied dermally was 104.2 ± 6.5 % (mean ± S.D.) of the target dosing volume of 60 µl. The average amount of radioactivity applied was 2.56 µCi/mouse. The hair on the back of each mouse was clipped on the day prior to dosing, and dose applied to the skin in an area of approximately 1.75 square centi.meters using a blunted microliter syringe. Three mice had the dose applied within a small glass ring (1.5 cm in diameter, 0.5 an in height) which had been adhered to the skin using cyanoacrylate about 15 hours prior
to dosing. After dosing, the ring was covered with a rigid piece of nylon screen attached with cyanoacrylate to restrict the animals access to the dosed skin. The remaming three mice did not have glass rings adhered to skin, but had free access to the dosing site. Immediately following dosing, the animals were placed in Roth cages for the separation and collection of urine and feces. Urine was collected a 6,12 and 24 hours post-dosing and feces was collected at 12 and 24 hours post-dosing. Blood samples were taken via the retro-orbital sinus just prior to sacrifice by cervical dislocation at 24 hours post-dosing. Following sacrifice, the skin from the dosed site was excised, the remaining skin removed, the liver and kidneys excised, and each Roth cage was washed with a solution of acetone and water. The glass rings used to restrict access to the dosed site were removed from the skin and washed with water to recover any residual radioactivity on the rings. Radioactivity in excreta, cage wash solution, ring wash solution, livers, kidneys, skin and remaining carcass were determined as described below.

Dermal administration using water as a vehicle -2000 mg/kg - mice. In order to investigate the effect of water as a dosing vehicle for TEA, twenty-one male mice were dosed dermally with a dose of 14C-TEA in aqueous solution with the pH of the dosing solution adjusted to neutrality. The applied dose was targeted at 2000 mg/kg with a target dosing volume of 200 µl. Prior to dosing
the hair on the back of the animals was dlipped. The dose was applied to the skin within a glass ring (as described above) which was adhered to the back with cyanoacrylate and covered with polyethylene screen to restrict access to the dose site and to aid in containing this larger volume of dose at one site. The rings were attached about 15 hours prior to dosing with the exception of
three animals where the rings were attached on the day of dosing. The mice were anesthetized with methoxyflurane during the attachment of the rings. The dosing volume applied dermally was 97.6 ± 7.6 % (mean ± S.D.) of the target dosing volume. The average amount of radioactivity applied was 8.2 µCi / mouse. Blood samples were taken from each animal via orbital Sinus puncture just prior to their sacrifice in groups of three at 1, 2, 4, 6, 12, 24 and 48 hours postdosing. Animals scheduled to be sacrificed at 48 hours were placed in Roth cages immediately after dosing. Following the sacrifice of the 48 hour group, the skin from the dose site was excised, the remaining skin removed, the liver and kidneys excised, and each Roth cage was washed with a solution of acetone and water. The glass rings used to restrict access to the dosed site were removed from the skin and washed with water to recover any residual radioactivity on the rings. Radioactivity in excreta, cage wash solution, ring wash solution, liver, kidneys, skin and remaining carcass were determined as described below.

Results and discussion

Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Absorption in different matrices:
Upon dermal application, triethanolamine was rapidly absorbed by the mouse skin. The dermal absorption is 94.5% after application of 1000 mg/kg bw and 97.8% after application of 2000 mg/kg bw.

Radioactivity was eliminated from mouse blood with a half-life time of 10 -18 hours following a first-order-process. 65 % of the applied dose was recovered from urine, 25 % from faeces.

Any other information on results incl. tables

Upon dermal application, triethanolamine was rapidly absorbed by the mouse skin while dermal absorption by rats was much lower. Radioactivity was was eliminated from mouse blood with a half-life time of 10 -18 hours following a first-order-process. 65 % of the applied dose was recovered from urine, 25 % from faeces.

Pharmacokinetics and metabolism of triethanolamine was found to be dose-independent in mice. 24 hours after dosing the remaining activity was found to be 3.6 % in mice after intravenous injection, 4.5 % after dermal application of 1000 mg/kg bw and 7.8 % after dermal application of 2000 mg/kg. The remaining activity was mainly found in liver and kidney.

Applicant's summary and conclusion