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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study, the study was not conducted according to guideline/s but the report contains sufficient data for interpretation of study results.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was designed to provide information on the absorption of the test material when applied dermally to female adult rhesus monkeys.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Source (non-radiolabeled): ANGUS Chemical Company
Source (radiolabeled): synthsized by the Institue for Ecological Chemistry/GSF in Neuherberg, West Germany.
Purity (non-radiolabeled): ~98%
14C-1-nitropropane: ~98% radiochemical purity, Sp. Act. 185 MBq/mmol, total activity: 370 MBq = 10 mCi in approx. 4 ml ethanol/ether
Radiolabelling:
yes

Test animals

Species:
monkey
Strain:
Macaca fascicularis
Sex:
female
Details on test animals and environmental conditions:
Source: White Sands Research Center colony

Administration / exposure

Route of administration:
dermal
Vehicle:
other: grain alcohol
Details on exposure:
Seventy-two hours prior to application, the back of each monkey was clipped free of hair. A 20 cm2 area was demarcated by tattooing as test site. Twenty-four hours prior to dosing the test site was cleaned with isopropanol. The animals were lightly sedated with ketamine HCI (10 mg/kg IM). Catheters for blood collection were introduced into the leg vein. The test solution (300 ul, means 15.28 mg) was evenly applied to the test site with a disposable syringe equipped with a feeding needle. A piece of plastic wrapping foil (saran wrap; a little bigger than 20 cm2) was taped tightly over the test site. Thereafter the animals were placed in restraint chairs. Twelve hours after dose application the animals were again slightly sedated. The patch was then removed and the test site was swabbed 3 times with a 2% solution of soap in distilled water. Two more swabs, dampened with acetone, were used as a final rinse.
Duration and frequency of treatment / exposure:
12 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
300 ul or 15.28 mg
No. of animals per sex per dose:
2 females
Control animals:
no
Positive control:
no
Details on study design:
Experimental Desipn
Two female rhesus monkeys (PH0140 and PH0142) were selected from the White Sands Research Center colony, examined by the study veterinarian and determined to be in good state of health. Seventy-two hours prior to application, the back of each monkey was clipped free of hair. A 20 cm2 area was demarcated by tattooing as test site. Twenty-four hours prior to dosing the test site was cleaned with isopropanol. The animals were lightly sedated with ketamine HCI (10 mg/kg IM). Catheters for blood collection were introduced into the leg vein. The test solution (300 ul, means 15.28 mg) was evenly applied to the test site with a disposable syringe equipped with a feeding needle. A piece of plastic wrapping foil (seran wrap; a little bigger than 20 cm2) was taped tightly over the test site. Thereafter the animals were placed in restraint chairs. Twelve hours after dose application the animals were again slightly sedated. The patch was then removed and the test site was swabbed 3 times with a 2% solution of soap in distilled water. Two more swabs, dampened with acetone, were used as a final rinse. Seventy-two hours after dose application, the animals were sedated. The test site and two small triangles of untreated skin (approximately 1.13 cm2) on both ends of the marked test site were excised. The subcutaneous fat and/or tissue was removed from the skin. The tissue samples were weighed before freezing them. The following samples were collected:
Urine (freeze-trapped, cooled with dry ice) post-dose intervals: 0-2, 2-4, 4-6, 6-8, 8-10 and 10-12 and at 12-hour intervals thereafter. After thawing, the volume of each sample was determined.

Feces post-dose intervals: 0-1, 4-8, 8-12 hours and at 12-hour intervals thereafter. Before freezing, each feces sample was weighed.

Blood (venipuncture): at 0.33, 0.66, 1, 2, 3, 4, 6, 8, 10 and 12 hours and at 12-hour intervals thereafter. The blood was collected into EDTA-coated tubes.

Histopathology: An approximate 1x1 cm section of treated and an approximate 1.13 cm2 area of nontreated skin was examined
histologically by utilizing hematoxylin and eosin staining and light microscopy.
Details on dosing and sampling:
Urine (freeze-trapped, cooled with dry ice) post-dose intervals: 0-2, 2-4, 4-6, 6-8, 8-10 and 10-12 and at 12-hour intervals thereafter. After thawing, the volume of each sample was determined.

Feces post-dose intervals: 0-1, 4-8, 8-12 hours and at 12-hour intervals thereafter. Before freezing, each feces sample was weighed.

Blood (venipuncture): at 0.33, 0.66, 1, 2, 3, 4, 6 , 8, 10 and 12 hours and at 12-hour intervals thereafter. The blood was collected into EDTA-coated tubes
Statistics:
None

Results and discussion

Preliminary studies:
None

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Observations- Neither animal showed any signs of toxicity. Feed and water consumption was low during the first 12 hours but normalized later. During the first 12 hours the urine output was partly very low or even nonexistent (i.e., urine 4-6 and 6-8 hours, post-dose for PH0140 and 8-10 hours post-dose for PH0142. PH0140 had no feces between 8 and 12 hours post-dose but otherwise had normal output. PH0142 had very few feces 8-12 hours and 12-24 hours post-dose. Animal PH0142 was mensing from the beginning of the study. The body weight remained within 5% of the weight from day 0 (monkey PH0140 day 0 weight: 4.43 kg; monkey PH0142 day 0 weight: 3.75 kg; day 0 = dosing day; monkey PH0140 day 3 weight: 4.29 kg; monkey pH0142 day 3 weight: 3.71 kg). The histological examination of the skin samples taken from the test site did not show any signs of skin damage or irritation.

Absorption-Seventy-two hours after dosing, the test site and 2 small adjacent triangles on both ends of the test site were excised and treated and untreated skin and subcutaneous fat and/or tissue were analyzed for radioactivity. The skin of PH0140 contained 6.60 ug 1-nitropropane (0.043% of the total dose). In the skin of PH0132 a quantity of 15.54 ug (approximately 2.5 times more than in PH0140) (i.e., 0.102% of the total dose) was determined. Included in these percentages are traces of 1-nitropropane found on the untreated skin (PH0140: <0.001%; PH0142: 0.001%). These low radioactivity levels probably reflect the manual contamination during application rather than an actual migration from the test site. The subcutaneous fat and/or tissue contained only very low amounts of test material in case of PH0140 (i.e., 0.001%). In PH0142 the amounts of 1-nitropropane in fat/tissue were under 0.001% AD. This indicates that 1-nitropropane or more probably metabolites are absorbed only in low amounts in the skin and the subcutaneous fat/tissue, respectively. Compared to the identical tests with 2-nitropropane, nitroethane and nitromethane, the values of 1-nitropropane are lower than with 2-nitropropane, but still higher than with nitromethane and nitroethane. The following absorption ranking could be made: nitromethane < nitroethane < 1-nitropropane < 2-nitropropane.
The above-mentioned percentages total 0.417% (monkey PH0140) or 0.611% (monkey PH0142). The very low recovery rate (e-g., twice as low as with 2-nitropropane) can be attributed to high evaporation of the test site. It has to be considered that large amounts of 1- nitropropane contained for a short period in the blood were exhaled without being trapped in scintillation fluid and counted. Previous oral studies with 1-nitropropane confirm the findings of !ow recovery. It also has to be assumed that the amounts of radioactivity determined in the skin after 72 hours can be partly
attributed to less volatile metabolites of I-nitropropane since the parent compound might be evaporated from the test site very fast.
Percent of Dose
Sample PH1040 PH1042
Urine 0.201 0.366
Feces 0.003 0.039
Skin 0.043 0.102
Subcutaneous
Fat/Tissue 0.001 0.12
12-hr swabs 0.115 0.064
Patch 0.054 0.040
Blood ----- -----
Unrecovered-
Radioactivity 99.583 99.389



Details on distribution in tissues:
Not examined
Details on excretion:
In the following text, the terms excretion, percent and total dose refer to the radioactivity and not to the weights and volumes of the corresponding samples; the numbers PH0140 and PH0142 refer to the WSRC animal numbers of the study animals.

Since the two monkeys showed too big discrepancies in all values, their results were not averaged. The total excretion of PH0140 was determined to be 31.37 ug, 97.8% of which was excreted in the urine. The total excretion of PH0142 was determined to be 61.65 ug 1-nitropropane, 90.6% of which was excreted in the urine. An average of 83.1% of the total urine radioactivity was collected within 24 hours (PH0140: 88.8%; PH0142: 77.3%). The co responding 48-hour figures are: average 94.8%; monkey PH0140: 96.0%; monkey PH0142: 93.6%. The values in the blood of the two animals differ very much: PH0140 had over the whole test period only values in, ihe background range in the blood. PH0142 had its maximum of 1-nitropropane in the blood after 2 hours ( i .e . 21.6 ng/ml which equals 21.6 ppb ) . After 36 hours there wrre no detectable traces of 1-nitropropane in the blood of PH0142. It might be assumed that the higher 1-nitropropane levels in the blood of PH0142 were caused by the mensing condition of the animal.
The excretion of 1-nitropropane in feces within 72 hours was also quite different in both animals (monkey PH0140: 0.68 ug . 0.003% of the total dose and monkey PH0142: 5.77 ug, 0.039% of the total dose). After 12 hours the test material remaining on the skin and not yet evaporated was wiped off with soap/water and acetone swabs. The swabs and the occlusive patches (seran wrap and tape separately) were extracted with acetone and alcohol,
respectively. The analysis of the swabs showed the following results in both animals. A quantity of 17.62 ug ( i.e. , 0.115% of the total dose) was washed off from the skin of animal PH0140. Approximately half of that, i.e., 9.80 ug 1-nitropropanc which equals 0.064% of the. total dose , was washed offrom PH0142 . Considering the fact that 1-nitropropane itself is a volatile compound and the carrier material was a low alcohol which promotes an easier evaporation, it has to be assumed that most of the test material ( average: 99.5% of the total dose) evaporated from the test site although it was covered airtight with a patch during the first twelve hours.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
No data

Any other information on results incl. tables

Considering the fact that technicians working with chemicals, for example, nitroalkanes. are equipped with appropriate garments (i.e., gloves), a direct dermal application has to be considered as the maximum amount which may penetrate the skin during improper handling or an accident. Due to the high volatility of the test material, the recovery in urine, feces and blood was very low or non-existent (i.e., blood of PH0140). The absorption in skin (i.e., 0.043% in pH0130 and 0.102% in PH0142) can be considered as low even though the values are slightly higher than the comparable values of nitroethane and nitromethane. The low amounts of radioactivity in the skin were probably due to metabolites. Since the absorption rate after extremely exposed conditions (i.e., direct application, application site covered for 12 hours with an occlusive patch) compared to usual working conditions was low, 1-nitropropane can be evaluated as not hazardous for the human skin. No damages or alterations of the skin due to the direct dermal application were found and listed in the histopathological report.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no data
Approximately ≤ 0.5% of the administered dose is absorbed following a 12 hour dermal exposure of 15.28 mg 1-nitropropane to the back of monkeys. Once absorbed, 1-nitropropane is primarily excreted in the urine.
Executive summary:

None