1-chloro-2,3-epoxypropane

Specific investigations: other studies

Administrative data

Endpoint:

specific investigations: other studies

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study was conducted prior to GLP and test guidelines, but sufficient data is available for interpretation of results

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1983

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

3-chloro-l,2-propaneoxide (epichlorohydrin, ECH), 3-chloro- 1,2-propanediol (alphachlorohydrin, ACH), and oxalic acid (OA) have been suggested as presumptive evidence that the metabolism of DBCP to OA, via ECH and ACH, is the cause of the resulting injuries to the kidney and, perhaps, to the epididymis and testis. To test this hypothesis, the comparative toxicities of these four chemicals were studied in male rats after single subcutaneous (SC) injections of maximally tolerated (nonlethal) doses. Kidney, testicular, and liver functions were monitored, and the occurrences of morphological changes in these and several other organs were evaluated 24 hr, 3, 8, 25, and 75 days post-treatment. Only data from epichlorohydrin is reported here.

GLP compliance:

not specified

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

1-chloro-2,3-epoxypropane

EC Number:

203-439-8

EC Name:

1-chloro-2,3-epoxypropane

Cas Number:

106-89-8

Molecular formula:

C3H5ClO

IUPAC Name:

2-(chloromethyl)oxirane

Details on test material:

Epichlorohydrin, >99% pure, Aldrich Chemical Co., Milwaukee, Wisconsin

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Administration / exposure

Route of administration:

subcutaneous

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Single application of 75 mg/kg ECH in corn oil was injected subcutaneously to a group of 40 male rats. Rats were approximately 15 weeks of age and 275 g at time of dosing.

Frequency of treatment:

One injection

Post exposure period:

Eight animals were killed 24 hr, 3,8, 25, and 75 days after chemical treatment.

No. of animals per sex per dose:

40 male rats received 75 mg/kg.

Results and discussion

Details on results:

The animals treated with ECH were generally lethargic for the initial 2 to 3 days post-treatment, but they remained responsive to external stimuli and exhibited normal respiratory rates and rhythms.

ECH caused polyuria within 24 hr.

Slight but statistically significant increases (0.01
Sperm concentrations in the cauda epididymides of the ECH-treated rats were reduced relative to controls at 25 and 75 days post-treatment, but not at 8 days or at earlier periods of analysis. ECH treatment also increased the percentage of morphologically abnormal sperm at these times. The most common abnormality in the controls (and in all treated groups exclusive of the 25 and 75 day periods) was the absence of hooks on the head of the sperm. Separation of the head and tail, and the absence of hooks on the head, however, were common in the ECH-treated groups 25 and 75 days post-treatment, when the percentages of abnormal sperm were increased.

Efects on Organ Weights and Morphological Parameters
Cytoplasmic swelling of hepatocytes in the periportal area, mild-to-moderate in severity, was observed 24 hr post-treatment in ECH-treated rats and persisted in a very mild form 3 days post-treatment in ECH-treated rats. Relative kidney weight (kidney to brain weight ratio) was increased significantly (p < 0.05) at 24 hr in the ECH-treated rats ( 1.34+/- 0.13, X +/- SD, in comparison to 1.07 +/- 0.08 in controls).

Mild swelling of the renal proximal tubular epithelium (both cortical and medullary) was observed 24 hr after treatment with ECH, but morphological changes in the kidney were not observed 3 or 8 days after treatment.

Testicular weight at 75 days post-treatment was reduced in the ECH-treated rats. The effects of ECH on the testis were qualitatively similar to those of DBCP which included a slight, bilateral disruption of the seminiferous tubular architecture within 24 hr, vacuolar degeneration of the tubular epithelium by 3 days, and necrosis and sloughing of the germinal cells with the formation of multinucleated giant cells by 8 days. These changes were accompanied by interstitial edema and dilatation of the seminiferous tubules, which were still lined by one or two layers of germinal cells. Many of the seminiferous tubules had become atrophic by 25 days post-treatment; the tubules were populated primarily by normal-appearing Sertoli cells. Tubular atrophy and edema were prominent 75 days after DBCP treatment.

ECH caused sperm granulomas and spermatocoeles in the caput epididymis. Also, the vacuolation occurred more rapidly and was more rapidly reversed in the ECH-treated rats than in the DBCP-treated rats.

Relative thymic weights were transiently reduced 3 days post-treatment by ECH. Other organ weights, including that of the brain, were unaffected by the chemical treatment.

Small pustules (circumscribed cavities filled with pus) located superficially in the mucosal layer of the forestomach were observed at 24 hr in 2/8 of the rats treated with ECH. Changes in the forestomach were characterized by hyperkeratosis, erosion, ulcer, edema, or focal peritonitis. By Day 3 a single ECH treated rat exhibited pustules and another had hyperkeratosis of the forestomach epithelium. Only minimal changes in the forestomach (acanthosis, hyperkeratosis, focal peritonitis) were observed in ECH-treated animals at 8 days post-treatment, and no marked effects were detected at 25 and 75 days.

Any other information on results incl. tables

HISTOPATHOLOGICAL CHANGES IN THE TESTIS

Chemical administered

Number of days post-treatment	Lesions	Control	ECH
3	Vacuolar degeneration of the seminiferous tubular epithelium	0/8	4/8
8	Degeneration or necrosis of the seminiferous tubular epithelium, edema, aspermatogenesis, multinucleated cells	0/8	8/8
25	Degeneration or necrosis of the seminiferous tubular epithelium, edema, aspermatogenesis, multinucleated cells, tubular atrophy	0/8	5/8
75	Seminiferous tubular atrophy, edema	0/8	7/8

HISTOPATHOLOGICAL CHANGES IN THE EPIDIDYMIS

Chemical administered

Number of days post-treatment	Lesions	Control	ECH
1	Vacuolar degeneration of the tubular epithelium and exfoliated cells in lumen	0/8	4/8
3	Vacuolar degeneration of the epithelium and exfoliated cells inlumen	0/8	0/8
	Exfoliated cells in lumen, no tubular degeneration	0/8	6/8
	Impacted sperm in tubules	0/8	0/8
8	Dilated tubular lumens, edema	0/8	8/8
	Exfoliated cells in lumens	0/8	4/8
	Sperm granuloma	0/8	6/8
25	Exfoliated cells in lumens	0/8	4/8
	Sperm granuloma	0/8	3/8
	Spermatocoele	0/8	2/8
75	Exfoliated cells in lumens	0/8	7/8
	Sperm granuloma	0/8	0/8

Applicant's summary and conclusion

Conclusions:

Subcutaneous administration of 75 mg/kg ECH produced effects on the forestomach, testis and epididymis of male rats.

Executive summary:

3-chloro-l,2-propaneoxide (epichlorohydrin, ECH), 3-chloro- 1,2-propanediol (alphachlorohydrin, ACH), and oxalic acid (OA) have been suggested as presumptive evidence that the metabolism of DBCP to OA, via ECH and ACH, is the cause of the resulting injuries to the kidney and, perhaps, to the epididymis and testis. To test this hypothesis, the comparative toxicities of these four chemicals were studied in male rats after single subcutaneous (SC) injections of maximally tolerated (nonlethal) doses. Kidney, testicular, and liver functions were monitored, and the occurrences of morphological changes in these and several other organs were evaluated 24 hr, 3, 8, 25, and 75 days post-treatment. (Only data from ECH was presented in this record).

DBCP caused renal dysfunction (alterations in urine composition and reduced glomerular filtration rate) and marked necrosis of the proximal tubular epithelium in the outer medulla of the kidney. ACH and OA also elicited renal dysfunction, but ACH produced only a mild swelling of the proximal tubular epithelium in the renal cortex and OA produced a focal necrosis anatomically associated with crystal deposition. ECH caused a swelling of the proximal tubular epithelium in the renal cortex, but not frank kidney dysfunction. DBCP also caused a reversible vacuolization of the tubular epithelium in the caput epididymis, progressive testicular atrophy, and a reduction of cauda epididymal sperm concentration. ACH and ECH produced similar effects, as well as epididymal sperm granulomas, spermatocoeles, and an increase in the number of morphologically abnormal spermatozoa. OA failed to produce discernible epididymal or testicular lesions at any time during the study.

The development of similar lesions in the epididymis and testes following DBCP, ECH and ACH treatments is consistent with the theory of metabolism of these chemicals to a common causative gonadotoxic agent. Oxalic acid (OA), however, would not appear to be the common gonadal toxicant. Differences in the effects, both morphological and functional, of DBCP, ECH, ACH, and OA on the kidney, moreover, indicate that DBCP nephropathy is not mediated through metabolism to OA and suggest, as well, that it differs causally from that induced by ECH or ACH. Therefore, the metabolism of DBCP to ECH or ACH, and of ECH or ACH to OA, is insufficient to explain totally the toxic effects of these agents on the urogenital system in male rats.