1,2-dichloropropane

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4700 (Reproduction and Fertility Effects)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1,2-dichloropropane

EC Number:

201-152-2

EC Name:

1,2-dichloropropane

Cas Number:

78-87-5

Molecular formula:

C3H6Cl2

IUPAC Name:

1,2-dichloropropane

Details on test material:

Name: 1,2-dichloropropane

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: drinking water

Details on mating procedure:

Premating Exposure Period
male: 10 - 14 wk
female: 10 - 14 wk

Duration of treatment / exposure:

41 wk (f0 adults)

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0.024%, 0.10%, 0.24%
Basis:

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

1

Key result

Dose descriptor:

NOAEL

Effect level:

0.024 other: %

Sex:

male/female

Basis for effect level:

reproductive performance

2

Key result

Dose descriptor:

NOEL

Effect level:

0.24 other: %

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: Generation: reproduction (migrated information)

Results: F1 generation

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

0.1 other: %

Sex:

male/female

Basis for effect level:

other: Decreased water consumption and lowered body weight, and increased hepatocellular granularity were present in parental animals from the 0.24% groups of both generations.

Results: F2 generation

Effect levels (F2)

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

0.1 other: %

Sex:

male/female

Basis for effect level:

other: Decreased water consumption and lowered body weight, and increased hepatocellular granularity were present in parental animals from the 0.24% groups of both generations.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Analysis of dosing solutions and received dose Mean exposure concentrations (determined on 3-4 occasions and presented as percent nominal with SD in parentheses) for the low, mid and high dose groups were as follows:

f0 males: 88.8 (6.1), 98.2 (7.3), 100.0 (8.2)

f0 females: 90.3 (6.9), 100.4 (4.3), 102.4 (8.4)

f1 males: 100.7 (29.0), 96.0 (0.9), 95.3 (2.2)

f1 females: 94.6 (21.8), 97.7 (2.6), 96.1 (3.1)

GENERAL

Endpoint	0.024% PDC		0.1% PDC		0.24% PDC
	F0	F1	F0	F1	F0	F1
Male Bwts			↓		↓	↓
Female Bwts (pre-breed)					↓	↓
Water Consumption (M + F)	↓	↓	↓	↓	↓	↓
Gestation Bwt				↓	↓	↓
Gestation Bwt Gain		Slight ↓	Slight ↓	↓	↓	↓
Gestation Water Consumption			↓	↓	↓	↓
Gestation Feed Consumption		Slight ↓		Slight ↓		↓
Lactation Bwt			↓		↓	↓
Lactation Bwt Gains		Slight ↓	↓		↓
Lactation Water Consumption	↓		↓	↓	↓	↓
Lactation Feed Consumption			↓		↓
	F1	F2	F1	F2	F1	F2
Litter Size					↓
Postnatal Survival					↓	↓
Neonatal Bwt					↓	↓

PARENTAL GENERATIONS

Received dose Based upon mean body weight and water consumption data, males of both generations from the low, mid and high dose groups received approx. 20 - 30, 70 - 130 and 130 - 250 mg/kg bwt/d. Equivalent female groups received 30 - 40, 110 - 140 and 190 - 270 mg/kg bwt/d. Female water consumption increased during lactation, with received doses of approx 60, 200 450-500 mg/kg bwt/d.

Group Phase		Received dose (mg/kg bwt/day)
		Treatment level
		0.024%	0.10%	0.24%
f0 males	pre-mating	28	91	161
	post-mating	18	65	131
f0 females	pre-mating	33	108	189
	gestation	38	121	217
	lactation*	58	196	507
f1 males	pre-mating	33	128	250
	post-mating	19	69	137
f1 females	pre-mating	41	140	269
	gestation	38	126	239
	lactation*	56	200	450

* Note: greater exposure reflects increased water consumption during lactation

In life observations

No treatment-related clinical signs were observed.

Food consumption

There were relatively minor and sporadic effects on food intake. f0 females from the high and low dose groups consumed 10% and 6% less than the controls, while f1 males from the high dose group showed an overall 8% reduction in food consumption (pre-mating and mating phases). Food intake data for the other groups were generally unremarkable.

Water consumption

A dose-related decrease in water consumption was apparent in animals from both the f0 and f1 generations, presumably reflecting reduced palatability in the mid and high dose groups. Overall, water consumption in high dose males and pregnant females was 50-60% of control, and 70% of control in lactating females. Water intake in mid dose males and mid dose pregnant females was 70 - 80% of control, and 75 - 85% of control consumption in mid dose lactating females. Results for the low dose animals were 90 - 104% of control. NOTE: Water consumption typically increases from around gestation day 13 in order to compensate for increased plasma and extracellular fluid volumes during the late stages of pregnancy. This was not the case in this study, due to the unacceptable palatability of the drinking water. This would be expected to have an adverse influence on fetal development. It is also pertinent that water consumption in untreated (control) females increased in this study during lactation, whereas major reductions were apparent in treated animals during lactation. This would be expected to have impacted post-natal survival of the pups.

Parental body weight

Body weights for the high dose animals were significantly (alpha = 0.05) lower than control in f0 and f1 generations of both sexes. In terms of affecting reproductive outcomes, effects in females appeared particularly important. Thus body weights for high dose f0 and f1 females were 5% and 11% lower than control during the pre-mating period, with a 10 - 12% decrement present during gestation and an approx. 15% reduction during lactation. Gestation body weight gains were decreased by approx. 20% in f0 and f1 females given 0.24% PDC, and by 7-13% in females given 0.1% PDC. Less consistent body weight decrements were noted in the mid dose animals, with negligible effects in the low dose generations.

Reproductive indices

There were no significant or obvious treatment-related differences in male or female reproductive performance, as assessed from mating- and conception indices, fertility or gestational period. Sporadic differences seen for some female parameters were not dose-related (ie present in low and/or mid but not high dose animals) or were within the range of historic control data. All females produced viable litters.

Hematology

Sporadic hematological changes noted in this study were not dose related and inconsistently expressed in males and females of the same generation and in same sex animals of different generations. Overall these effects appeared incidental and unrelated to treatment with PDC.

Necropsy observations

Increased relative kidney weight values in high dose animals (both sexes) appeared secondary to a lower terminal body weight. No gross pathological changes were noted in any of the parental animals.

Histology

Treatment-related histologic changes were limited to increased hepatocellular granularity (adaptive change) in males and females of both generations at all dose levels. Although no statistical analyses are reported, the incidence in high dose females (17% and 10% for f0 and f1, resectively) and high dose f1 males (13%) appears greater than control (0 - 2% for all sex/generation groups). The response in f1 high dose males (5% incidence) and mid and low dose animals of the other generations were less pronounced (2 - 8% incidence) and/or not dose related. All other tissues, including reproductive organs from both sexes, were unremarkable.

LITTER DATA

There were no significant treatment-related external observations or difference in sex ratio in either generation. The number of pups born alive was similar in the control and test groups from both phases of the study, however postnatal survival in high dose f1 litters was significantly lower than control while that of the high dose f2 litters was 10% lower than controls on PND 14 and 21; these effects appeared treatment-related. Bodyweights for high dose f0 neonates were significantly decreased, with day 21 values approx. 15% lower than control. Bodyweights of f1 litters were less severely affected (4 - 7% reduction), and attained significance only on lactation day 21.

WEANLING DATA

An increased hemoglobin concentration in high dose f1 males and an increased mean relative kidney weight in high dose f1 females appeared related to a lowered water intake and body weight, respectively. All other hematological and gross necropsy observations were comparable to control in both the f1 and the f2 generations.

Applicant's summary and conclusion

Conclusions:

Propylene dichloride was not a reproductive toxin when tested over 2 generations in SD rats exposed to 0.024%, 0.1% and 0.24% in drinking water.
Decreased water consumption (presumably reflecting unacceptable palatability of the test solution) and lowered body weight, and increased hepatocellular granularity (adaptive change), were present in parental animals from the 0.24% groups of both generations. Neonatal growth and survival were decreased in the 0.24% treatment groups, probably in response to decreased maternal water intake and lower growth. There was no effect on reproductive performance, live births or litter size in any of the test groups. Thus the NOAEL for adults and neonatal effects was 0.1% PDC
while the reproductive NOEL was 0.24% PDC, the limit of solubility.