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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published, reliable proprietary data. Contains relevant information on toxicity to reproduction.
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1973
Reference Type:
study report
Title:
Unnamed
Year:
1972

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The reproductive capacity was assessed after ingestion of 50 to 200 mg/day of DMT for 115 days. The pregnancy rate and the mortality rate of the young was noted.
GLP compliance:
no
Remarks:
: older study, pre-dates GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Dimethyl terephthalate manufactured by the Tennessee Eastman Company, and described as a white crystalline solid. Eastman Organic Chemicals Cat. No. 6580.

Test animals

Species:
rat
Strain:
Long-Evans
Sex:
male/female
Details on test animals and environmental conditions:
120 weanling male, hooded Long Evans rats purchased from Blue Spruce Farms, Inc., Altamont, New York were randomly divided into four groups of 30 animals each. The animals were housed five per cage in wire-bottomed cages (except during mating - see below). Water and the appropriate diet were available ad lib.
Virgin females were mated with test males. Females were housed singly post-mating.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
corn oil
Details on exposure:
Dimethyl terephthalate was fed for 115 days at concentrations of 0.25, 0.5 and 1.0% in a basal diet of ground Purina Laboratory Chow to which 2.0% Mazola corn oil (w/w) had been added. The compound was added to the measured amount of corn oil and put into solution by adding 1000 g of chloroform and heating. This solution was added to the ground chow and homogenised using an automatic food mixer. The diets were then spread onto shallow open trays to allow the chloroform to evaporate. A control diet was handled similarly except for the addition of compound.

Details on mating procedure:
20 male rats from each test group were selected for long term observation, maintained on the control diet. Prior to putting these animals on the control diet, they were mated with virgin female rats 1:1 for one week. Copulation was assumed to have occurred based on the appearance of vaginal plugs. The presumably pregnant females were singly housed from this point.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
There are no details given on analytical verification of doses.
Duration of treatment / exposure:
The duration of treatment was 115 days for males.
Females were exposed to test diets for 6 days prior to mating, during the 1 week mating period, and through gestation until weaning (lactation day 21).
Frequency of treatment:
Daily - ad libitum feeding
Details on study schedule:
At the time of pairing, the males had been on their respective test (or control) diets for 115 days. Females had been exposed to these test diets for 6 days. Both sexes were maintained on test diets during the week of mating, after which all males were put onto the control diet for long term observation. Females remained on their assigned test diets throughout gestation, parturition and lactation. The offspring were weaned on lactation day 21.
Doses / concentrations
Remarks:
Doses / Concentrations:
0.25, 0.5, or 1% in the diet.
Basis:
nominal in diet
No. of animals per sex per dose:
Twnety males were used per dose level. Each group of twenty males were mated with twenty virgin females.
Control animals:
yes, concurrent no treatment
Details on study design:
Dose levels were chosen based on previous testing conducted at the laboratory, which indicated that DMT has a very low oral toxicity in rats and mice. A preliminary feeding study was conducted at a level of 5% for 28 days, in 5 rats. Administration resulted in a continuous loss of body weight resulting in the death of all animals. It was concluded that feeding 5% DMT resulted in food refusal with death by starvation. Based on this data, a top dose of 1% was selected for the 96 day study.

Interim necropsies and clinical parameters were determined on satellite groups of 10 male rats/dose, the results are reported in section 7.5.1. The remaining animals were used in the reproductive toxicity study.
Positive control:
There was no positive control used.

Examinations

Parental animals: Observations and examinations:
Male rats: body weights, group feed consumption, clinical chemistry and haematology were determined (reported in detail in section 7.5.1).
No maternal observations were reported.
Oestrous cyclicity (parental animals):
Oestrus cyclicity was not examined.
Sperm parameters (parental animals):
Sperm parameters were not measured.
Litter observations:
Average litter size, mortality at birth and from birth to weaning, average weigh of the pups at weaning.
Postmortem examinations (parental animals):
There was no postmortem examination: after mating males were transferred to a long-term observation study.
Postmortem examinations (offspring):
There was no postmortem examination.
Statistics:
Statistics were not conducted beyond comparison of means.
Reproductive indices:
Percentage of inseminations and pregnances, average gestation time.
Offspring viability indices:
There are no offspring viability indices to report.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS
No signs of toxicity were reported.

BODY WEIGHT
High dose males exhibited statistically significantly decreased body weight gain over after 91 days feeding compared to controls (see section 7.5.1).

REPRODUCTIVE PERFORMANCE
Male rats treated with dimethyl terephthalate showed normal mating behaviour, DMT had no effect on the ability of the males to inseminate a female. All treatment groups had a higher percentage of inseminations than the control group. Ninety-five to 100% of these inseminations resulted in pregnancy with normal gestation period and litter size.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
: reproductive
Effect level:
10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Reproduction (no effects at this dose level)
Dose descriptor:
NOAEL
Remarks:
: toxicity
Effect level:
5 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Bodyweight effects in males

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Details on results (F1)

The litter size was normal. Mortality of young at birth to weaning was not affected in the treatment groups indicating good viability of pups and normal lactation in the dam. The one significant effect noted in the reproduction study was a dose dependent reduction in mean body weight of the pups at weaning. Statistically the weight of the pups in the 1.0% and 0.5% groups was lower than that of the control weight.

Effect levels (F1)

Dose descriptor:
NOAEL
Remarks:
: toxicity
Generation:
F1
Effect level:
2 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Reduced body weights at higher doses

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Reproductive summary data.

Dose Group

Control

1.0%

0.5%

0.25%

Males/females

20/20

19/19

20/20

20/20

% inseminations

75

100

95

85

% pregnancies

100

95

95

100

Mean gestation period (days)

21.5

21.5

21.5

21.5

Mean Litter Size

11.8

11.4

12.4

11.5

Mortality % at birth

0.6

3.0

0.4

1.0

Mortality % birth to weaning

5.7

2.0

1.8

1.0

Mean Pup wt (g) at weaning

39.6

(32-62)a

29.4b

(19-51)

33.7b

(24-41)

38.2

(31-45)

aNumber in parentheses are extremesbStatistically different from control, p<0.05

Applicant's summary and conclusion

Conclusions:
The single generation reproduction study revealed no adverse effects on libido, pregnancy, gestation, litter size or on the viability of the young. Reduced bodyweight was apparent in parental males at the highest dose levels of 1.0%. The only effect seen in offspring was a reduction in body weight at weaning in the compared to the control in the 0.5 and 1.0% dose group.
Executive summary:

Dimethyl terephthalate was administered to groups of 20 male rats in the diet for 115 days, at doses of 0, 0.25, 0.5 and 1.0%.

The male rats were then mated with twenty virgin females which had also been fed the dimethterephthalate diet for 6 days prior to mating. Male rats treated with dimethyl terephthalate showed normal mating behaviour. All treatment groups had a higher percentage of inseminations than the control group. Ninety-five to 100% of these inseminations resulted in a pregnancy with a normal gestation period and litter size. The only effect seen in pups was a statistically significant reduction in body weight at weaning compared to the control in the 0.5 and 1.0% dose groups. The NOAEL for reproductive toxicity can be considered to be 1% dimethyl terephthalate in the diet, the NOAEL for parental toxicity was 0.5% and the NOAEL for offspring toxicity was 0.25%.