Hydrogen chloride

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified. Published in 1976

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was carried out at an extremely toxic concentration, causing deaths and severe clinical signs in mothers and confounding any possible interpretation of actual effect of exposure to the foetuses. Materials and methods as well as results of this study are poorly reported and do not reflect present study standards and requirements.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1976

Materials and methods

Test guideline

Qualifier:

no guideline followed

Deviations:

not applicable

Principles of method if other than guideline:

GLP was not compulsory at the time the study was conducted.

GLP compliance:

no

Remarks:

GLP was not ocmpulsory at the time the study was conducted

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Hydrogen chloride

EC Number:

231-595-7

EC Name:

Hydrogen chloride

Cas Number:

7647-01-0

Molecular formula:

Cl H

IUPAC Name:

hydrogen chloride

Details on test material:

Test material: Hydrochloric acid gas
No more details specified.

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not specified.
- Age at study initiation: not specified.
- Weight at study initiation: 180-200 g
- Fasting period before study: not specified.
- Housing: not specified.
- Diet (e.g. ad libitum): not specified.
- Water (e.g. ad libitum):not specified.
- Acclimation period:not specified.


ENVIRONMENTAL CONDITIONS
-not specified.

IN-LIFE DATES: not specified.

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

other: not stated: Presumably whole body

Vehicle:

other: not stated: Presumably air

Details on exposure:

Not specified.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not specified.

Details on mating procedure:

Not specified.

Duration of treatment / exposure:

One hour exposure at either day 9 of pregnancy or 12 days before mating.
Post-exposure: animals were allowed to deliver naturally. Progeny were tested at the age of two and three months.

Frequency of treatment:

single exposure

Duration of test:

one hour

No. of animals per sex per dose:

8-15 animals for a total of 160 animals.

Control animals:

other: yes, presumably untreated

Details on study design:

Not specified.

Examinations

Maternal examinations:

Tests for lungs (respiration rate, blood oxygen saturation, vital staining of lung tissue), liver (Quick-Pytel test) and kidney (diuresis, chlorides, protein) function. Relative organ weights also determined.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: No data

Fetal examinations:

Number of foetuses per litter, postnatal mortality, body weight changes up to 4 weeks of age.
Function test at 2 or 3 months of age: exposure to hypoxic conditions (mimicking an altitude of 3500 m in a pressure chamber) measuring the blood oxygen saturation when the inspired air contained 10% oxygen; additional exposure to HCl (1/10 CL50 = 52 mg/m3) after which the absorption of vital dye (Neutral red) in the lungs was determined. Hepatic and renal function as on the mothers. Oxygen consumption, total serum protein, and relative organ weights also determined.

Statistics:

Not stated however, in the legend below the first table of the original paper, the sentence “Values for p > 0.05 are not given” can be found.

Indices:

Not specified

Historical control data:

Not specified.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Exposure to HCl caused deaths of 1/3 of the animals in both groups with signs of severe dyspnoea and cyanosis. The lungs of the dying rats were congested, with areas of oedema and haemorrhage.
Other parameters affected are summarized in Table A6.8.1/01-1 and included decreased blood (mixed) oxygen saturation both in pregnant and non pregnant rats on the 5th day following exposure, increased absorption of Neutral Red by the lung tissue of pregnant rats on the 8th day following exposure, increased chlorides and increased protein concentration in the urine of pregnant and non pregnant rats, respectively, increased content of hippuric acid following loading with sodium benzoate in the urine of pregnant rats only. Relative liver weight resulted to be increased in non pregnant rats, but no difference was noted for pregnant animals, compared to controls.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
There was an increase in mortality among the progeny of rats exposed at day 9 of pregnancy but not in those exposed before mating (31.9 ± 9.2% vs 5.6 ± 3.7% in the control group). Reduced body weight gain was recorded at 4 weeks of age in the latter group (males: 66.8 ± 2.4 g vs 75.5 ± 2.3 g in controls; females: 63.2 ± 3.1 g vs 72.2 ± 1.7 g in controls).
Other parameters affected at 2 months of age are summarized in Table A6.8.1/01-2, and were related to the kidney function. These included increased diuresis in male young rats of both experimental groups but reduced in young females of group whose mothers were treated before mating, and decrease of protein content of urine in male young rats whose mothers were exposed at day 9 of pregnancy.
Results obtained in 3-month young rats are summarized in Table A6.8.1/01-3 and again showed effects on kidney function, limited to the male young rats, with increased chlorides and decrease protein concentration in urine in rats whose mothers were exposed on day 9 of pregnancy or before mating, respectively.
The hypoxic test showed no disturbance of lung function in either group.
The additional exposure to HCl caused changes in absorption of vital dye by the lung of male animals of both groups, and reduced excretion of hippuric acid in urine in male animals whose mothers were exposed before mating. The relative kidney weight was also increased in both groups.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

1 hour exposure of female rats at the CL50 concentration of 450 mg/m^3  resulted in mortality of 1/3 of exposed animals of both groups (exposure  at day 9 of pregnancy or 12 days before mating), with signs of severe  dyspnoea and cyanosis. The lungs of the dying rats were congested, with  areas of oedema and haemorrhage. Decreased blood (mixed) oxygen  saturation both in pregnant and non pregnant rats on the 5th day  following exposure, increased absorption of Neutral Red by the lung  tissue of pregnant rats on the 8th day following exposure, increased  chlorides and increased protein concentration in the urine of pregnant  and non pregnant rats, respectively, increased content of hippuric acid  following loading with sodium benzoate in the urine of pregnant rats only  were noted at tests for organ function. Relative liver weight resulted to  be increased in non pregnant rats, but no difference was noted for  pregnant animals, compared to controls.

There was an increase in mortality among the progeny of rats exposed at  day 9 of pregnancy but not in those exposed before mating. Reduced body  weight gain was recorded at 4 weeks of age in the latter group.

At 2 months of age dysfunction of the kidney was noted in young rats,  including increased diuresis in males of both experimental groups but  reduced in females of groups whose mothers were treated before mating,  and decrease of protein content of urine in male young rats whose mothers  were exposed at day 9 of pregnancy.

Results obtained in 3-month young rats showed again effects on kidney  function, limited to the male young rats, with increased chlorides and  decreased protein concentration in urine in rats whose mothers were  exposed on day 9 of pregnancy or before mating, respectively.

The hypoxic test showed no disturbance of lung function in either group.

The additional exposure to HCl caused changes in absorption of vital dye  by the lungs of male animals of both groups, and reduced excretion of  hippuric acid in urine in male animals whose mothers were exposed before  mating. The relative kidney weight was also increased in both groups.

Summary of affected parameters in mothers

 

Parameter	Time point	Group
		Control	Exposed on day 9 of pregnancy	Control	Exposed 12 days before mating
Lung function
Blood (mixed) oxygen saturation (% ± SD)	5^thday after exposure	68.7 ± 2.7	56.8 ± 3.4*	64.4 ± 3.6	5.29 ± 4.2*
Absorption of vital dye (Neutral red) by the lung (extinction unit ± SD)	8^thday after exposure	0.77 ± 0.04	1.01 ± 0.05**	Not determined	Not determined
Kidney function
Chlorides concentration in urine (mg/mL ± SD)	Not stated	0.94 ± 0.02	1.48 ± 0.01**	Not reported	Not reported
Protein concentration in urine (mg/mL ± SD)	Not stated	Not reported	Not reported	0.78 ± 0.10	1.53 ± 0.17**
Liver function	`
Hippuric acid in urine (mg ± SD)	Not stated	73.1 ± 4.7	89.2 ± 2.3**	No difference compared to controls
Relative liver weight	Not stated	No difference compared to controls		4.55 ± 0.15	4.91 ± 0.13*
* p<0.05, ** p<0.01

The blood (mixed) oxygen saturation value for females exposed 12 days before mating at the 5^thday following exposure is likely to be incorrect.

Summary of affected parameters in progeny at 2 months of age

 

Parameter	Group
	Control	Mothers exposed on day 9 of pregnancy	Control	Mothers exposed 12 days before mating
Kidney function
Diuresis (mL ± SD)	7.5 ± 0.7	10.1 ± 0.8*	7.5 ± 0.7* males 8.6 ± 0.9* females	10.1 ± 0.9* males 6.5 ± 0.4 females
Protein concentration in urine (mg/mL ± SD)	2.26 ± 0.16 males	1.76 ± 0.11** males	Not reported	Not reported
* p<0.05, ** p<0.01 or p<0.02

Summary of affected parameters in progeny at 3 months of age

 

Parameter	Males			Females
	Control	Mothers exposed on day 9 of pregnancy	Mothers exposed 12 days before mating	Control	Mothers exposed on day 9 of pregnancy	Mothers exposed 12 days before mating
Kidney function
Chlorides concentration in urine (mg/mL ± SD)	1.48±0.10	1.20±0.06*	0.88±0.07**	1.20±0.15	1.11±0.13	1.07±0.15
Protein concentration in urine (mg/mL ± SD)	2.37±0.23	2.85±0.27	3.25±0.24**	0.71±0.12	0.82±0.11	0.69±0.11
Relative kidney weight	0.62±0.01	0.61±0.02	0.66±0.01**	0.65±0.02	0.65±0.03	0.69±0.02
Liver function
Hippuric acid in urine (mg ± SD)	96.00±4.5	93.6±2.8	81.2±3.2*	81.3±3.7	78.5±6.1	77.5±5.1
Lung function (after additional exposure to HCl at 54 mg/m^3)
Absorption of vital dye (Neutral red) by the lung (extinction unit ± SD)	0.92±0.03	1.16±0.04**	1.15±0.07**	1.04±0.06	1.16±0.04	1.11±0.05
* p<0.05, ** p<0.01 or p<0.02

Applicant's summary and conclusion

Conclusions:

As the study was carried out at an extremely high dose, it is considered that effects observed in progeny were due to maternal toxicity and that the study did not demonstrate any increased sensitivity of foetuses compared to the mothers.